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1.
EBioMedicine ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31668570

RESUMO

BACKGROUND: KRAS mutations are the most frequent oncogenic aberration in lung adenocarcinoma. KRAS mutant isoforms differentially shape tumour biology and influence drug responses. This heterogeneity challenges the development of effective therapies for patients with KRAS-driven non-small cell lung cancer (NSCLC). METHODS: We developed an integrative pharmacogenomics analysis to identify potential drug targets to overcome MEK/ERK inhibitor resistance in lung cancer cell lines with KRAS(G12C) mutation (n = 12). We validated our predictive in silico results with in vitro models using gene knockdown, pharmacological target inhibition and reporter assays. FINDINGS: Our computational analysis identifies casein kinase 2A1 (CSNK2A1) as a mediator of MEK/ERK inhibitor resistance in KRAS(G12C) mutant lung cancer cells. CSNK2A1 knockdown reduces cell proliferation, inhibits Wnt/ß-catenin signalling and increases the anti-proliferative effect of MEK inhibition selectively in KRAS(G12C) mutant lung cancer cells. The specific CK2-inhibitor silmitasertib phenocopies the CSNK2A1 knockdown effect and sensitizes KRAS(G12C) mutant cells to MEK inhibition. INTERPRETATION: Our study supports the importance of accurate patient stratification and rational drug combinations to gain benefit from MEK inhibition in patients with KRAS mutant NSCLC. We develop a genotype-based strategy that identifies CK2 as a promising co-target in KRAS(G12C) mutant NSCLC by using available pharmacogenomics gene expression datasets. This approach is applicable to other oncogene driven cancers. FUND: This work was supported by grants from the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Lung Cancer Research Foundation and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation.

2.
J Colloid Interface Sci ; 560: 293-302, 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31670102

RESUMO

Hierarchical copper sulfide/bismuth tungstate (CuS/Bi2WO6) p-n junction with two-dimensional (2D) interfacial coupling were prepared through a two-step hydrothermal method. The as-prepared samples were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, diffuse reflectance spectroscopy, photoluminescence spectroscopy, photocurrent and electrochemical impedance spectroscopy. CuS nanoplates anchored on the surface of hierarchical Bi2WO6 microspheres consisting of Bi2WO6 nanosheets to form a CuS/Bi2WO6 p-n junction photocatalyst. The photocatalytic activity of glyphosate degradation over CuS/Bi2WO6 under 44 W light-emitting diode (LED) light irradiation (λ > 400 nm) was investigated. The results indicate that the CuS/Bi2WO6 heterojunctions display higher photocatalytic activity than pure CuS and Bi2WO6. The improved photocatalytic activity of the CuS/Bi2WO6 heterostructures can be attributed to strong visible light absorption and enhanced separation of photogenerated charge carriers by the internal electric field near the interface of the p-n junction. In addition, the CuS/Bi2WO6 p-n junction photocatalysts consisting of nanosheets are beneficial for the transport of photoexcited charge carriers, thus resulting in the increase of the photocatalytic activity of glyphosate degradation. This work provides the new avenue for the development and design p-n junction materials for photocatalytic applications.

3.
Cell Res ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595041

RESUMO

Protein biogenesis at the endoplasmic reticulum (ER) in eukaryotic cells is monitored by a protein quality control system named ER-associated protein degradation (ERAD). While there has been substantial progress in understanding how ERAD eliminates defective polypeptides generated from erroneous folding, how cells remove nascent chains stalled in the translocon during co-translational protein insertion into the ER is unclear. Here we show that ribosome stalling during protein translocation induces the attachment of UFM1, a ubiquitin-like modifier, to two conserved lysine residues near the COOH-terminus of the 60S ribosomal subunit RPL26 (uL24) at the ER. Strikingly, RPL26 UFMylation enables the degradation of stalled nascent chains, but unlike ERAD or previously established cytosolic ribosome-associated quality control (RQC), which uses proteasome to degrade their client proteins, ribosome UFMylation promotes the targeting of a translocation-arrested ER protein to lysosomes for degradation. RPL26 UFMylation is upregulated during erythroid differentiation to cope with increased secretory flow, and compromising UFMylation impairs protein secretion, and ultimately hemoglobin production. We propose that in metazoan, co-translational protein translocation into the ER is safeguarded by a UFMylation-dependent protein quality control mechanism, which when impaired causes anemia in mice and abnormal neuronal development in humans.

