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1.
Inflamm Res ; 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32350570

RESUMEN

OBJECTIVE: Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. METHODS: SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS: SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1ß and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1ß and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. CONCLUSION: SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway.

2.
J Struct Biol ; : 107510, 2020 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-32353513

RESUMEN

Enterovirus D68 (EV-D68) is an emerging viral pathogen belonging to the Enterovirus genus of the Picornaviridae family, which is a serious threat to human health and has resulted in significant economic losses. The EV-D68 genome encodes an RNA-dependent RNA polymerase (RdRp) 3Dpol, which is central for viral genome replication and considered as a promising target for specific antiviral therapeutics. In this study, we report the crystal structures of human EV-D68 RdRp in the apo state and in complex with the inhibitor NADPH, which was selected by using a structure-based virtual screening approach. The EV-D68-RdRp-NADPH complex is the first RdRp-inhibitor structure identified in the species Enterovirus D. The inhibitor NADPH occupies the RNA template binding channel of EV-D68 RdRp with a novel binding pocket. Additionally, residues involved in the NADPH binding pocket of EV-D68 RdRp are highly conserved in RdRps of enteroviruses. Therefore, the enzyme activity of three RdRps from EV-D68, poliovirus, and enterovirus A71 is shown to decrease when titrated with NADPH separately in vitro. Furthermore, we identified that NADPH plays a pivotal role as an RdRp inhibitor instead of a chain terminator during restriction of RNA-dependent RNA replication. In the future, derivatives of NADPH may pave the way for novel inhibitors of RdRp through compound modification, providing potential antiviral agents for treating enteroviral infection and related diseases.

3.
Artículo en Inglés | MEDLINE | ID: mdl-32353834

RESUMEN

The structure and magnetic properties are studied in co-doped Cs2-xKxCuBr4-xClx and pressurized Cs2CuBr4 samples. No structural phase transition is found with doping concentration x ≤ 0.1 and pre-compression pressure up to 4.5 GPa. The maximum susceptibility temperature Tmax of the zero-field-cooling (ZFC) susceptibility curves decreases slightly with increasing doping concentration and pre-compression pressure, indicating only small changes in the exchange coupling constants. However, an unusual enhancement of the magnetic moment deduced from the ZFC susceptibility is observed in both series samples. A maximum increase of 40% is obtained in Cs1.9K0.1CuBr3.9Cl0.1 sample. The magnetic moment increases almost linearly with decreasing Δ, i. e., defined as the wavenumber difference between the short- and long-bond stretching modes of the CuBr42 tetrahedra in the Raman spectra. The effect is likely due to the recovery of the Cu-3d orbital magnetic moments by strain-induced suppression of Jahn-Teller distortion in CuBr42 tetrahedra.

4.
Artículo en Inglés | MEDLINE | ID: mdl-32356178

RESUMEN

PURPOSE: We aimed to investigate the treatment effect of chemotherapy on ground-glass opacity (GGO)-featured lung adenocarcinoma radiologically and pathologically. METHODS: This retrospective study included patients who met the following criteria: (1) presence of lung GGO lesions before chemotherapy for other concurrent malignancies; (2) underwent surgical resection of GGO-featured primary lung adenocarcinoma. The last computed tomography images before chemotherapy (CT1) and the last images before GGO resection (CT2) were reviewed to assess radiologic response. Specimens of the resected tumors were reviewed to evaluate the histopathologic response. Immunohistochemical staining of ki-67, caspase-3 and ß-gal was performed and compared between these tumors and a propensity score-matched (1:1) cohort of GGO-featured lung adenocarcinoma without prior chemotherapy. RESULTS: Forty-four patients with 55 GGO lesions were included. There were 20 mixed GGOs and 22 invasive adenocarcinomas. These patients all received at least three cycles of chemotherapy for other concurrent malignancies in breast, lung, cervix, ovary or rectum. Thirty-four (77%) patients received chemotherapy regimens that contained platinum, pemetrexed, paclitaxel, docetaxel or gemcitabine. The median interval between CT1 and CT2 was 10 months. Radiologically, all the GGO lesions either remained unchanged or enlarged. There was no chemotherapy-induced histopathologic response (necrosis, fibrosis or inflammation) in any of these tumors. The protein expression of ki-67, caspase-3 and ß-gal was comparable between GGO-featured lung adenocarcinoma with or without prior chemotherapy. CONCLUSION: GGO-featured lung adenocarcinoma has no response to chemotherapy. For these patients, chemotherapy should not be a treatment option.

