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1.
PLoS One ; 17(5): e0267855, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35511922

RESUMO

Most of the AML patients in remission develop multidrug resistance after the first-line therapy and relapse. AML stem cells have gained attention for their chemoresistance potentials. Chemoresistance is a multifactorial process resulting from altered survival signaling pathways and apoptosis regulators such as MAPK, NF-κB activation and ROS production. We targeted the survival pathway p38 MAPK, NF-κB and ROS generation in human chemoresistant AML stem cell line KG1a, susceptible to enhance cell sensitivity to the chemotherapy drug 5-Fluorouridine, compared to the chemosensitive AML cell line HL60. After confirming the phenotypic characterization of KG1a and HL60 cells using flow cytometry and transcriptomic array analyses, cell treatment with the NF-κB inhibitor IKKVII resulted in a complete induction of apoptosis, and a few p38 MAPK inhibitor SB202190-treated cells underwent apoptosis. No change in the apoptosis status was observed in the ROS scavenger N-acetylcysteine-treated cells. The p38 MAPK pathway blockade enhanced the KG1a cell sensitivity to 5-Fluorouridine, which was associated with the upregulation of microribonucleic acid-(miR-)328-3p, as determined by the microarray-based miRNA transcriptomic analysis. The downregulation of the miR-210-5p in SB202190-treated KG1a cells exposed to FUrd was monitored using RT-qPCR. The miR-328-3p is known for the enhancement of cancer cell chemosensitivity and apoptosis induction, and the downregulation of miR-210-5p is found in AML patients in complete remission. In conclusion, we highlighted the key role of the p38 MAPK survival pathway in the chemoresistance capacity of the AML stem cells and potentially involved miRNAs, which may pave the way for the development of a new therapeutic strategy targeting survival signaling proteins and reduce the rate of AML relapse.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Apoptose , Linhagem Celular , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio , Recidiva , Células-Tronco/metabolismo , Uridina/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Nucleic Acids Res ; 50(9): 5299-5312, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35524551

RESUMO

The essential pre-mRNA splicing factor U2AF2 (also called U2AF65) identifies polypyrimidine (Py) tract signals of nascent transcripts, despite length and sequence variations. Previous studies have shown that the U2AF2 RNA recognition motifs (RRM1 and RRM2) preferentially bind uridine-rich RNAs. Nonetheless, the specificity of the RRM1/RRM2 interface for the central Py tract nucleotide has yet to be investigated. We addressed this question by determining crystal structures of U2AF2 bound to a cytidine, guanosine, or adenosine at the central position of the Py tract, and compared U2AF2-bound uridine structures. Local movements of the RNA site accommodated the different nucleotides, whereas the polypeptide backbone remained similar among the structures. Accordingly, molecular dynamics simulations revealed flexible conformations of the central, U2AF2-bound nucleotide. The RNA binding affinities and splicing efficiencies of structure-guided mutants demonstrated that U2AF2 tolerates nucleotide substitutions at the central position of the Py tract. Moreover, enhanced UV-crosslinking and immunoprecipitation of endogenous U2AF2 in human erythroleukemia cells showed uridine-sensitive binding sites, with lower sequence conservation at the central nucleotide positions of otherwise uridine-rich, U2AF2-bound splice sites. Altogether, these results highlight the importance of RNA flexibility for protein recognition and take a step towards relating splice site motifs to pre-mRNA splicing efficiencies.


Assuntos
Nucleotídeos , Precursores de RNA , Humanos , Nucleotídeos/metabolismo , RNA/metabolismo , Precursores de RNA/metabolismo , Splicing de RNA , Fator de Processamento U2AF/metabolismo , Uridina/metabolismo
3.
Small ; 18(16): e2106269, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35266630

RESUMO

Exploring appropriate precursors has been proposed to be a promising strategy for the creation of artificial enzymes that are emerging as alternatives of natural enzymes. Herein, inspired by the catalytic activities of ribose nucleic acid, using ribonucleosides as precursors including adenosine, guanosine, cytidine, and uridine, respectively, four carbonic aggregates, namely, carbon dots (A-CDs, G-CDs, C-CDs, and U-CDs) to mimic artificial enzymes are synthesized. All the CDs show a planar graphene-like structure and thus can intercalatively bind with DNA double helix. Different from the other three CDs, the uridine-derived U-CDs exhibit unique catalytic property, which can mediate the topological transformation of DNA from supercoiled to nicked open-circular conformation. U-CDs can catalyze oxidation of O2 to generate singlet oxygen 1 O2 via a Haber-Weiss reaction, and consequently mediate oxidative cleavage of phosphate backbone in DNA and release the torsional energy stored in supercoiled DNA. Explorations reveal that the unique highly active oxygenated species, namely, quinone groups that are on the edge of U-CDs, play a key role in the catalytic production of 1 O2 . This work represents a new insight that using natural biomolecules in living systems as precursors can create new species beyond life.


Assuntos
Grafite , Pontos Quânticos , Ribonucleosídeos , Carbono/química , Catálise , Pontos Quânticos/química , Uridina
4.
Molecules ; 27(6)2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35335131

RESUMO

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraYAA transferase activity, and the most active compound with an original (S,S)-tartaric diamide linker inhibits MraY activity with an IC50 equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.