4.
Curr Eye Res ; : 1-7, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31587582

RESUMO

Purpose: To evaluate macular and radial peripapillary capillary vessel densities (RPC VD) across normal, pre-perimetric (PPG), and early perimetric primary open-angle glaucoma (EG) using optical coherence tomography angiography (OCTA). Materials and Methods: Forty-four PPG eyes, 42 EG eyes, and 41 normal eyes were consecutively enrolled. All subjects underwent visual field, OCT, and OCTA examinations. Macular vessel densities were measured in the superficial layer. RPC VD was measured within a 750-µm-wide elliptical annulus extending outward from disc boundary. Diagnostic ability was evaluated with area under the receiver operating curve. Results: Parafoveal vessel densities (ParaVDs) in the PPG group were comparable to the normal group (p > .05), except for temporal quadrant (p = .044), while perifoveal vessel densities (PeriVD) were lower in the PPG group (p < .05). ParaVD and PeriVD were lower in the EG group compared with the normal group (p < .001). Superior-temporal and inferior-temporal retinal nerve fiber layers (RNFLs) were significantly decreased in the EG group compared with the PPG group (p < .05), while only inferior-temporal RPC VD was lower in the EG group (p < .05). RPC VD was comparable to RNFL and ganglion cell complex (GCC) in the diagnosis of PPG (p > .05). Macular whole image vessel density and PeriVD were comparable to RPC VD, RNFL, and GCC in diagnosing EG (p > .05). Conclusions: In early primary open-angle glaucoma, significant microvascular damage was present in both macular and peripapillary areas. The damage of macular microvasculature was more prominent in the peripheral area. Vessel density parameters showed promising diagnostic ability in early glaucoma. Abbreviations: POAG = primary open-angle glaucoma; RGC = retinal ganglion cell; OCTA = optical coherence tomography angiography; RNFL = retinal nerve fiber layer; PPG = pre-perimetric primary open-angle glaucoma; EG = early perimetric primary open-angle glaucoma; IOP = intraocular pressure; PSD = pattern standard deviation; MD = mean deviation; GCC = ganglion cell complex; SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure; MOPP = mean ocular perfusion pressure; wiVD = whole image vessel density; ParaVD = parafoveal vessel density; PeriVD = perifoveal vessel density; RPC VD = radial peripapillary capillary vessel density; AUC = area under the receiver operating curve.

5.
JAMA Ophthalmol ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621813
6.
BMC Nephrol ; 20(1): 364, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601196

RESUMO

BACKGROUND: Chronic allograft damage (CAD) is the leading cause of long-term graft dysfunction. A noninvasive method that can diagnose CAD early and monitor its development is needed. METHODS: Kidneys from Fisher rats were transplanted into Lewis rats to establish a CAD model (n = 20). The control group underwent syngeneic kidney transplantation (n = 20). The serum creatinine of the rats was monitored. At 4, 12, and 20 weeks after modeling, a magnetic resonance imaging (MRI) examination was performed. The apparent diffusion coefficient (ADC), pseudo diffusion coefficient (D*), true diffusion coefficient (D) and perfusion fraction (f) of the two groups were analyzed. Chronic allograft damage index (CADI) scoring was used to evaluate the transplanted kidney specimens. Immunohistochemistry was used to detect the expression of fibrosis markers in the transplanted kidney tissues and to analyze their correlations with all MRI parameters. RESULTS: The transplanted kidneys in the experimental group developed CAD changes before the appearance of elevated creatinine. The MRI parameters in the experimental group [ADC (1.460 ± 0.109 VS 2.095 ± 0.319, P < 0.001), D (1.435 ± 0.102 VS 1.969 ± 0.305, P < 0.001), and f (26.532 ± 2.136 VS 32.255 ± 4.013, P < 0.001)] decreased, and D* (20.950 ± 2.273 VS 21.415 ± 1.598, P = 0.131) was not significantly different from those in the control group. ADC, D and f were negatively correlated with the CADI and the α-SMA and vimentin expression levels. CONCLUSION: Intravoxel incoherent motion (IVIM) imaging could detect CAD earlier than creatinine and reflect the degree of fibrosis in grafts quantitatively.