5.
Menopause ; 2020 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-32379216

RESUMEN

OBJECTIVE: The aim of the study was to investigate the effectiveness and safety of a new, improved herbal formula of a traditional Chinese medicine, improved Gengnianchun (I-GNC), on hot flushes, depression, anxiety, and sleep in peri- and postmenopausal women in China. METHODS: A randomized, single-blind, placebo-controlled trial of peri- and postmenopausal women with Kupperman Index (KMI) scores of 15 or higher was conducted for 12 weeks. Hot flush frequencies, KMI scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and Pittsburgh Sleep Quality Index scores were evaluated. Each outcome was evaluated every 4 weeks. RESULTS: Ninety-eight participants completed the study. The I-GNC formula significantly reduced the mean (SD) frequency of hot flushes from 7 (4.554) to 1.2 (1.675) in the I-GNC group and from 6.74 (3.43) to 3.66 (2.635) in the placebo group (P < 0.01). The KMI (P < 0.01), Hamilton depression scale (P < 0.01), and Hamilton anxiety scale (P < 0.01) scores decreased in both groups after treatment, and significant differences were observed between the two groups (P < 0.01); however, no significant difference in the Pittsburgh Sleep Quality Index score was observed. I-GNC had no effect on serum follicle-stimulating hormone or E2 levels. There were no obvious adverse effects. CONCLUSIONS: The traditional Chinese medicine herbal formula I-GNC can alleviate the symptoms of menopausal syndrome and improve quality of life among peri- and postmenopausal women. I-GNC is safe and has no notable adverse effects.

6.
Curr Neurovasc Res ; 2020 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-32370715

RESUMEN

OBJECTIVE: Early exposure to general anesthesia in children might be a potentially high-risk factor for learning and behavioral disorders. The mechanism of neurotoxicity induced by general anesthesia was not defined. miR-496 could regulate cerebral injury, while the roles of miR-496 in neurotoxicity were not elucidated. Therefore, we aimed to investigate the effects of miR-496 in neurotoxicity induced by propofol. METHODS: Primary prefrontal cortical (PFC) neurons were isolated from neonatal rats and treated with propofol to induce neurotoxicity. Cell viability was detected by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The target relationship of miR-496 and Rho Associated Coiled-Coil Containing Protein Kinase 2 (ROCK2) was explored using luciferase assays. RESULTS: Propofol decreased cell viability, promoted cell apoptosis, and decreased the expression of miR-496 in PFC neurons in a dose-dependent manner. Overexpression of miR-496 attenuated neurotoxicity induced by propofol in PFC neurons. ROCK2 was a target of miR-496, and miR-496 oppositely modulated the expression of ROCK2. Besides, propofol increased the expression of ROCK2 through inhibiting miR-496 in PFC neurons. Overexpression of miR-496 attenuated propofolinduced neurotoxicity by targeting ROCK2 in PFC neurons. CONCLUSION: miR-496 was decreased in PFC neurons treated with propofol, and overexpression of miR-496 attenuated propofol-induced neurotoxicity by targeting ROCK2. miR-496 and ROCK2 may be promising targets for protecting propofol-induced neurotoxicity.

7.
J Craniofac Surg ; 2020 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-32371705

RESUMEN

OBJECTIVE: The purpose of this research was to investigate the effectiveness on postoperative pharyngalgia of filling the endotracheal catheter (ETC) cuffs with air, double distilled water, 2% lidocaine hydrochloride, and 1.73% lidocaine carbonate. METHODS: A group of 80 female patients were divided into 4 groups randomly. The ETC cuffs were filled with air (Group A), double distilled water (Group B), 2% lidocaine hydrochloride (Group C), and 1.73% lidocaine carbonate (Group D) after endotracheal intubation in corresponding patients. Sore throat, hoarseness, bucking, perioperative hemodynamic changes were examined in all participants. RESULTS: The Group D had significantly less severity of POST (P < 0.05), postoperative hoarseness (P < 0.05) and bucking on emergence from general anesthesia (P < 0.01) than patients from other groups. The Group D reported significantly less hemodynamic changes after extubation 1, 5, 10 minutes (P < 0.05). CONCLUSION: Lidocaine carbonate injected into the ETC cuffs decreased the severity of postoperative pharyngalgia, postoperative hoarseness and bucking on emergence from general anesthesia.

