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1.
J Nanosci Nanotechnol ; 20(4): 2617-2621, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492285

RESUMO

Pure phase polycrystalline BiFeO3 film was deposited onto FTO substrate by RF magnetron sputtering method. SEM result shows that BiFeO3 film has the obvious porosity and large clusters which lead to the poor ferroelectric and photovoltaic properties in FTO/BiFeO3/Ag device. However, these properties are improved in p-i-n structured FTO/TiO2/BiFeO3/HTM/Ag device by incorporating the electron and hole transport materials. The hysteresis loop measurement demonstrates the excellent ferroelectric property with large remnant polarization (2Pr = 180 µC/cm²) and low leakage current. The J-V curve shows the short-circuit current density is dozens of times larger than that of FTO/BiFeO3/Ag device. Moreover, the photovoltaic output depends on the poling field where the positive poling improves the short-circuit current density to -85 µA/cm2 and the negative poling reduces both the photocurrent and photovoltage. It is believed that the ferroelectric polarization plays a dominant role in the photovoltaic effect.

2.
J Nanosci Nanotechnol ; 20(1): 564-567, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383211

RESUMO

A polycrystalline BiFeO3 film was deposited on ITO substrate by RF magnetron sputtering method. Small crystallite size and compact structure are obtained for BiFeO3 film which has the excellent ferroelectric properties. The measured photovoltaic response reveals an open-circuit voltage of ~0.52 V and a short-circuit current density of ~10 µA/cm² under the illumination of 100 mW/cm² irradiance. Moreover, a tunable photovoltaic effect with light illumination is observed under different voltage sweep mode. High initial sweep voltage can enhance the photovoltaic effect largely, however, the photovoltaic response decreases with the increase of voltage sweep interval. The results indicate the ferroelectric polarization plays an important role in the photovoltaic effect.

3.
Cell Res ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31488882

RESUMO

Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31480192

RESUMO

Objective: Considering the physiological and clinical importance of LEPR in regulating obesity and the fact that porcine LEPR expression is not known to be controlled by lncRNAs and miRNAs, we aim to characterize this gene as a potential target of SSC-miR-323 and the lncRNA TCONS_00010987. Methods: Bioinformatics analyses revealed that lncRNA TCONS_00010987 and LEPR have SSC-miR-323-binding sites and that LEPR might be a target of lncRNA TCONS_00010987 based on cis prediction. Wild-type and mutant TCONS_00010987-target sequence fragments and wild-type and mutant LEPR 3'-UTR fragments were generated and cloned into pmiR-RB-REPORTTM-Control vectors to construct respective recombinant plasmids. HEK293T cells were co-transfected with the SSC-miR-323 mimics or a negative control with constructs harboring the corresponding binding sites and relative luciferase activities were determined. Tissue expression patterns of lncRNA TCONS_00010987, SSC-miR-323, and LEPR in Anqing six-end-white (AQ, the obese breed) and Large White (LW, the lean breed) pigs were detected by real-time quantitative PCR; backfat expression of LEPR protein was detected by western blotting. Results: Target gene fragments were successfully cloned, and the four recombinant vectors were constructed. Compared to that with the negative control, SSC-miR-323 mimics significantly inhibited luciferase activity from the wild-type TCONS_00010987-target sequence and wild-type LEPR-3'-UTR (P < 0.01 for both) but not from the mutant TCONS_00010987-target sequence and mutant LEPR-3'-UTR (P > 0.05 for both). Backfat expression levels of TCONS_00010987 and LEPR in AQ pigs were significantly higher than those in LW pigs (P < 0.01), whereas levels of SSC-miR-323 in AQ pigs were significantly lower than those in LW pigs (P < 0.05). LEPR protein levels in the backfat tissues of AQ pigs were markedly higher than those in LW pigs (P < 0.01). Conclusion: LEPR is a potential target of SSC-miR-323, and TCONS_00010987 might act as a sponge for SSC-miR-323 to regulate LEPR expression.

