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1.
Adv Exp Med Biol ; 1280: 201-218, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33791984

RESUMEN

Nuclear magnetic resonance (NMR) spectroscopy offers reproducible quantitative analysis and structural identification of metabolites in various complex biological samples, such as biofluids (plasma, serum, and urine), cells, tissue extracts, and even intact organs. Therefore, NMR-based metabolomics, a mainstream metabolomic platform, has been extensively applied in many research fields, including pharmacology, toxicology, pathophysiology, nutritional intervention, disease diagnosis/prognosis, and microbiology. In particular, NMR-based metabolomics has been successfully used for cancer research to investigate cancer metabolism and identify biomarker and therapeutic targets. This chapter highlights the innovations and challenges of NMR-based metabolomics platform and its applications in cancer research.


Asunto(s)
Líquidos Corporales , Neoplasias , Biomarcadores , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Metabolómica
2.
Infect Genet Evol ; : 104831, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33798758

RESUMEN

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused global pandemic with alarming speed, comprehensively analyzing the mutation and evolution of early SARS-CoV-2 strains contributes to detect and prevent such virus. Here, we explored 1962 high-quality genomes of early SARS-CoV-2 strains obtained from 42 countries before April 2020. The changing trends of genetic variations in SARS-CoV-2 strains over time and country were subsequently identified. In addition, viral genotype mapping and phylogenetic analysis were performed to identify the variation features of SARS-CoV-2. Results showed that 57.89% of genetic variations involved in ORF1ab, most of which (68.85%) were nonsynonymous. Haplotype maps and phylogenetic tree analysis showed that amino acid variations in ORF1ab (p.5828P > L and p.5865Y > C, also NSP13: P504L and NSP13: Y541C) were the important characteristics of such clade. Furthermore, these variants showed more significant aggregation in the United States (P = 2.92E-66, 95%) than in Australia or Canada, especially in strains from Washington State (P = 1.56E-23, 77.65%). Further analysis demonstrated that the report date of the variants was associated with the date of increased infections and the date of recovery and fatality rate change in the United States. More importantly, the fatality rate in Washington State was higher (4.13%) and showed poorer outcomes (P = 4.12E-21 in fatality rate, P = 3.64E-29 in death and recovered cases) than found in other states containing a small proportion of strains with such variants. Using sequence alignment, we found that variations at the 504 and 541 sites had functional effects on NSP13. In this study, we comprehensively analyzed genetic variations in SARS-CoV-2, gaining insights into amino acid variations in ORF1ab and COVID-19 outcomes.

3.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806315

RESUMEN

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague-Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.

4.
Chemosphere ; 278: 130413, 2021 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-33823349

RESUMEN

The study was based on the removal of nitrate and sulfide, and aimed to nitrite accumulation. The process of autotrophic denitrification driven by sulfide as an electron donor was investigated in a sequencing batch reactor. The research showed that autotrophic denitrification successfully started on day 22, and the removal rates of NO3--N and S2--S were 95.8% and 100%, respectively, when the S/N molar ratio was 1.45. When the S/N ratio was reduced to 0.94, the phenomenon of NO2--N accumulation was observed. NO2--N continuously accumulated, and the maximum accumulation rate was 55.3% when the S/N ratio was 0.8. In the batch test, the study showed that NO2--N accumulation was optimal when the S/N ratio was 0.8, and the NO2--N concentration increased with increasing NO3--N concentration at the same S/N ratio. Microbial communities also changed based on the high-throughput analysis, and Proteobacteria (59.5%-84%) was the main phylum. Arenimonas (11.4%-28.2%) and uncultured_f_ Chromatiaceae (5.7%-27.5%) were the dominant bacteria, which complete denitrification and desulfurization throughout the operating system. Therefore, this study provided a theoretical basis for the simultaneous removal of NO3--N and S2--S, as well as the accumulation of nitrite, and provided material support for anaerobic ammonia oxidation technology.

5.
Sci Rep ; 11(1): 6993, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772068

RESUMEN

The low proportion of gastric cancer (GC) patients with high HER2 expression limits the clinical application of trastuzumab, a humanized epidermal growth factor receptor 2 (HER2) antibody targeting for GC treatment. We found that Dicer was positively correlated with HER2 expression in GC tissue by immunostaining as well as induce HER2 overexpression without increasing invasiveness of GC cell. In addition, both the growth of GC referring to cell proliferation, invasion, migration and apoptosis was inhibited by Dicer overexpression. Moreover, the HER2 overexpression induced by Dicer provided more effective and additive target for trastuzumab to amplify the inhibition effect for GC cells in vitro and in vivo. Furthermore, as assessed in a subsequent experiment, calcitriol induced HER2 overexpression and amplified the inhibition effect of trastuzumab in GC cells referring to proliferation. Our finding demonstrated the calcitriol might increase indication of trastuzumab by inducing HER2 overexpression in GC patients. Dicer would be a potential target that extend the clinical indications of HER2 antibody in patients with low or negative HER2, who were not fit for HER2 antibody treatment before.

