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1.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33804866

RESUMO

Most protein-coding genes in eukaryotes possess at least two poly(A) sites, and alternative polyadenylation is considered a contributing factor to transcriptomic and proteomic diversity. Following transcription, a nascent RNA usually undergoes capping, splicing, cleavage, and polyadenylation, resulting in a mature messenger RNA (mRNA); however, increasing evidence suggests that transcription and RNA processing are coupled. Plants, which must produce rapid responses to environmental changes because of their limited mobility, exhibit such coupling. In this review, we summarize recent advances in our understanding of the coupling of transcription with RNA processing in plants, and we describe the possible spatial environment and important proteins involved. Moreover, we describe how liquid-liquid phase separation, mediated by the C-terminal domain of RNA polymerase II and RNA processing factors with intrinsically disordered regions, enables efficient co-transcriptional mRNA processing in plants.

2.
J Genet Genomics ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832859

RESUMO

Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation. However, as mouse Cdk1 embryos die early, the role of CDK1 in regulating the cell cycle and embryo development remains unclear. Here, we showed that zebrafish cdk1-/- embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry, M phase progression, and cell differentiation but not in interkinetic nuclear migration. We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis. While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells, the depletion of cyclin B1 led to M phase arrest. Moreover, phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2 mutants, but not in ccnb1 mutants. Furthermore, overexpression of TOP2AS1213D, the phosphomimetic form of human TOP2A, rescued S phase entry and alleviated the microphthalmia defects in both cdk1-/- and ccna2-/- embryos. Taken together, our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression.

4.
Acta Pharmacol Sin ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767379

RESUMO

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.

5.
Int J Oncol ; 58(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760107

RESUMO

MicroRNAs (miRNAs/miRs) are a class of small non­coding RNAs that maintain the precise balance of various physiological processes through regulating the function of target mRNAs. Dysregulation of miRNAs is closely associated with various types of human cancer. miR­222­3p is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in tumor occurrence and progression. miR­222­3p in human biofluids, such as urine and plasma, may be a potential biomarker for the early diagnosis of tumors. In addition, miR­222­3p acts as a prognostic factor for the survival of patients with cancer. The present review first summarizes and discusses the role of miR­222­3p as a biomarker for diverse types of cancers, and then focuses on its essential roles in tumorigenesis, progression, metastasis and chemoresistance. Finally, the current understanding of the regulatory mechanisms of miR­222­3p at the molecular level are summarized. Overall, the current evidence highlights the crucial role of miR­222­3p in cancer diagnosis, prognosis and treatment.

6.
BMC Health Serv Res ; 21(1): 258, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743706

RESUMO

BACKGROUND: To investigate the impact of the US Medicaid expansion on care utilization and health outcomes of patients treated in the inpatient rehabilitation facilities (IRF). METHODS: A retrospective observational study with a difference-in-difference design. The data was obtained from Inpatient Rehabilitation Facility - Patient Assessment Instrument (IRF-PAI). Sample included all Medicaid beneficiaries (aged 18-64 years) who received initial inpatient rehabilitation for stroke, hip fracture (acute conditions), or joint replacement (elective condition) (N = 14,917) before (2013) and after (2016) the expansion. The study estimated the differences in length of stay, functional improvement, and possibility of returning to community before and after ACA Medicaid expansion in the expansion regions relative to the non-expansion regions. The analysis was fully adjusted for patient demographics, health conditions, facility characteristics and time trends. RESULTS: Compared with non-expansion states, service volume in the expansion regions increased more for the two acute conditions (49 and 27% vs. 1% and - 4%) and decreased less for the selective condition (- 12% vs. -34%) after ACA Medicaid expansion. Medicaid expansion was associated with significant decreases in patient functional improvements (- 1.63 points for stroke, - 3.61 points for fracture and - 2.73 points for joint; P < 0.05). Length of stay and the possibility of returning to community after discharge were not significantly different. CONCLUSIONS: Medicaid expansion was associated with increases in the utilization of inpatient rehabilitation services and decreases in the patient functional improvements. Cautions should be taken with the decreases in functional improvements among some subpopulation in the short-term; longer follow up periods are needed to account for gradual changes in patient needs.

7.
Nat Commun ; 12(1): 1812, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753739

RESUMO

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.