8.
Nat Commun ; 11(1): 2193, 2020 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-32366851

RESUMEN

Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5'ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3-/- primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells.

9.
J Nanobiotechnology ; 18(1): 69, 2020 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-32375799

RESUMEN

BACKGROUND: Cell-bound membrane vesicles (CBMVs) are a type of membrane vesicles different from the well-known extracellular vesicles (EVs). In recent years, the applications of EVs as drug delivery systems have been studied widely. A question may arise whether isolated CBMVs also have the possibility of being recruited as a drug delivery system or nanocarrier? METHODS: To test the possibility, CBMVs were isolated/purified from the surfaces of cultured endothelial cells, loaded with a putative antitumor drug doxorubicin (Dox), and characterized. Subsequently, cellular experiments and animal experiments using mouse models were performed to determine the in vitro and in vivo antitumor effects of Dox-loaded CBMVs (Dox-CBMVs or Dox@CBMVs), respectively. RESULTS: Both Dox-free and Dox-loaded CBMVs were globular-shaped and nanometer-sized with an average diameter of ~ 300-400 nm. Dox-CBMVs could be internalized by cells and could kill multiple types of cancer cells. The in vivo antitumor ability of Dox-CBMVs also was confirmed. Moreover, Quantifications of blood cells (white blood cells and platelets) and specific enzymes (aspartate aminotransferase and creatine kinase isoenzymes) showed that Dox-CBMVs had lower side effects compared with free Dox. CONCLUSIONS: The data show that the CBMV-entrapped Doxorubicin has the antitumor efficacy with lower side effects. This study provides evidence supporting the possibility of isolated cell-bound membrane vesicles as a novel drug nanocarrier.

10.
Sensors (Basel) ; 20(9)2020 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-32403250

RESUMEN

Most studies on light pollution are based on light intensity retrieved from nighttime light (NTL) remote sensing with less consideration of the population factors. Furthermore, the coarse spatial resolution of traditional NTL remote sensing data limits the refined applications in current smart city studies. In order to analyze the influence of light pollution on populated areas, this study proposes an index named population exposure to light pollution (PELP) and conducts a street-scale analysis to illustrate spatial variation of PELP among residential areas in cites. By taking Shenzhen city as a case, multi-source data were combined including high resolution NTL remote sensing data from the Luojia 1-01 satellite sensor, high-precision mobile big data for visualizing human activities and population distribution as well as point of interest (POI) data. Results show that the main influenced areas of light pollution are concentrated in the downtown and core areas of newly expanded areas with obvious deviation corrected like traditional serious light polluted regions (e.g., ports). In comparison, commercial-residential mixed areas and village-in-city show a high level of PELP. The proposed method better presents the extent of population exposure to light pollution at a fine-grid scale and the regional difference between different types of residential areas in a city.

11.
New Phytol ; 2020 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-32406528

RESUMEN

C2H2-type zinc finger transcription factor STOP1 plays an essential role in aluminum (Al) resistance in Arabidopsis thaliana by controlling the expression of a set of Al-resistance genes including the malate transporter-encoding gene AtALMT1 that is critically required for Al resistance. STOP1 is suggested to be modulated by Al at posttranscriptional and/or posttranslational levels. However, the underlying molecular mechanisms remain to be demonstrated. We carried out a forward genetic screen on an EMS-mutagenized population, which contains the AtALMT1 promoter-driven luciferase reporter gene (pAtALMT1:LUC), and identified HPR1, which encodes a subunit of the THO/TREX complex. We investigate the effect of hpr1 mutations on the expression of Al-resistance genes and Al resistance, and we also examined the regulatory role of HPR1 in nuclear mRNA and protein accumulation of STOP1 gene. Mutation of HPR1 reduces the expression of STOP1-regulated genes and the associated Al resistance. The hpr1 mutations increase STOP1 mRNA retention in the nucleus and consequently decrease STOP1 protein abundance. Mutation of RAE1 that mediates STOP1 degradation in the hpr1 mutant background can partially rescue the deficient phenotypes of hpr1 mutants. Our results demonstrate that HPR1 modulates Al resistance partly through the regulation of nucleocytoplasmic STOP1 mRNA export.