6.
Dev Dyn ; 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772937

RESUMEN

BACKGROUND: Mutation in Odontogenesis-associated phosphoprotein (ODAPH) has been reported to cause recessive hypomineralized amelogenesis imperfecta (AI) in human. However, the exact role of ODAPH in amelogenesis is still unknown. RESULTS: ODAPH was identified as a novel constituent of the atypical basal lamina located at the interface between maturation ameloblasts and the enamel by dual immunofluorescence staining of ODAPH and LAMC2. Odaph knockout mice were generated to explore the function of ODAPH in amelogenesis. Odaph-/- mice teeth showed severely attrition and reduced enamel mineralization. Histological analysis showed from transition or early-maturation stage, ameloblasts were rapidly shortened, lost cell polarity, and exhibited cell pathology. Abundant enamel matrix marked by amelogenin was retained. Temporary cyst-like structures were formed between flattened epithelial cells and the enamel from maturation stage to eruption. The integrity of the atypical basal lamina was impaired indicated by the reduced diffuse expression of LAMC2 and AMTN. The expression of maturation stage related genes of Amtn, Klk4, Integrinß6 and Slc24a4 were significantly decreased. CONCLUSIONS: Our results suggested Odaph played vital roles during amelogenesis by maintaining the integrity of the atypical basal lamina in maturation stage, which may contribute to a better understanding of the pathophysiology of human AI.

7.
J Gynecol Obstet Hum Reprod ; 50(8): 102121, 2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33746078

RESUMEN

PURPOSE: To evaluate the efficacy of additional treatment with hydroxychloroquine (HCQ) for pregnant women with persistent positive antiphospholipid antibodies or antiphospholipid antibody syndrome (APS). METHOD: We conducted a systematic search of the PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases from inception to 31th December 2019. Two authors performed study selection, data collection, and data analysis independently. RESULT: Five retrospective studies involving 477 pregnancies were selected. The live birth rate was significantly improved in the experimental group (OR, 3.29; 95 % CI, 1.45-7.49; P = 0.004). Additionally, pregnancy loss was associated with the additional use of HCQ (OR, 0.30;95 % CI, 0.13-0.69; P = 0.004). However, HCQ had no significant association with preterm delivery (OR, 0.43; 95 % CI, 0.13-1.37; P = 0.16) and fetal growth restriction showed an OR of 0.22 (95 % CI, 0.13-1.88; P = 0.55). CONCLUSION: These data suggest that receiving HCQ as an additional treatment can improve the live birth rate in pregnant women with persistent antiphospholipid antibodies.

8.
FASEB J ; 35(4): e21326, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33710666

RESUMEN

Histone modifications play critical roles in DNA damage repair to safeguard genome integrity. However, how different histone modifiers coordinate to build appropriate chromatin context for DNA damage repair is largely unknown. Here, we report a novel interplay between the histone methyltransferase KMT5A and two E3 ligases RNF8 and RNF168 in establishing the histone modification status for DNA damage repair. KMT5A is a newly identified substrate of RNF8 in vitro and in vivo. In response to DNA double-strand breaks (DSBs), RNF8 promotes KMT5A recruitment onto damaged chromatin in a ubiquitination-dependent manner. RNF8-induced KMT5A ubiquitination increases the binding capacity of KMT5A to RNF168. Interestingly, KMT5A not only drives a local increase in H4K20 monomethylation at DSBs, but also promotes RNF168's activity in catalyzing H2A ubiquitination. We proved that the interaction between the H2A acidic patch and KMT5A R188/R189 residues is critical for KMT5A-mediated regulation of H2A ubiquitination. Taken together, our results highlight a new role for KMT5A in linking H4K20 methylation and H2A ubiquitination and provide insight into the histone modification network during DNA damage repair.