Assuntos
Carcinogênese/metabolismo , Hexoquinase/metabolismo , Mitocôndrias/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Docetaxel/farmacologia , Hexoquinase/genética , Humanos , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Ligação Proteica , Sumoilação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
BMJ Open ; 11(2): e043385, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579767

RESUMO

INTRODUCTION: Shared decision making is endorsed by guidelines for both acute kidney injury and critical care medicine. However, there is still a huge need for effective interventions, especially those focusing on decisions about renal replacement therapy for intensive care unit (ICU) patients with acute kidney injury. The decision aids provide evidence-based support for shared decision making, to achieve better decisions through enhanced knowledge of treatment options and treatment aligns with patients' preferences and values. Therefore, our objectives are to develop and evaluate a decision aid systematically and rigorously for family surrogate decision makers of ICU patients with acute kidney injury who need renal replacement therapy. METHODS AND ANALYSIS: We will use a systematic development process that focuses on user-centred design to develop and evaluate the decision aid in three phases: (1) development of a draft prototype for the decision aid based on extensive literature reviews, interviews with key stakeholders and evidence synthesis; (2) alpha testing ('near live' usability) the decision aid during simulated clinical encounters to test its comprehensibility, acceptability and usability and (3) beta testing ('live' usability) to examine the aid's clinical feasibility. User testing will be conducted using mixed-methods approach to support iterative revision of the decision aid. The IPDASi (V.4.0) will be used for following qualitative assessment. All interviews will be analysed by Colaizzi's seven-step approach to qualitative analysis. The coding scheme will use to analyse user interactions. Questionnaire surveys will be analysed using paired sample t-tests when related to the before-and-after survey, otherwise using one-sample t-test. ETHICS AND DISSEMINATION: Ethical approval for this research was obtained from the Ethics Committee of the First Affiliated Hospital of Army Medical University, PLA (Ref: KY2020104). All participants will sign a formal informed consent form. The findings will be published in peer-reviewed journals and reported in appropriate meetings. TRIAL REGISTRATION NUMBER: ChiCTR2000031613.

9.
J Med Virol ; 93(5): 3033-3046, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33538342

RESUMO

We primarily quantified exposure patterns, transmission characteristics, and the clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among household contacts of individuals with severe coronavirus disease-2019 (COVID-19). We conducted a retrospective cohort study of 20 index patients hospitalized with severe COVID-19 and 79 of their household contacts. We determined the transmission frequency, range of manifestations of SARS-CoV-2 infection, and factors associated with infection in household settings. Of the 79 household contacts, 53 (67%) developed SARS-CoV-2 infection (49 [62%] symptomatic, 4 [5%] asymptomatic). Eight patients (10%) developed severe COVID-19, and one died of COVID-19 pneumonia (case-fatality rate: 1.9%). The probability of SARS-CoV-2 infection was similar in children and adults (55% vs. 72%, p = .14), with children being less likely to develop the symptomatic disease (46% vs. 68%, p = .06). Handwashing ≥ 5 times/day was associated with reduced infection risk (52.8% vs. 76.9%, p = .04). SARS-CoV-2 has a high frequency of transmission among household contacts. Nonhospitalized individuals with SARS-CoV-2 infection should be quarantined in patient care facilities rather than at home to minimize spread, if possible, and frequent handwashing should be practiced to prevent transmission.

10.
Ying Yong Sheng Tai Xue Bao ; 32(1): 154-162, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33477223

RESUMO

Rational application of organic fertilizers is an effective approach to improve soil fertility, crop yield, and zero growth of chemical fertilizer in agricultural production. The rice variety 'Shennong9816' was planted in Shenyang, Liaoning Province, under seven different treatments: zero nitrogen fertilizer (CK), low nitrogen, 150 kg·hm-2(LN), medium nitrogen, 240 kg·hm-2 (MN), high nitrogen, 330 kg·hm-2(HN), medium nitrogen with replacement of chemical N by 10% organic manure (OMN10), medium nitrogen with replacement of chemical N by 20% organic manure (OMN20), and medium nitrogen with replacement of chemical N by 30% organic manure (OMN30). The effects of different treatments on photosynthetic rate, nitrogen absorption, nitrogen use efficiency, and yield were examined and the optimal fertilization scheme was determined. The results showed that the photosynthetic rate, biomass and yield were increased with the increases of nitrogen application rate, while the nitrogen use efficiency was decreased significantly. Compared with the MN treatment, the photosynthetic rate of OMN10 and OMN20 in filling stage was increased by 22.9% and 9.9%, respectively. The yield of OMN20 was increased by 3.8% compared to that of MN. The nitrogen agronomic efficiency and physiological efficiency of OMN20 were significantly improved by 8.1% and 13.3%, respectively. Moreover, the nitrogen agronomic efficiency and physiological efficiency of OMN20 were improved by 27.2% and 37.2% compared with the HN treatment. Thus, we concluded that the organic fertilizer replacement treatment could conserve soil fertility, achieve high yield and high nitrogen use efficiency, while reduce chemical nitrogen fertilizer application. The OMN20 treatment was recommended as a fertilizer application model due to its superior performance among the seven treatments.