7.
Plant Dis ; : PDIS04190781RE, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31613192

RESUMO

Phytophthora cinnamomi is an ecologically and agriculturally significant plant pathogen. Early and accurate detection of P. cinnamomi is paramount to disease prevention and management. In this study, a loop-mediated isothermal amplification (LAMP) assay utilizing a new target gene Pcinn100006 identified from genomic sequence data was developed and evaluated for the detection of P. cinnamomi. This Pcinn100006 LAMP assay was found highly specific to P. cinnamomi. All 10 tested isolates of P. cinnamomi yielded positive results, whereas 50 isolates belonging to 16 other Phytophthora species, Globisporangium ultimum, and 14 fungal species lacked detection. This assay was 10 times more sensitive (100 pg in a 25-µl reaction mixture) than a conventional PCR assay (2 ng in a 50-µl reaction mixture) for detecting the genomic DNA of P. cinnamomi. In addition, it detected P. cinnamomi from artificially inoculated leaves of Cedrus deodara. Moreover, detection rates of P. cinnamomi using environmental DNAs extracted from 13 naturally infested rhizosphere samples were 100% in the Pcinn100006 LAMP assay versus 46% in the conventional PCR assay. Considering its higher accuracy and shorter time span, this Pcinn100006 LAMP assay is a promising diagnostic tool to replace conventional PCR-based and culture-dependent assays for screening of P. cinnamomi in regions at risk of infection or contamination.

8.
Int J Mol Med ; 44(5): 1899-1907, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485642

RESUMO

Patients with ischemic hearts who have refused coronary vascular reconstruction may exhibit dynamic myocardial remodeling and cardiac dysfunction. In the present study, the role of miRNA­1 and its association with the ubiquitin­proteasome system (UPS) in regulating myocardial remodeling was investigated. A myocardial infarction (MI) model was constructed and the hearts were treated with miRNA­1 antagomir, miRNA­1 lentiviral vectors and the UPS proteasome blocker bortezomib. The expression levels of miRNA­1 were evaluated using reverse transcription PCR and the abundance of the ubiquitin­proteasome protein and caspase­3 were evaluated via western blot analysis. Furthermore, the collagen volume fraction was calculated using Masson's trichrome staining, and the apoptosis index was detected via terminal deoxynucleotidyl transferase dUTP­biotin nick end labeling staining. Transforming growth factor (TGF)­ß expression was assessed via immunohistochemical staining. Echocardiographic characteristics and myocardial infarct size were analyzed. miRNA­1 expression levels were found to be increased following MI. miRNA­1 antagomir administration clearly inhibited miRNA­1 expression, whereas the miRNA­1 lentiviral vector exerted the opposite effect. The levels of 19s proteasome, 20S proteasome and ubiquitin ligase E3 were decreased in the miRNA­1 antagomir group, but were significantly increased in the miRNA­1 lentiviral group; however, only 20S proteasome expression was decreased in the bortezomib group. Collagen hyperplasia and TGF­ß expression were decreased in both the miRNA­1 antagomir and bortezomib groups, although the effects of the miRNA­1 antagomir were more noticeable. The miRNA­1 antagomir and the UPS proteasome blocker both alleviated the ultrastructural impairments, demonstrated by a decreased left ventricular (LV) end­diastolic diameter and LV mass, but the miRNA­1 antagomir was also able to increase LV ejection fraction and LV fractional shortening. miRNA­1 regulated UPS­associated mRNA expression and affected the majority of the UPS components in the myocardium, thereby leading to increased myocardial cell apoptosis, myocardial fibrosis and remodeling. The miRNA­1 antagomir exerted a more prominent cardioprotective effect compared with the UPS proteasome blocker bortezomib.