12.
Diabetes Obes Metab ; 2020 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-32406594

RESUMEN

AIMS: Since the pandemic outbreak of COVID-19, limited information is available on diabetic patients with COVID-19. MATERIALS AND METHODS: We retrospectively analysed 166 COVID-19 patients at Tongji Hospital (Wuhan) from February 8 to March 21, 2020. Clinical characteristics and outcomes (as of April 4, 2020) were compared among control (group 1), secondary hyperglycaemia (group 2: no diabetes history, FPG levels ≥7.0 mmol/L once and HbA1c values <6.5%) and diabetic (group 3) patients. RESULTS: Compared to group 1, groups 2 and 3 had higher rates of leukocytosis, neutrophilia, lymphocytopenia, eosinopenia, and levels of sCRP, ferritin and d-dimer (P < 0.05 for all). Group 2 patients have higher levels of LDH, prevalence of liver dysfunction and increased IL-8 than those in group 1, a higher prevalence of increased IL-8 was found in group 2 than in group 3 (P < 0.05 for all). The proportions of critical patients in groups 2 and 3 were significantly higher compared to group 1 (38.1%, 32.8% vs. 9.5%, P < 0.05 for both). Groups 2 and 3 had significantly longer hospital stays than group 1, which was nearly one week longer. The composite outcomes risks were 5.47 (1.56-19.82) and 2.61 (0.86-7.88) times greater in group 2 and 3 than in group 1. CONCLUSIONS: Hyperglycemia in both diabetes and secondary hyperglycemia patients with COVID-19 may indicate poor prognoses. There were differences between secondary hyperglycemia and diabetes patients. We recommend that clinicians pay more attention to the blood glucose status of COVID-19 patients, even those not diagnosed with diabetes before admission.

13.
Mol Med Rep ; 22(1): 474-482, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32377742

RESUMEN

Periodontal accelerate osteogenesis orthodontics (PAOO) is an extension of described techniques that surgically alter the alveolar bone; however, the specific mechanism underlying the technique is not completely understood. The aim of the present study was to evaluate the roles of microRNA (miR)­21 during PAOO. Sprague­Dawley rats were divided into the following four groups: i) Group tooth movement (TM), underwent TM and were administered normal saline (NS); ii) Group PAOO, underwent PAOO + TM and were administered NS; iii) Group agomiR­21, underwent PAOO + TM and were administered agomiR­21; and iv) Group antagomiR­21, underwent PAOO + TM and were administered antagomiR­21. To validate the rat model of PAOO, morphological analyses were performed and measurements were collected. Reverse transcription­quantitative PCR, western blotting and immunohistochemical staining were performed to examine the expression levels of programmed cell death 4 (PDCD4), activin A receptor type 2B (ACVR2b), receptor activator of NF­κΒ ligand (RANKL) and C­Fos. Dual­luciferase reporter assays were performed to validate PDCD4 as a target of miR­21 in vitro. Following 7 days of treatment, the TM distance of group PAOO was longer compared with groups TM and antagomiR­21 (P<0.05), but shorter compared with group agomiR­21 (P<0.05). Tartrate­resistant acid phosphatase staining indicated that following treatment with agomiR­21, osteoclast activity was notably increased, whereas the mRNA and protein expression levels of PDCD4 were notably decreased compared with group PAOO. The mRNA and protein expression levels of RANKL and C­Fos in group agomiR­21 were notably increased compared with group PAOO, whereas group antagomiR­21 displayed the opposite pattern (P<0.05). With regard to ACVR2b, no significant differences were observed among the group agomiR­21 and antagomiR­21 compared with group PAOO. Bioinformatics analysis predicted that PDCD4 was a potential target gene of miR­21, and dual­luciferase reporter assays demonstrated that miR­21 directly targeted PDCD4. In conclusion, the present study demonstrated that miR­21 serves an important role during PAOO­mediated orthodontic TM.