9.
Neurosci Lett ; 750: 135810, 2021 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-33705929

RESUMEN

Although clinical efficacy of waggle needling has been confirmed, therapeutic mechanisms still remain poorly understood. Reduction of GABA was involved in the etiology of spasticity. Recently, accumulated evidences suggest that the inhibitory effect of GABA is determined by low intracellular chloride concentration, which is predominantly mediated by KCC2. This study was designed to investigate whether KCC2-GABAA pathway was involved in the mechanism underlying acupuncture intervention in rats with middle cerebral artery occlusion (MCAO). Three days after modeling, the rats received waggle needling, routine needling and placebo needling for 7 consecutive days. After treatment, the muscle spasticity, motor function and infarct volumes were tested. KCC2 and GABAAγ2 levels were detected via western blotting, RT-PCR and immunofluorescence. KCC2 antagonist and agonist were administered after the last intervention. We found that acupuncture, particularly waggle needling, could remarkably alleviate muscle spasticity, reverse motor deficits and reduce cerebral infraction in MCAO rats, possibly due to its effects on up-regulating expressions of KCC2 and GABAAγ2 in the cortical infarct regions. However, the effects were blocked by KCC2 antagonist. In summary, this study suggests that improvements in muscle spasticity and motor function induced by waggle needling correlates with the activation of KCC2-GABAA pathway.

10.
Artículo en Inglés | MEDLINE | ID: mdl-33774759

RESUMEN

A facultatively anaerobic bacterium, strain M1531T, was isolated from a red alga (Porphyra) at coastal water in Weihai, China. Cells of the novel strain were Gram-stain-negative, rod-shaped, motile by means of a single polar flagellum and around 0.6-0.8 × 2.0-3.0 µm in size. Optimum growth occurred at 30 °C, with 2% (w/v) NaCl and at pH 6.5-7.0. On the basis of the result of phylogenetic analysis of the 16S rRNA gene sequence, stain M1531T had close relative with Thalassotalea euphylliae KCTC 42743T (96.9%). Genome sequencing revealed a genome size of 4,061,950 bp, a G + C content of 39.1 mol% and four protein-coding genes related to the degradation of alginate. According to the data obtained, strain M1531T shared ANI value below 95-96%, dDDH value below 23.8% with the closely related type species. Strain M1531T had Q-8 as the predominant isoprenoid quinone and possessed Summed Features 3 (C16:1 ω7c/C16:1 ω6c), C16:0 and Summed Features 8 (C18:1 ω7c/C18:1 ω6c) as the major fatty acids. The polar lipids of strain M1531T were identified as phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid, one unidentified aminolipid and four unidentified lipids. According to the results of the phenotypic, chemotaxonomic characterization, phylogenetic properties and genome analysis, strain M1531T represents a novel specie of the genus Thalassotalea, for which the name Thalassotalea algicola sp. nov. is proposed. The type strain is M1531T (= MCCC 1H00400T = KCTC 72865T).

11.
Scand J Caring Sci ; 2021 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-33778974

RESUMEN

BACKGROUND: Researchers have identified several factors that correlate with the caring behaviours of formal caregivers in long-term care facilities (LTCFs). However, a limited range of socio-demographic factors has been discussed, and no studies have discussed the combined effects of the institutional characteristics of the LTCF and the personal characteristics (i.e. bio-psycho-socio-spiritual attributes) of the formal caregiver on the caring behaviour. AIM: The aim of this study was to examine caring behaviours of formal caregivers for older residents of LTCFs and to explore factors that explain and predict the caring behaviours of them. METHODS: A valid sample of 224 formal caregivers (nurses and nurse aids) employed at 56 LTCFs (21 nursing homes and 35 assisted living facilities) was analysed. Hierarchical regression analysis with two-tailed significance test was used to investigate whether the caring behaviours of the caregivers were independently associated with the characteristics of the caregivers or the institutions. FINDINGS: Caring behaviours of the formal caregivers had significant positive associations with their job satisfaction (ß = 0.152, p < 0.05) and with their perceived satisfaction of LTCF residents (ß  = 0.214, p < 0.001).The organisational-level analysis revealed that caring behaviours had positive associations with accreditation level (ß = 0.163, p < 0.01) and with nurse-aid staffing level (ß = 0.126, p < 0.05). Additionally, the caring behaviour had positive associations with their attitude towards older adults (ß  = 0.193, p < 0.01) and with their self-transcendence (ß  = 0.184, p < 0.01). These two factors explained 42.2% of the variance in the caring behaviours of caregivers. CONCLUSION AND IMPLICATIONS: Caring behaviours were related to both personal characteristics (attributes, mindset) and organisational characteristics. By clarifying factors in the caring behaviours of caregivers, this study provides information that LTCFs can use to develop strategies for managing their caregivers and that policymakers can use to establish and implement healthcare policies for older populations.