9.
Proc Natl Acad Sci U S A ; 116(40): 20097-20103, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31527255

RESUMO

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing "psychosine hypothesis." We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.

10.
Chem Commun (Camb) ; 55(80): 12072-12075, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31536093

RESUMO

An efficient synthesis of a variety of quinazolinone derivatives via a direct cyclization reaction between commercially available anthranils and cyclic amines is described. The developed transformation proceeds with the merits of high step- and atom-efficiency, a broad substrate scope, and good to excellent yields, without additional catalysts, and offers a practical way for the preparation of rutaecarpine and its derivatives with structural diversity.

11.
Exp Cell Res ; 384(1): 111558, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472118

RESUMO

Hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) is a key lipid metabolic enzyme with a novel role in carcinogenesis. We previously reported that HADHA, a prognostic marker, was downregulated in clear cell renal cell carcinoma (ccRCC). Herein, the tumor inhibitory role of HADHA overexpression in ccRCC was investigated further. The quantitative proteomic analysis displayed that a total of 1293 and 1293 proteins were identified in HADHA overexpressed 786-O-hadha and vector-transfected control 786-O-vc cells, respectively, and 206 proteins were found to be up- or downregulated. PANTHER, OmicsNet, STRING, and DAVID tools were utilized on the dysregulated proteins in order to elucidate multiple metabolic pathways (especial lipid metabolism) and lipid metabolism-related proteins (e.g. ACAT1, ACLY). The dysregulation of the lipid metabolic enzymes, ACAT1, ACLY, CYB5R3 and FASN, were confirmed by Western blotting. Further assays demonstrated that HADHA overexpression significantly inhibited cell growth, induced cell apoptosis, and decreased the formation of cytoplasmic lipid droplets (LDs); moreover, it also inhibited tumor growth and lessened the formation of LDs in xenografted mouse. Collectively, these data revealed that HADHA overexpression disrupted lipid metabolism and inhibited tumor growth, which shed light on HADHA as a potential therapeutic target for clinical intervention of ccRCC.

12.
Compr Psychiatry ; 94: 152122, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473552

RESUMO

BACKGROUND: Schizophrenia is a mental disorder characterized by hyperlocomotion, cognitive symptoms, and social withdrawal. Brain-derived neurotrophic factor (BDNF) and postsynaptic density (PSD)-95 are related to schizophrenia-like deficits via regulating the synaptic ultrastructure, and play a role in drug therapy. Vinpocetine is a nootropic phosphodiesterase-1 (PDE-1) inhibitor that can reverse ketamine-induced schizophrenia-like deficits by increasing BDNF expression. However, the effects of vinpocetine on alleviating schizophrenia-like deficits via reversing the synaptic ultrastructure by regulating BDNF-related PSD-95 have not been sufficiently studied. METHODS: In this study, the schizophrenic model was built using ketamine (30 mg/kg) for 14 consecutive days. The effect of vinpocetine on reversing schizophrenia-like behaviors was examined via behavioral testing followed by treatment with certain doses of vinpocetine (20 mg/kg, i.p.). The BDNF and PSD-95 levels in the posterior cingulate cortex (PCC) were measured using biochemical assessments. In addition, the synaptic ultrastructure was observed using transmission electron microscopy (TEM). RESULTS: Ketamine induced drastic schizophrenia-like behaviors, lower protein levels of BDNF and PSD-95, and a change in the synaptic ultrastructure in the PCC. After treatment, the vinpocetine revealed a marked amendment in schizophrenia-like behaviors induced by ketamine, including higher locomotor behavior, lower cognitive behavior, and social withdrawal defects. Vinpocetine could increase the PSD-95 protein level by up-regulating the expression of BDNF. In addition, the synaptic ultrastructure was changed after vinpocetine administration, including a reduction in the thickness and curvature of the synaptic interface, as well as an increase in synaptic cleft width in the PCC. CONCLUSION: Vinpocetine can reverse the synaptic ultrastructure by regulating BDNF-related PSD-95 to alleviate schizophrenia-like deficits induced by ketamine in rats.