Assuntos
Fertilizantes , Oryza , Agricultura , Esterco , Nitrogênio/análise , Solo
11.
Mikrochim Acta ; 188(1): 24, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33404755

RESUMO

A rolling circle amplification chemiluminescence immunoassay (RCA-CLIA) was developed for precise quantitation of Aß in plasma. Capture antibodies conjugated with magnetic beads and detection antibodies with collateral single-stranded DNA (ssDNA) were bound to Aß42/Aß40 antigens to form a typical double-antibody sandwich structure. The RCA reaction was triggered by the addition of ssDNA, which generated products with a large number of sites for the binding of acridinium ester (AE)-labeled detection probes, thereby realizing the purpose of the amplification. The RCA-CLIA method had higher sensitivity than conventional CLIA without loss of specificity. Under optimum conditions, the linear range of Aß42 and Aß40 detection was 3.9-140 pg/mL and 3.9-180 pg/mL, respectively, with corresponding low detection limits of 1.99 pg/mL and 3.14 pg/mL, respectively. Plasma Aß42 and Aß40 were detected in the blood of 21 AD patients and 22 healthy people, wherein this ratio could significantly distinguish AD patients from healthy individuals with a sensitivity of 90.48% and specificity of 63.64% for a cutoff value of 154. The Aß42/Aß40 ratio of plasma acts as an accurate indicator for AD diagnosis; therefore, detection of plasma Aß using the RCA-CLIA exhibits great potential in noninvasive diagnosis and progressive assessment of AD.

12.
Neurosurgery ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33475732

RESUMO

BACKGROUND: The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. OBJECTIVE: To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. METHODS: Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. RESULTS: End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. CONCLUSION: Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.

13.
Bioresour Technol ; 326: 124749, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33508644

RESUMO

The aim of this work was to study the bioaugmentation of hydrolysis acidification (HA) by a halophilic bacterial consortium. A bacterial consortium was enriched at 5% salinity, and it decolorized metanil yellow G (MYG) at salinities of 1%-15% and dye concentrations of 100-400 mg/L under static conditions. A HA system was constructed to assess the effectiveness of bioaugmentation by the halophilic bacterial consortium. The HA system showed obviously better performance for decolorization and CODMn removal and presented higher the 5-day biological oxygen demand (BOD5)/CODMn (B/C) ratio after bioaugmentation. MiSeq sequencing results indicated that the bacterial communities remarkably shifted and that the bacterial diversity was increased after bioaugmentation. Marinobacterium invaded the native microbe community and became the dominant bacterial genus in the bioaugmented HA, and it played a key role in azo dye decolorization. Therefore, bioaugmentation with a halophilic bacterial consortium improved the HA system for decolorization of azo compounds.


Assuntos
Corantes , Salinidade , Archaea , Compostos Azo , Biodegradação Ambiental
14.
Anal Chim Acta ; 1145: 46-51, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33453880

RESUMO

In this work, a facile ratiometric fluorescence sensor for GSH measurement was designed based on MnO2 nanosheet (NS), carbon dots (CDs), as well as a simple substrate o-phenylenediamine (OPD). Herein, MnO2 NS played triple essential roles in the sensing system. First, it could be reduced by GSH through a special reaction, and therefore served as GSH recognizer. Second, it played as a fluorescence nanoquencher to strongly quench the fluorescence of CDs. Third, it could directly oxidize OPD to yield a luminescent product 2, 3-diaminophenazine (DAP) via the intrinsic oxidase-like activity. It revealed that MnO2 NS could be reduced to Mn2+ in the presence of GSH. Thus its oxidase-like activity and fluorescence quenching abilities were inhibited, which then restricted the generation of DAP and recovered the fluorescence of CDs. Based on this phenomenon, a novel ratiometric fluorescence sensor for GSH determination was fabricated by measuring the ratio of fluorescent intensity of DAP to that of CDs. Besides, the constructed ratiometric fluorescent sensor, which could be facilely operated with single-wavelength excitation, exhibited high sensitivity and selectivity with a wider linear range and a lower detection limit.