12.
BMC Surg ; 21(1): 137, 2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731072

RESUMEN

BACKGROUND: To analyze whether neoadjuvant chemoradiotherapy (nCRT) could improve the survival for patients with adenocarcinoma of the esophagogastric junction compared with neoadjuvant chemotherapy (nCT). Both neoadjuvant chemotherapy alone and chemoradiotherapy before surgery have been shown to improve overall long-term survival for patients with adenocarcinoma in the esophagus or esophagogastric junction compared to surgery alone. It remains controversial whether nCRT is superior to nCT. METHODS: 170 Patients with locally advanced (cT3-4NxM0) Siewert II and III adenocarcinoma of the esophagogastric junction (AEG) were treated with neoadjuvant chemotherapy consisting of capecitabine plus oxaliplatin with or without concurrent radiotherapy in the Fourth Hospital of Hebei Medical University. Intensity-modulated radiation therapy (IMRT) was used and delivered in 5 daily fractions of 1.8 Gy per week for 5 weeks (total dose of PTV: 45 Gy). 120 Patients were included in the propensity score matching (PSM) analysis to compare the effects of nCRT with nCT on survival. RESULTS: With a median follow-up of 41.2 months for patients alive after propensity score matching analysis, the 1- and 3-year OS were 84.8%, 55.0% in nCRT group and 78.3%, 38.3% in nCT group (P = 0.040; HR = 1.65, 95% CI 1.02-2.69). The 1- and 3-year PFS were 84.9%, 49.2% in nCRT group and 68.3%, 29.0% in nCT group (P = 0.010; HR = 1.80, 95% CI 1.14-2.85). The pathological complete response (pCR) was 17.0% in nCRT group and 1.9% in nCT group (P = 0.030). No significant difference was observed in postoperative complications between the two groups. CONCLUSION: The nCRT confers a better survival with improved R0 resection rate and pCR rate compared with nCT for the patients with locally advanced AEG.


Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Neoplasias Esofágicas/terapia , Terapia Neoadyuvante/métodos , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Puntaje de Propensión , Tasa de Supervivencia
13.
Int J Oral Sci ; 13(1): 12, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33762576

RESUMEN

As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.

14.
J Mol Histol ; 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33763807

RESUMEN

Junctional epithelium (JE) attaching to the enamel surface seals gaps around the teeth, functioning as the first line of gingival defense. Runt-related transcription factor 2 (Runx2) plays a role in epithelial cell fate, and the deficiency of Runx2 in JE causes periodontal destruction, while its effect on the barrier function of JE remains largely unexplored. In the present study, hematoxylin-eosin (H&E) staining revealed the morphological differences of JE between wild-type (WT) and Runx2 conditional knockout (cKO) mice. We speculated that these changes were related to the down-regulation of E-cadherin (E-cad), junctional adhesion molecule 1 (JAM1), and integrin ß6 (ITGB6) in JE. Moreover, immunohistochemistry (IHC) was conducted to assess the expressions of these proteins. To verify the relationship between Runx2 and the three above-mentioned proteins, human gingival epithelial cells (HGEs) were cultured for in vitro experiment. The expression of Runx2 in HEGs was depleted by lentivirus. Quantitative real-time PCR (qRT-PCR) and Western blotting analysis were adopted to analyze the differences in mRNA and protein expressions. Taken together, Runx2 played a crucial role in maintaining the structure and function integrality of JE via regulating the expressions of E-cad and JAM1.

15.
CNS Neurosci Ther ; 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33764684

RESUMEN

AIMS: The basal forebrain (BF) plays an essential role in wakefulness and cognition. Two subtypes of BF gamma-aminobutyric acid (GABA) neurons, including somatostatin-expressing (GABASOM ) and parvalbumin-positive (GABAParv ) neurons, function differently in mediating the natural sleep-wake cycle. Since the loss of consciousness induced by general anesthesia and the natural sleep-wake cycle probably share similar mechanisms, it is important to clarify the accurate roles of these neurons in general anesthesia procedure. METHODS: Based on two transgenic mouse lines expressing SOM-IRES-Cre and PV-IRES-Cre, we used a combination of genetic activation, inactivation, and chronic ablation approaches to further explore the behavioral and electroencephalography (EEG) roles of BFSOM and BFParv neurons in general anesthesia. After a single intravenous injection of propofol and the induction and recovery times of isoflurane anesthesia, the anesthesia time was compared. The changes in cortical EEG under different conditions were also compared. RESULTS: Activation of BF GABASOM neurons facilitates both the propofol and isoflurane anesthesia, manifesting as a longer anesthesia duration time with propofol anesthesia and a fast induction time and longer recovery time with isoflurane anesthesia. Moreover, BF GABASOM -activated mice displayed a greater suppression of cortical electrical activity during anesthesia, showing an increase in δ power bands or a simultaneous decrease in high-frequency power bands. However, only a limited and nuanced effect on propofol and isoflurane anesthesia was observed with the manipulated BF GABAParv neurons. CONCLUSIONS: Our results suggested that BF GABASOM neurons play a critical role in propofol and isoflurane general anesthesia, while BF GABAParv neurons appeared to have little effect.