5.
Exp Mol Med ; 51(8): 92, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387986

RESUMO

Excessive activation of the NLRP3 inflammasome is a key component contributing to the pathogenesis of various inflammatory diseases. However, the molecular mechanisms underlying its activation and regulation remain poorly defined. The objective of this study was to explore the possible function of the K+ channel pore-forming subunit Kir6.1 in regulating NLRP3 inflammasome activation and insulin resistance. Here, we demonstrate that Kir6.1 depletion markedly activates the NLRP3 inflammasome, whereas enhanced Kir6.1 expression produces opposing effects both in mice in vivo and in primary cells in vitro. We also demonstrate that Kir6.1 controls insulin resistance by inhibiting NLRP3 inflammasome activation in mice. We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome and insulin resistance, which is mediated by virtue of its ability to inhibit NLRP3 inflammasome assembly. These data provide novel insights into the regulatory mechanism of NLRP3 inflammasome activation and suggest that Kir6.1 is a promising therapeutic target for inflammasome-mediated inflammatory diseases.

6.
J Exp Clin Cancer Res ; 38(1): 372, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438996

RESUMO

BACKGROUND: The interaction between tumor cells and their immunosuppressive microenvironment promotes tumor progression and drug resistance. Thus, simultaneously targeting tumor cells and stromal cells is expected to have synergistic antitumor effects. Herein, we present for the first time a preclinical antitumor investigation of 3D185, a novel dual inhibitor targeting FGFRs, which are oncogenic drivers, and CSF-1R, which is the major survival factor for protumor macrophages. METHODS: The antitumor characteristics of 3D185 were assessed by a range of assays, including kinase profiling, cell viability, cell migration, immunoblotting, CD8+ T cell suppression, and in vivo antitumor efficacy, followed by flow cytometric and immunohistochemical analyses of tumor-infiltrating immune cells and endothelial cells in nude mice and immune-competent mice. RESULTS: 3D185 significantly inhibited the kinase activity of FGFR1/2/3 and CSF-1R, with equal potency and high selectivity over other kinases. 3D185 suppressed FGFR signaling and tumor cell growth in FGFR-driven models both in vitro and in vivo. In addition, 3D185 could inhibit the survival and M2-like polarization of macrophages, reversing the immunosuppressive effect of macrophages on CD8+ T cells as well as CSF1-differentiated macrophage induced-FGFR3-aberrant cancer cell migration. Furthermore, 3D185 inhibited tumor growth via remodeling the tumor microenvironment in TAM-dominated tumor models. CONCLUSIONS: 3D185 is a promising antitumor candidate drug that simultaneously targets tumor cells and their immunosuppressive microenvironment and has therapeutic potential due to synergistic effects. Our study provides a solid foundation for the investigation of 3D185 in cancer patients, particularly in patients with aberrant FGFR and abundant macrophages, who respond poorly to classic pan-FGFRi treatment.

7.
Sci Rep ; 9(1): 11871, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31417129

RESUMO

Transport fluxes and properties of riverine organic carbon in the tropical monsoon region were the vital parameters in the global riverine organic carbon fluxes budget. The study focused on the riverine organic carbon in the Changhuajiang River (CHJR), locating at the mid-west of the Hainan Island, China. Dissolved organic carbon (DOC) concentrations in the CHJR ranged from 0.22 mg/L to 11.75 mg/L with an average of 1.75 mg/L, which was lower than the average of global rivers and had a significantly temporal and spatial variation. Output flux of riverine DOC was calculated as 0.55 t/km2/y, which could be revised up to 1.03 t/km2/y, considering that the riverine discharge before dam construction. A linear model of riverine DOC flux suitable in CHJR basin was established, which involved the factors, such as soil organic carbon, runoff depth and slope, etc. There was a large variation of POC concentrations in the CHJR where the average POC concentration in the dry season was 2.41 times of the wet season. Riverine POC flux in CHJR basin was calculated as 1.78 t/km2/y, higher than the average of global rivers and far lower than those in other domestic larger rivers. About 8.28 × 103 t POC were exported yearly in CHJR, of which, 7.15 × 103 t originated from terrestrial ecosystem and 1.13 × 103 t stemmed from aquatic ecosystem. Meanwhile, about 87.74% of terrestrial source happened in the wet season and 12.26% in the dry season. This research revealed that the riverine organic carbon mainly stemmed from the surface erosion processes in the drainage basin during the wet season.