14.
J Exp Clin Cancer Res ; 39(1): 84, 2020 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-32393392

RESUMEN

BACKGROUND: The Ecotropic viral integration site 5 (EVI5), an important protein in regulating cell cycle, cytokinesis and cellular membrane traffic, functions as a stabilizing factor maintaining anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 in S/G2 phase. However, the mechanism by which EVI5 promotes malignant transformation of non-small cell lung cancer (NSCLC) remains unknown. In the present study, we addressed the role of EVI5 in NSCLC by regulating tumor growth, migration and invasion. METHODS: The expression levels of EVI5 and miR-486-5p in NSCLC tissues and cells were measured by real-time PCR. Meanwhile, EVI5 and its associated protein expression were analyzed by western blot and co-immunoprecipitation assay. Flow cytometry was performed to determine cell proliferation and apoptosis. CCK-8 and clonogenic assays were used to analyze cell viability. Wound healing, transwell migration and matrigel invasion assays were utilized to assess the motility of tumor cells. To investigate the role of EVI5 in vivo, lung carcinoma xenograft mouse model was applied.. RESULTS: EVI5 was upregulated in NSCLC tissues and cell lines when compared with that in normal tissues and cell line. Knockdown of EVI5 in vitro inhibited tumor cell proliferation, migration and invasion in NSCLC cells. Further, inoculation of EVI5-deficient tumor cells into nude mice suppressed tumor proliferation and metastasis compared to control mice inoculated with unmanipulated tumor cells. These data indicated that EVI5 promote the proliferation of NSCLC cells which was consistent with our previous results. Additionally, we showed that EVI5 was directly regulated by miR-486-5p, and miR-486-5p-EVI5 axis affected the NSCLC migration and invasion through TGF-ß/Smad signaling pathway by interacting with TGF-ß receptor II and TGF-ß receptor I. CONCLUSIONS: Based on these results, we demonstrated a new post-transcriptional mechanism of EVI5 regulation via miR-486-5p and the protumoral function of EVI5 in NSCLC by interacting with Emi1 and/or TGF-ß receptors, which provides a new insight into the targeted therapy of NSCLC.

15.
Bioinformatics ; 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32413103

RESUMEN

MOTIVATION: Apicomplexan parasites, including Toxoplasma, Plasmodium and Babesia, are important pathogens that affect billions of humans and animals worldwide. Usually a microscope is used to detect these parasites, but it is difficult to use microscopes and clinician requires to be trained. Finding a cost-effective solution to detect these parasites is of particular interest in developing countries, in which infection is more common. RESULTS: Here we propose an alternative method, deep cycle transfer learning (DCTL), to detect Apicomplexan parasites, by utilizing deep learning-based microscopic image analysis. DCTL is based on observations of parasitologists that Toxoplasma is banana-shaped, Plasmodium is generally ring-shaped, and Babesia is typically pear-shaped. Our approach aims to connect those microscopic objects (Toxoplasma, Plasmodium, Babesia and erythrocyte) with their morphological similar macro ones (banana, ring, pear and apple) through a cycle transfer of knowledge. In the experiments, we conduct DCTL on 24,358 microscopic images of parasites. Results demonstrate high accuracy and effectiveness of DCTL, with an average accuracy of 95.7% and an area under the curve (AUC) of 0.995 for all parasites types. This paper is the first work to apply knowledge from parasitologists to Apicomplexan parasite recognition, and it opens new ground for developing AI-powered microscopy image diagnostic systems. AVAILABILITY AND IMPLEMENTATION: Code and dataset available at https://github.com/senli2018/DCTL. CONTACT AND SUPPLEMENTARY INFORMATION: Email: zhangyang07@hit.edu.cn. Supplementary data are available at Bioinformatics online.

16.
Biomed Pharmacother ; 127: 110121, 2020 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-32407984

RESUMEN

OBJECTIVE: Nicorandil exerts a protective effect against coronary microvascular dysfunction in acute myocardial infarction (AMI) patients. However, the mechanism and effect of nicorandil in hyperhomocysteinemia (HHcy) AMI patients remain unclear. METHODS: C57/BL6 mice with mild to moderate HHcy and human coronary artery endothelial cells (HCAECs) cotreated with HHcy (1 mmol/L) for 24 h and hypoxia for 6 h were selected as models. Small animal ultrasound detection was used to compare cardiac function. CD31 immunofluorescence staining and tomato lectin staining were used to assess the number of microcirculation changes in vivo. MTT, tube formation and western blotting assays were used to evaluate the effect of nicorandil on HCAECs and the PI3K/Akt/eNOS pathway. RESULTS: The results showed that nicorandil improved cell viability and p-PI3K/PI3K, p-Akt/Akt, and p-eNOS/eNOS expression in the vitro HHcy and hypoxia models. The beneficial effects of nicorandil on HCAECs could be inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the nitric oxide synthase (NOS) inhibitor L-NAME. In vivo, nicorandil improved the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the post-HHcy + MI model, and the levels of CD31 and tomato lectin expression were higher in the nicorandil treatment group. The effectiveness of nicorandil was inhibited in the PI3K and L-NAME groups. CONCLUSION: The results suggest that nicorandil improves Hcy-induced coronary microvascular dysfunction through the PI3K/Akt/eNOS signalling pathway.