15.
Int J Nanomedicine ; 16: 31-45, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33442248

RESUMO

Background: Dentin hypersensitivity (DH) is a common dental clinical condition presented with a short and sharp pain in response to physical and chemical stimuli. Currently no treatment regimen demonstrates long-lasting efficacy in treating DH, and unesthetic yellow tooth color is a concern to many patients with DH. Aim: To develop a bi-functional material which can occlude dentinal tubules in-depth and remineralize dentin for long-lasting protection of the dentin-pulp complex from stimuli and bleach the tooth at the same time. Methods: A mixture containing CaO, H3PO4, polyethylene glycol and H2O2 at a specific ratio was mechanically ground using a planetary ball. The mineralizing complex paste was characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Dentin was exposed to the synthesized paste for 8 h and 24 h in vitro. The mineralizing property was evaluated using SEM and microhardness tests. Red tea-stained tooth slices were exposed to the synthesized paste for 8 h and 24 h in vitro. The bleaching effect was characterized by a spectrophotometer. Results: The complex paste had very a fine texture, was injectable, and had a gel-like property with 2.6 (mass/volume) % H2O2 concentration. The X-ray diffraction pattern showed that the inorganic phase was mainly monetite (CaHPO4). The mineralizing complex paste induced the growth of inorganic crystals on the dentin surface and in-depth occlusion of dentin tubules by up to 80 µm. The regenerated crystals were integrated into the dentin tissue on the dentin surface and the wall of dentinal tubules with a microhardness of up to 126 MPa (versus 137 Mpa for dentin). The paste also bleached the stained dental slices. Conclusion: The mineralizing complex paste is a promising innovative material for efficient DH management by remineralizing dentin and in-depth occlusion of dentin tubules, as well as tooth bleaching.


Assuntos
Fosfatos de Cálcio/farmacologia , Ácidos Fosfóricos/farmacologia , Clareamento Dental , Dentina/efeitos dos fármacos , Dentina/ultraestrutura , Dureza , Humanos , Peróxido de Hidrogênio/análise , Remineralização Dentária , Difração de Raios X
16.
J Environ Sci (China) ; 99: 100-109, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33183687

RESUMO

In this study, different carbon quantum dots (CQDs)/NaBiO3 hybrid materials were synthesized as photocatalysts to effectively utilize visible light for the photocatalytic degradation of contaminants effectively. These hybrid materials exhibit an enhanced photocatalytic reduction of hexavalent chromium (Cr(VI)) in the aqueous medium. Zero-dimensional nanoparticles of CQDs were embedded within the two-dimensional NaBiO3 nanosheets by the hydrothermal process. Compared with that of the pure NaBiO3 nanosheets, the photocatalytic performance of the hybrid catalysts was significantly high and 6 wt.% CQDs/NaBiO3 catalyst exhibited better photocatalytic performance. We performed the first-principles density functional theory calculations to study the interfacial properties of pure NaBiO3 nanosheets and hybrid photocatalysts, and confirmed the CQDs played an important role in the CQDs/NaBiO3 composites. The experimental results indicated that the enhanced reduction of Cr(VI) was probably due to the high loading of CQDs (electron acceptor) on NaBiO3, which made NaBiO3 nanomaterials to respond in visible light and significantly improved their electron-hole separation efficiency.


Assuntos
Pontos Quânticos , Carbono , Cromo , Luz
17.
Diabetes Res Clin Pract ; 172: 108645, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33359751

RESUMO

The microbiome is greatly significant for immune system development and homeostasis. Dysbiosis in gut microbial composition and function is linked to immune responses and the development of metabolic diseases, including diabetes mellitus (DM). However, skin microbiome changes in diabetic patients and their role in DM are poorly elucidated. In this review, we summarize recent findings about the association between the gut and skin microbiota and DM, highlighting their roles in the proinflammatory status of DM. Moreover, although there is evidence that the connection between the gut and skin causes the same activated innate immune response, additional studies are needed to explore the mechanism. These findings might inform future DM prevention, diagnosis and treatment.