8.
Biomed Pharmacother ; 117: 109178, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387193

RESUMO

OBJECTIVE: The purpose of this study is to illustrate the therapeutic effect of which kind of polarized macrophages-based cell therapy in hepatic fibrosis caused by cystic echinococcosis. METHODS: The isolation culture and polarization induction of mouse bone marrow-derived macrophages (BMDM) are established in an in vitro environment. A model of Echinococcus granulosus infection is established by direct injection of the Echinococcus granulosus suspension into the left hepatic lobe. The macrophages are labeled in vitro and the localization of the returned macrophages in the liver of the mice is determined by in vivo tracing. Macrophages of different polarization types are injected into the successfully modeled mice through the tail vein, and the results of HE, Masson, Sirius Red, Desmin immunohistochemistry and Hyp content are inspected to evaluate by liver tissue. Liver pathology and changes in the degree of fibrosis. RESULTS: Bone marrow-derived macrophages have been successfully obtained and induced into M1 and M2 macrophages by different conditions; a model of Echinococcus granulosus infection was successfully established. Macrophages labeled in vitro were returned to the model through the tail vein and they can be located in the liver; a variety of experimental results show that compared with the PBS group, the degree of fibrosis in the M0 group and the M1 group have been reduced, with statistical difference, and the M1 is better than M0 in terms of the therapeutic effect. There is no significant change in the degree of fibrosis in the M2 group. CONCLUSION: Both M1 and M0 macrophages can alleviate liver fibrosis caused by persistent infection of Echinococcus granulosus, but the treatment effect of M1 macrophages is more significant. Cell therapy based on M1 macrophages may be a new idea for treating liver fibrosis caused by persistent infection of Echinococcus granulosus.

9.
J Transl Med ; 17(1): 259, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395064

RESUMO

BACKGROUND: Ovarian cancer is the leading cause of death in gynecological cancer. Cancer stem cells (CSCs) contribute to the occurrence, progression and resistance. Small nucleolar RNAs (SnoRNAs), a class of small molecule non-coding RNA, involve in the cancer cell stemness and tumorigenesis. METHODS: In this study, we screened out SNORNAs related to ovarian patient's prognosis by analyzing the data of 379 cases of ovarian cancer patients in the TCGA database, and analyzed the difference of SNORNAs expression between OVCAR-3 (OV) sphere-forming (OS) cells and OV cells. After overexpression or knockdown SNORD89, the expression of Nanog, CD44, and CD133 was measured by qRT-PCR or flow cytometry analysis in OV, CAOV-3 (CA) and OS cells, respectively. CCK-8 assays, plate clone formation assay and soft agar colony formation assay were carried out to evaluate the changes of cell proliferation and self-renewal ability. Scratch migration assay and trans-well invasion analysis were used for assessing the changes of migration and invasion ability. RESULTS: High expression of SNORD89 indicates the poor prognosis of ovarian cancer patients and was associated with patients' age, therapy outcome. SNORD89 highly expressed in ovarian cancer stem cells. The overexpression of SNORD89 resulted in the increased stemness markers, S phase cell cycle, cell proliferation, invasion and migration ability in OV and CA cells. Conversely, these phenomena were reversed after SNORD89 silencing in OS cells. Further, we found that SNORD89 could upregulate c-Myc and Notch1 expression in mRNA and protein levels. SNORD89 deteriorates the prognosis of ovarian cancer patients by regulating Notch1-c-Myc pathway to promote cell stemness and acts as an oncogene in ovarian tumorigenesis. Consequently, SNORD89 can be a novel prognostic biomarker and therapeutic target for ovarian cancer.