16.
Nanotechnology ; 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33765668

RESUMEN

Low-viscosity UV-curable resins are widely used in industry as they allow for UV curing materials with reduced amounts of reactive diluents to adjust the viscosity. But their mechanical properties and waterproof performance after curing as UV coatings still need to be improved. Here, a series of low-viscosity bio-based UV-curable polyester methacrylates were synthesized through L-lactide (LA) and ε-caprolactone (CL) monomers. The results show that the introduction of star-shaped structure and random copolymerization of LA and CL can effectively reduce the viscosity of the resin to 313 mPa·s and at the same time increase the double bond conversion rate and maintain good mechanical properties. The composite resin was prepared by blending the star-shaped low-viscosity polyester methacrylate resin with cellulose nanocrystals (CNCs), and the microstructure was characterized by XRD and TEM. The curing kinetics, mechanical properties, thermal properties and waterproof properties of the composite resin were further tested. When the mass fraction of CNCs is 2.5 wt %, the water absorption rate of the pine samples coated with UV-cured composite resin is reduced to 17%, which is 65% lower than that of the uncoated samples and 20% lower than that of the samples coated with resin without CNC. This article provides a feasible and effective method for improving the mechanical properties and waterproof performance of low-viscosity UV-curing resins.

17.
Acta Pharmacol Sin ; 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767379

RESUMEN

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50 value of 2.08 ± 0.31 µM, which was similar to that of RDEA3170 (its IC50 value was 1.47 ± 0.23 µM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50 value of 91.55 ± 15.28 µM, whereas RDEA3170 at 100 µM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg-1 · d-1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg-1 · d-1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 µM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

18.
Small ; : e2007717, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33690967

RESUMEN

As a promising candidate for the high energy density cells, the practical application of lithium-metal batteries (LMBs) is still extremely hindered by the uncontrolled growth of lithium (Li) dendrites. Herein, a facile strategy is developed that enables dendrite-free Li deposition by coating highly-lithiophilic amorphous SiO microparticles combined with high-binding polyacrylate acid (SiO@PAA) on polyethylene separators. A lithiated SiO and PAA (lithiated-SiO/PAA) protective layer with synergistic flexible and robust features is formed on the Li metal anode via the in situ reaction to offer outstanding interfacial stability during long-term cycles. By suppressing the formation of dead Li and random Li deposition, reducing the side reaction, and buffering the volume changes during the lithium deposition and dissolution, such a protective layer realizes a dendrite-free morphology of Li metal anode. Furthermore, sufficient ionic conductivity, uniform lithium-ion flux, and interface adaptability is guaranteed by the lithiated-SiO and Li polyacrylate acid. As a result, Li metal anodes display significantly enhanced cycling stability and coulombic efficiency in Li||Li and Cu||Li cells. When the composite separator is applied in a full cell with a carbonate-based electrolyte and LiNi0.8 Mn0.1 Co0.1 O2 cathode, it exhibits three times longer lifespan than control cell at current density of 5 C.

19.
Genetics ; 217(1): 1-16, 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33683366

RESUMEN

To regenerate, damaged tissue must heal the wound, regrow to the proper size, replace the correct cell types, and return to the normal gene-expression program. However, the mechanisms that temporally and spatially control the activation or repression of important genes during regeneration are not fully understood. To determine the role that chromatin modifiers play in regulating gene expression after tissue damage, we induced ablation in Drosophila melanogaster imaginal wing discs, and screened for chromatin regulators that are required for epithelial tissue regeneration. Here, we show that many of these genes are indeed important for promoting or constraining regeneration. Specifically, the two SWI/SNF chromatin-remodeling complexes play distinct roles in regulating different aspects of regeneration. The PBAP complex regulates regenerative growth and developmental timing, and is required for the expression of JNK signaling targets and the growth promoter Myc. By contrast, the BAP complex ensures correct patterning and cell fate by stabilizing the expression of the posterior gene engrailed. Thus, both SWI/SNF complexes are essential for proper gene expression during tissue regeneration, but they play distinct roles in regulating growth and cell fate.

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