13.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502570

RESUMO

Radioresistance is a material obstacle for effective treatment of colorectal cancer (CRC). Thus, the discovery of a novel biomarker for determining the CRC radiosensitivity is necessary. Recent studies have confirmed that miR-183-3p regulates cell phenotypes and tumor growth in various cancers. However, the role and mechanism of this micro-ribonucleic acid in CRC radiosensitivity remains unclear. Here, the abundances of miR-183-5p and ATG5 mRNAwere detected by a real-time quantitative reverse transcription polymerase chain reaction. Kaplan-Meier survival analysis was carried out to explore the correlation between miR-183-5p and patient prognosis. Cell viability was evaluated by the MTT assay. Survival fraction analysis through colony formation was performed to assess the cell radiation response. Bioinformatic, luciferase and western blot assays were employed to verify the targeted interaction between miR-183-5p and ATG5. The results showed that an elevated abundance of miR-183-5p and a reduced ATG5 level in CRC were associated with the poor prognosis. The knockdown of miR-183-5p enhanced the sensitivity of CRC cells to radiation, inflected by the decreased cell viability and survival fraction. Mechanically, ATG5 was targeted by miR-183-5p. The addition of ATG5 conferred the radiosensitivity of the CRC cells, which was revered by miR-183-5p restoration. Furthermore, miR-183-5p knockdown hindered the tumor growth by repressing ATG5 in vivo after radiation treatment. In summary, the output data indicated that miR-183-5p heightened the radiation response of the CRC cells by targeting ATG5, promising a novel therapeutic target for CRC patients with radioresistance.

14.
Opt Express ; 27(16): 23250-23261, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31510606

RESUMO

Multi-frequency Terahertz (THz) detectors have shown great application potentials in THz imaging and sensing systems. For the first time to our knowledge, a novel dual-frequency THz detector with the stacked structure consisting of a silicon-based plasmonic antenna and a metal-based antenna in one compact unit is proposed and fabricated in standard CMOS technology. Compared with the metal antenna, the antenna based on heavy-doped poly-silicon materials enables the detector to excite localized surface plasmon resonance mode, making the effective absorption of the THz waves and thus resulting in the significant responsivity enhancement of the detector. The experimental results show a maximum voltage responsivity up to about 2000 V/W and 450 V/W, while the noise equivalence power is as low as 23 pW/Hz0.5 and 110 pW/Hz0.5 for the silicon antenna and metal antenna at the frequency of 220 GHz and 650 GHz, respectively. The presented dual-frequency detector can be easily implemented in a small size in favor of high-density array integration.

15.
Aging (Albany NY) ; 11(17): 6999-7020, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31493764

RESUMO

Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including AGPAT9, AQP7, HMGCS2, KLF15, MLXIPL, PPARGC1A, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of MIXIPL and PPARGC1A was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.

16.
J Hazard Mater ; 381: 121159, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31557713

RESUMO

Photocatalytic activity is largely restricted by insufficient photoabsorption and intense recombination between charge carriers. Here, we first synthesized Bi4NbO8Cl nanosheets with {001} exposing facets by a molten-salt growth method, which shows largely promoted photocatalytic performance for the degradation of tetracycline (TC) and bisphenol A (BPA) in comparison with Bi4NbO8Cl particles obtained by solid-state reaction. The 2D/2D Bi4NbO8Cl/g-C3N4 heterojunction photocatalysts were then fabricated via high-energy ball-milling and post-sintering to realize intimate interfacial interaction. The photocatalytic activity of all the Bi4NbO8Cl/g-C3N4 composites largely enhances compared to Bi4NbO8Cl nanosheets and g-C3N4, also far exceeding the mechanically-mixed Bi4NbO8Cl nanosheets and g-C3N4. The impact of different reaction parameters on the photocatalytic degradation activities was investigated, including catalyst concentration, pH value and TC concentration. In addition, Bi4NbO8Cl/g-C3N4 also presents improved photocatalytic CO2 reduction activity for CO production. The large enhancement on photocatalytic activity of Bi4NbO8Cl/g-C3N4 composites is owing to the synergistic effect of favorable 2D/2D structure and construction of type II heterojunction with intimate interfacial interaction, thus boosting the charge separation. The formation of type II heterojunction was evidenced by selective photo-deposition of Pt and MnOx, which demonstrate that the reductive sites and oxidative sites are on Bi4NbO8Cl nanosheets and g-C3N4, respectively. This work may provide some insights into fabrication of efficient visible-light driven photocatalysts for environmental and energy applications.