10.
Sci Total Environ ; 687: 946-955, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412498

RESUMO

Environmental metal pollution is known to adversely affect bird reproduction, for which the variations of egg characteristics are considered very important. Our study explored whether variations in egg characteristics, such as egg volume, eggshell spotting pattern, eggshell coloration, and eggshell thickness, were correlated with heavy metal levels (Cu, Zn, Pb, and Cd) and Ca levels in the eggshells of tree sparrows (Passer montanus), a widespread passerine species. Eggs were collected from a long-term heavy metal polluted area (Baiyin, BY, northwest China) and a relatively unpolluted area (Liujiaxia, LJX, northwest China). Our results showed that the embryonated (eggshell: Cu: p = 0.003, Pb: p = 0.002) and non-embryonated (egg contents: Pb: p = 0.044, Ca: p = 0.045) eggs collected from BY contained relatively higher metal concentrations than those from LJX. Eggs from BY were smaller in volume (p < 0.01) and thinner in eggshell thickness (p < 0.01) than those from LJX. Mean egg volume increased with clutch size in BY (p = 0.017), which was also accompanied by an increase in the within-clutch coefficient of variation (CV) for egg volume (p = 0.045). Clutches with a higher CV for egg volume tended to contain higher concentrations of Zn and Pb (Zn: p = 0.084; Pb: p = 0.081) in the eggshells from BY. No differences were found in the eggshell spotting coverage ratio of eggs; however, eggshells were much darker in BY than in LJX. A more aggregated eggshell spotting distribution indicated higher eggshell Zn and Pb levels (BY: Zn: p = 0.040, Pb: p = 0.076; LJX: Pb: p = 0.066). The results demonstrate that the egg characteristics of tree sparrows can be used as indicators of metal pollution, especially for the within-clutch CV for egg volume, eggshell spotting pattern and eggshell coloration.

11.
Seizure ; 71: 214-218, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394368

RESUMO

PURPOSE: This study aimed to identify disease-causing gene mutations in individuals belonging to the Southern Chinese Han population diagnosed with fever-associated seizures or epilepsy (FASE). METHODS: Blood samples and clinical data were collected from 78 children with FASE. All subjects were screened for mutations using whole-exome sequencing, and mutations were validated using the Sanger sequencing method. RESULTS: Three novelSCN9A heterozygous missense mutations (I775M, R429C and A442T) were noted, which are associated with febrile seizures (FS), febrile seizures plus (FS+) and genetic epilepsy with febrile seizures plus (GEFS+), respectively. The R429C and A442T mutations are located in the large cytoplasmic loop between transmembrane topological domains, whereas I775M is located in the topological domain DIIS2. The I775M and R429C mutations have highly evolutionarily conserved residues and are predicted to affect the SCN9A protein function according to bioinformatics tools. These three mutations were not identified in 300 unrelated control subjects. CONCLUSIONS: Mutations in theSCN9A gene may be linked with FASE.

12.
Environ Toxicol Chem ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31433519

RESUMO

To estimate the risks of metal (Cu, Zn, Pb and Cd) exposure of tree sparrows through food at different life stages (including nestling, juvenile, adult in summer and adult in winter), metal daily intake (MDI), metal daily intake per unit of body weight (MDIBW ) and exposure risks (hazard quotient and hazard index) of tree sparrows at different life stages from a polluted area, Baiyin (BY) and a control area, Liujiaxia (LJX) were assessed. MDIs and MDIBW s of tree sparrows from BY were higher than those from LJX, which can be attributed to higher metal concentrations of food sources in BY than those in LJX. MDIs and MDIBW s of nestlings were higher than those of adults and juveniles. This difference is observed probably because non-phytophagous invertebrates (nph-in), the predominant food fed to nestlings, possessed the highest metal concentrations. In addition, adults in summer had higher MDIs and MDIBW s than juveniles and adults in winter. This finding may be observed because juveniles and adults in winter consumed higher proportions of maize with the lowest metal concentrations. Besides, the biomagnification of four metals through the food chain increased the health risks of tree sparrows. Exposure risks of metals to tree sparrows were comparable with those of waterfowl and raptors, even when soil metals were below thresholds. This article is protected by copyright. All rights reserved.