18.
Phytomedicine ; 80: 153374, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33075645

RESUMO

BACKGROUND: Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities. PURPOSE: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo. METHODS: We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and 14C-urate uptake assays. To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds. RESULTS: BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC50 values of 30.17 ± 8.68 µM and 31.56 ± 1.37 µM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1. CONCLUSION: These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity.


Assuntos
Flavanonas/farmacologia , Hiperuricemia/tratamento farmacológico , Ácido Úrico/urina , Xantina Oxidase/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Flavanonas/química , Flavanonas/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Células HEK293 , Humanos , Hiperuricemia/induzido quimicamente , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/química , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Ácido Úrico/sangue
19.
Biomed Pharmacother ; 133: 111048, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378955

RESUMO

Subarachnoid hemorrhage (SAH) is an acute and severe disease with high disability and mortality. Inflammatory reactions have been proven to occur throughout SAH. Extracellular vesicles derived from mesenchymal stem cells (MSCs-EVs) have shown broad potential for the treatment of brain dysfunction and neuroprotective effects through neurogenesis and angiogenesis after stroke. However, the mechanisms of EVs in neuroinflammation during the acute phase of SAH are not well known. Our present study was designed to investigate the effects of MSCs-EVs on neuroinflammation and the polarization regulation of microglia to the M2 phenotype and related signaling pathways after SAH in rats. The SAH model was induced by an improved method of intravascular perforation, and MSCs-EVs were injected via the tail vein. Post-SAH assessments included neurobehavioral tests as well as brain water content, immunohistochemistry, PCR and Western blot analyses. Our results showed that MSCs-EVs alleviated the expression of inflammatory cytokines in the parietal cortex and hippocampus 24 h and 48 h after SAH and that MSCs-EVs inhibited NF-κB and activated AMPK to reduce inflammation after SAH. Furthermore, MSC-EVs regulated the polarization of microglia toward the M2 phenotype by downregulating interleukin-1ß, cluster of differentiation 16, cluster of differentiation 11b, and inducible nitric oxide synthase and upregulating the expression of cluster of differentiation 206 and arginase-1. Additionally, MSCs-EVs inhibited the neuroinflammatory response and had neuroprotective effects in the brain tissues of rats after SAH. This study may support their use as a potential treatment strategy for early SAH in the future.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Encéfalo/enzimologia , Vesículas Extracelulares/transplante , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Microglia/enzimologia , NF-kappa B/metabolismo , Hemorragia Subaracnóidea/cirurgia , Animais , Encéfalo/patologia , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Vesículas Extracelulares/enzimologia , Masculino , Células-Tronco Mesenquimais/enzimologia , Microglia/patologia , Fenótipo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Hemorragia Subaracnóidea/enzimologia , Hemorragia Subaracnóidea/patologia
20.
Biomed Res Int ; 2020: 4746929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33294444

RESUMO

Background: S100 family genes exclusively encode at least 20 calcium-binding proteins, which possess a wide spectrum of intracellular and extracellular functions in vertebrates. Multiple lines of evidences suggest that dysregulated S100 proteins are associated with human malignancies including colorectal cancer (CRC). However, the diverse expression patterns and prognostic roles of distinct S100 genes in CRC have not been fully elucidated. Methods: In the current study, we analyzed the mRNA expression levels of S100 family genes and proteins and their associations with the survival of CRC patients using the Oncomine analysis and GEPIA databases. Expressions and mutations of S100 family genes were analyzed using the cBioPortal, and protein-protein interaction (PPI) networks of S100 proteins and their mutation-related coexpressed genes were analyzed using STRING and Cytoscape. Results: We observed that the mRNA expression levels of S100A2, S100A3, S100A9, S100A11, and S100P were higher and the level of S100B was lower in CRC tissues than those in normal colon mucosa. A high S100A10 levels was associated with advanced-stage CRC. Results from GEPIA database showed that highly expressed S100A1 was correlated with worse overall survival (OS) and disease-free survival (DFS) and that overexpressions of S100A2 and S100A11 were associated with poor DFS of CRC, indicating that S100A1, S100A2, and S100A11 are potential prognostic markers. Unexpectedly, most of S100 family genes showed no significant prognostic values in CRC. Conclusions: Our findings, though still need to be ascertained, offer novel insights into the prognostic implications of the S100 family in CRC and will inspire more clinical trials to explore potential S100-targeted inhibitors for the treatment of CRC.

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