17.
Thorac Cancer ; 2020 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-32433828

RESUMEN

BACKGROUND: Although many studies have defined mechanisms of resistance to EGFR-TKIs, acquired resistance remains the major limitation of monotherapy with EGFR-TKIs. METHODS: Cell viability was analyzed using a Cell Counting Kit-8 (CCK-8) assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNAs from HCC827 and HCC827 gefitinib-resistant (GR) cells were analyzed by genome analyzer-based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence-activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the effect of anlotinib on HCC827 GR cells. RESULTS: The T790M mutation was found in the PC-9 GR cell line but not in the HCC827 GR cell line. Anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase-3. CONCLUSIONS: FGFR1 overexpression could be the mechanism of EGFR-TKI acquired resistance and anlotinib can suppresse the growth of EGFR-TKI-resistant NSCLC cells without T790M mutation.

18.
Brief Bioinform ; 2020 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-32436937

RESUMEN

X-ray crystallography is the major approach for determining atomic-level protein structures. Because not all proteins can be easily crystallized, accurate prediction of protein crystallization propensity provides critical help in guiding experimental design and improving the success rate of X-ray crystallography experiments. This study has developed a new machine-learning-based pipeline that uses a newly developed deep-cascade forest (DCF) model with multiple types of sequence-based features to predict protein crystallization propensity. Based on the developed pipeline, two new protein crystallization propensity predictors, denoted as DCFCrystal and MDCFCrystal, have been implemented. DCFCrystal is a multistage predictor that can estimate the success propensities of the three individual steps (production of protein material, purification and production of crystals) in the protein crystallization process. MDCFCrystal is a single-stage predictor that aims to estimate the probability that a protein will pass through the entire crystallization process. Moreover, DCFCrystal is designed for general proteins, whereas MDCFCrystal is specially designed for membrane proteins, which are notoriously difficult to crystalize. DCFCrystal and MDCFCrystal were separately tested on two benchmark datasets consisting of 12 289 and 950 proteins, respectively, with known crystallization results from various experimental records. The experimental results demonstrated that DCFCrystal and MDCFCrystal increased the value of Matthew's correlation coefficient by 199.7% and 77.8%, respectively, compared to the best of other state-of-the-art protein crystallization propensity predictors. Detailed analyses show that the major advantages of DCFCrystal and MDCFCrystal lie in the efficiency of the DCF model and the sensitivity of the sequence-based features used, especially the newly designed pseudo-predicted hybrid solvent accessibility (PsePHSA) feature, which improves crystallization recognition by incorporating sequence-order information with solvent accessibility of residues. Meanwhile, the new crystal-dataset constructions help to train the models with more comprehensive crystallization knowledge.

19.
Health Phys ; 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32427639

RESUMEN

Biokinetics underlies the basis for assessment of internal exposures. This paper develops a biokinetic method on simultaneous intake of radionuclides from multiple intake scenarios in internal exposures. With numerical techniques that transform the whole biokinetics between the coupled and decoupled representations of the same problem, this method applies to coupled biokinetics with complex structures and has no restrictions of practical importance on the number of intake scenarios, the number of intake parent radionuclides and decay products, and the complexity of decay relationships between parent and progeny nuclides. For illustration, this method is applied to an assumed case of mixed inhalation and ingestion of weapon-grade plutonium material for reference workers that is focused on Pu and Am. Due to coupled biokinetics between the direct intake and ingrowth parts in different intake pathways, the multiple intake results (the contents of lungs, daily excretions, and cumulative contents) display richer behaviors as compared to single intake cases. This method benefits both the prospective and retrospective assessment of internal exposures for complex intake cases in actual applications.

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