17.
Biochem Biophys Res Commun ; 518(1): 120-126, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31405565

RESUMO

Type 2 diabetes (T2D) is characterized by lack of insulin, insulin resistance and high blood sugar. However, the underlying mechanisms of insulin resistance during T2D development remains unclear. As the most common mRNAs modification, N6-Methyladenosine (m6A) is involved in many of pathological processes in aging disease. However, it remains unclear whether m6A is involved in T2D development and what is the regulatory mechanism. This study is aimed to illustrate the roles of m6A and its methyltransferase METTL3 in the regulation of blood glucose homeostasis and insulin sensitivity. The results showed that m6A methylated RNA level and its N6-methyladenosine methylase METTL3 were consistently up-regulated in the liver tissues from patients with T2D. Moreover, both m6A methylated RNA and METTL3 levels showed positive correlation with HOMA-IR and negative correlation with HOMA-ß. The m6A methylated RNA and METTL3 levels were also up-regulated in mouse with 16 weeks high-fat diet (HFD), compared with mice fed a standard chow diet (CD). Hepatocyte-specific knockout of METTL3 in mice fed a HFD improved insulin sensitivity and decreased fatty acid synthesis. Furthermore, mechanism analysis demonstrates that METTL3 silence decreased the m6A methylated and total mRNA level of Fatty acid synthase (Fasn), subsequently inhibited fatty acid metabolism. Adeno-associated virus mediated Fasn overexpression in METTL3 knockout mice abrogates the improved insulin sensitivity and decreased fatty acid synthesis. Collectively, these results reveal that RNA N6-methyladenosine methylase METTL3 inhibits hepatic insulin sensitivity via N6-methylation of Fasn mRNA and promoting fatty acid metabolism.

18.
ACS Appl Mater Interfaces ; 11(33): 29985-29992, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31364834

RESUMO

Prussian blue analogs (PBAs) with stable framework structures are ideal cathodes for rechargeable sodium-ion batteries. The chelating agent-assisted coprecipitate method is an effective way to obtain low-defect PBAs that can limit the appearance of too many vacancies and water molecules and achieve an optimized Na-storage performance. However, for this method, the mechanism of chelating agent-assisted synthesis is still unclear. Herein, the synthesis process of nickel hexacyanoferrate (NiHCF) has been investigated by in situ infrared spectroscopy detection. The results show that the chelating agent oxalate slows down the nucleation process and effectively inhibits the formation of the Fe-C≡N-Ni frame in the aging process, producing highly crystallized and low-defect NiHCF samples. High-quality NiHCF presents a high specific capacity of 86.3 mAh g-1 (a theoretical value of ∼85 mAh g-1), an ultrastable cyclic retention of 90% over 800 cycles, and a remarkable high capacity retention of 74.6% at a current density of 4250 mA g-1 (50C). Particularly, the NiHCF//hard carbon full cell presents a high specific energy density of over 210 Wh kg-1 and an outstanding cyclic stability without obvious capacity attenuation over 1000 cycles.

19.
Aging (Albany NY) ; 11(16): 6503-6521, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31446433

RESUMO

Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan-Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all p<0.01). Genetic mutation of PLOD1/2/3 was present in ~3% of ccRCC patients and was associated with significantly poorer prognosis compared with expression of wild-type PLOD1/2/3 (p<0.001). This study thus identifies tumor expression of wild-type or mutated PLOD1/2/3 mRNA as a potential predictive biomarker for ccRCC patients and sheds light on the underlying molecular pathogenesis of ccRCC.

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