13.
Clin Cancer Res ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285373

RESUMO

Background: Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.Methods: BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo Results: Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo Conclusions: We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.

14.
ACS Appl Mater Interfaces ; 11(31): 28352-28358, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31291719

RESUMO

Neuromorphic devices and systems with ultralow power consumption are important in building artificial intelligent systems. Here, indium tin oxide (ITO)-based oxide neuromorphic transistors are fabricated using poly(vinyl alcohol) (PVA)-based proton-conducting electrolytes as gate dielectrics. The electrical performances of the transistors can be modulated with the ITO channel thickness. Fundamental synaptic functions, including excitatory postsynaptic current, paired-pulse facilitation, and multistore memory, are successfully emulated. Most importantly, the PVA-gated neuromorphic devices demonstrate ultralow energy consumption of ∼1.16 fJ with ultrahigh sensitivity of ∼5.4 dB, as is very important for neuromorphic engineering applications. Because of the inherent environmental-friendly characteristics of PVA, the devices possess security biocompatibility. Thus, the proposed PVA-gated oxide neuromorphic transistors may find potential applications in "green" ultrasensitive neuromorphic systems and efficient electronic biological interfaces.

15.
J Med Chem ; 62(15): 7302-7308, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31298540

RESUMO

Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B, exhibited an IC50 of 27.5 nM against the EGFRL858R/T790M/C797S mutant, while being a significantly less potent for EGFRWT (IC50 > 1.0 µM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

16.
J Neuroeng Rehabil ; 16(1): 96, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345240

RESUMO

BACKGROUND: Cervical spondylotic myelopathy (CSM) is a degenerative cervical disease in which the spinal cord is compressed. Patients with CSM experience balance disturbance because of impaired proprioception. The weighting of the sensory inputs for postural control in patients with CSM is unclear. Therefore, this study investigated the weighting of sensory systems in patients with CSM. METHOD: Twenty-four individuals with CSM (CSM group) and 24 age-matched healthy adults (healthy control group) were analyzed in this observational study. The functional outcomes (modified Japanese Orthopaedic Association Scale [mJOA], Japanese Orthopaedic Association Cervical Myelopathy Questionnaire [JOACMEQ], Nurick scale) and static balance (eyes-open and eyes-closed conditions) were assessed for individuals with CSM before surgery, 3 and 6 months after surgery. Time-domain and time-frequency-domain variables of the center of pressure (COP) were analyzed to examine the weighting of the sensory systems. RESULTS: In the CSM group, lower extremity function of mJOA and Nurick scale significantly improved 3 and 6 months after surgery. Before surgery, the COP mean velocity and total energy were significantly higher in the CSM group than in the control group for both vision conditions. Compared with the control group, the CSM group exhibited lower energy content in the moderate-frequency band (i.e., proprioception) and higher energy content in the low-frequency band (i.e., cerebellar, vestibular, and visual systems) under the eyes-open condition. The COP mean velocity of the CSM group significantly decreased 3 months after surgery. The energy content in the low-frequency band (i.e., visual and vestibular systems) of the CSM group was closed to that of the control group 6 months after surgery under the eyes-open condition. CONCLUSION: Before surgery, the patients with CSM may have had compensatory sensory weighting for postural control, with decreased weighting on proprioception and increased weighting on the other three sensory inputs. After surgery, the postural control of the patients with CSM improved, with decreased compensation for the proprioceptive system from the visual and vestibular inputs. However, the improvement remained insufficient because the patients with CSM still had lower weighting on proprioception than the healthy adults did. Therefore, patients with CSM may require balance training and posture education after surgery. TRIAL REGISTRATION: Trial Registration number: NCT03396055 Name of the registry: ClinicalTrials.gov Date of registration: January 10, 2018 - Retrospectively registered Date of enrolment of the first participant to the trial: October 19, 2015.

18.
Acta Pharmacol Sin ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316177

RESUMO

KRAS is one of the most important proto-oncogenes. Its mutations occur in almost all tumor types, and KRAS mutant cancer is still lack of effective therapy. Prenyl-binding protein phosphodiesterase-δ (PDEδ) is required for the plasma membrane association and subsequent activation of KRAS oncogenic signaling. Recently, targeting PDEδ has provided new promise for KRAS mutant tumors. However, the therapeutic potential of PDEδ inhibition remains obscure. In this study, we explored how PDEδ inhibition was responded in KRAS mutant cancer cells, and identified KRAS mutant subset responsive to PDEδ inhibition. We first performed siRNA screen of KRAS growth dependency of a small panel of human cancer lines, and identified a subset of KRAS mutant cancer cells that were highly dependent on KRAS signaling. Among these cells, only a fraction of KRAS-dependent cells responded to PDEδ depletion, though KRAS plasma membrane association was effectively impaired. We revealed that the persistent RAF/MEK/ERK signaling seemed responsible for the lack of response to PDEδ depletion. A kinase array further identified that the feedback activation of EPH receptor A2 (EPHA2) accounted for the compensatory activation of RAF/MEK/ERK signaling in these cells. Simultaneous inhibition of EPHA2 and PDEδ led to the growth inhibition of KRAS mutant cancer cells. Together, this study gains a better understanding of PDEδ-targeted therapeutic strategy and suggests the combined inhibition of EPHA2 and PDEδ as a potential therapy for KRAS mutant cancer.

19.
Acta Pharmacol Sin ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316181

RESUMO

Bruton's tyrosine kinase (BTK) is a key component of the B cell receptor (BCR) signaling pathway and plays a crucial role in B cell malignancies and autoimmune disorders; thus, it is an attractive target for the treatment of B cell related diseases. Here, we evaluated the BTK inhibitory activity of a series of pyrimido[4,5-d][1,3]oxazin-2-one derivatives. Combining this evaluation with structure-activity relationship (SAR) analysis, we found that compound 2 exhibited potent BTK kinase inhibitory activity, with an IC50 of 7 nM. This derivative markedly inhibited BTK activation in TMD8 B cell lymphoma cells and thus inhibited the in vitro growth of the cells. Further studies revealed that compound 2 dose dependently arrested TMD8 cells at G1 phase, accompanied by decreased levels of Rb, phosphorylated Rb, and cyclin D1. Moreover, following treatment with compound 2, TMD8 cells underwent apoptosis associated with PARP and caspase 3 cleavage. Interestingly, the results of the kinase activity assay on a small panel of 35 kinases showed that the kinase selectivity of compound 2 was superior to that of the first-generation inhibitor ibrutinib, suggesting that compound 2 could be a second-generation inhibitor of BTK. In conclusion, we identified a potent and highly selective BTK inhibitor worthy of further development.

20.
Haematologica ; 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289198

RESUMO

Aberrant expression of CDK9/cyclin T1 has been found in diffuse large B-cell lymphoma, and suggest that CDK9 seems to be a potential therapeutic target for diffuse large B-cell lymphoma. Here, we firstly demonstrated that CDKI-73, a novel CDK inhibitor, potently blocks CDK9, triggered apoptosis and dramatically repressed diffuse large B-cell lymphoma cell growth owing to CDK9 inhibition. CDK9 inhibitors specifically elevated the trimethylation of H3K27, which we speculate was due to reduced expression of JMJD3/UTX. Considering the important role of the trimethylation of H3K27 in tumor progression, the synergistic effect of the combination therapy of CDK9 inhibitors with EZH2 inhibitors was investigated. EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited diffuse large B-cell lymphoma and other solid tumors growth in vitro and in vivo. These findings provide a rational basis for the application of CDK9 inhibitors in combination with EZH2 inhibitors in clinical trials.

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