Assuntos
Diamida , Transferases , Proteínas de Bactérias/química , Simulação de Dinâmica Molecular , Transferases/química , Transferases (Outros Grupos de Fosfato Substituídos) , Uridina/química , Uridina/farmacologia
5.
Bioengineered ; 13(2): 3724-3738, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35105283

RESUMO

Aging has become an irreversible trend in the world, the health problems caused by aging cannot be ignored. The physiological functions of human body begin to decline with aging, the decline of gastrointestinal function caused by aging is an important problem that needs to be resolved. In this work, we evaluated the anti-aging effect of uridine in the senescent gastric epithelial cell model, and found that the aging level of gastric epithelial cell was significantly down-regulated by uridine treatment, uridine could obviously down-regulate the ratio of the SA-ß-gal-positive senescent cells. Furthermore, aging-related marker molecules (such as p16 and p21) were also significantly down-regulated under uridine treatment. Additionally, the levels of inflammation and oxidative stress were also significantly reduced by uridine treatment. Next, our further studies the effect of aging on FGF activity on gastric epithelial cell, and found that FGF/FGFR-mediated signaling pathways were significantly down-regulated. However, uridine treatment can not only alleviate the senescence of gastric epithelial cell, but also can partially restore the sensitivity of FGF signaling. Taken together, the current work indicates that uridine shows a good anti-aging effect, which lays a solid foundation for the related research in this filed.


Assuntos
Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Envelhecimento , Células Epiteliais , Fatores de Crescimento de Fibroblastos/farmacologia , Humanos , Uridina/farmacologia
6.
J Am Chem Soc ; 144(9): 3761-3765, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35224970

RESUMO

The Covid-19 pandemic highlights the urgent need for cost-effective processes to rapidly manufacture antiviral drugs at scale. Here we report a concise biocatalytic process for Molnupiravir, a nucleoside analogue recently approved as an orally available treatment for SARS-CoV-2. Key to the success of this process was the development of an efficient biocatalyst for the production of N-hydroxy-cytidine through evolutionary adaption of the hydrolytic enzyme cytidine deaminase. This engineered biocatalyst performs >85 000 turnovers in less than 3 h, operates at 180 g/L substrate loading, and benefits from in situ crystallization of the N-hydroxy-cytidine product (85% yield), which can be converted to Molnupiravir by a selective 5'-acylation using Novozym 435.


Assuntos
Antivirais , COVID-19/tratamento farmacológico , Citidina Desaminase/metabolismo , Citidina/análogos & derivados , SARS-CoV-2 , Biocatálise , Citidina/biossíntese , Citidina/metabolismo , Citidina Desaminase/genética , Escherichia coli/enzimologia , Escherichia coli/genética , Hidroxilaminas , Engenharia Metabólica , Engenharia de Proteínas , Uridina/metabolismo
7.
Cell Cycle ; 21(1): 33-48, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34974808

RESUMO

Osteoarthritis (OA) is a degenerative disease of extremely high incidence in the elderly. Therefore, anti-aging may be an important prerequisite for treating OA. The senescence of chondrocytes and mesenchymal stem cells (MSCs) is one of the important factors that causes OA. Here, the effect of uridine (which is a functional food derived from plants or animals) on senescence of chondrocytes and MSCs was evaluated in in vivo and in vitro experiments. For this, we established the senescence model of chondrocyte and MSCs in vitro, and established the OA model in vivo, and a series of experiments (such as CLSM, ELISA, Western blot, etc.) were conducted to evaluate the effect of uridine on chondrocyte and MSCs senescence. The results showed that uridine could alleviate chondrocyte and MSCs senescence in vitro by evaluating a series of aging markers. Furthermore, uridine could also relieve OA in vivo. In summary, in the present work, we found that uridine can alleviate chondrocyte and MSCs senescence in in vitro and in vivo experiments. Uridine has shown great potential in the treatment of OA in vivo, suggesting that uridine could be used to treat and prevent OA induced by aging, and has potential clinical applications in future.


Assuntos
Células-Tronco Mesenquimais , Osteoartrite , Envelhecimento , Animais , Senescência Celular , Condrócitos , Osteoartrite/terapia , Uridina/farmacologia
8.
J Immunol Methods ; 502: 113228, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35074315

RESUMO

Quantitative detection of T cell proliferation is an important readout in immunology research, as it is one of the hallmarks of T cell activation. Fluorescence-based methods for T cell proliferation mostly rely on the usage of probes that non-specifically conjugate to free primary amine groups in cells. Each cell division then results in a two-fold dilution of the probes which is detectable with flow cytometry. However, questions have been raised about cytotoxicity of these dilution-based T cell proliferation probes and they potentially affect T cell activation. An alternative assay relies on the incorporation of the uridine analog BrdU in the DNA of dividing T cells that can be detected with an antibody, but this requires harsh fixation and denaturation conditions. Recently, a new assay for detection of cell proliferation has been developed, based on the incorporation of the bioorthogonally-functionalized uridine analog 5-ethynyl-2'-deoxyuridine (EdU). Goal of this study was to compare the sensitivity and cytotoxicity of the EdU assay with a widely-used dilution-based T cell proliferation probe, CellTrace Far Red. We found that, compared to the dilution-based probe, the EdU-based assay better preserves T cell viability, is more sensitive for detecting T cell proliferation, and allows for better discernable interferon gamma responses.


Assuntos
Antineoplásicos , Desoxiuridina , Antineoplásicos/farmacologia , Bromodesoxiuridina/farmacologia , Proliferação de Células , Citometria de Fluxo/métodos , Coloração e Rotulagem , Linfócitos T/metabolismo , Uridina/farmacologia
9.
J Virol ; 96(5): e0208621, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-34985993

RESUMO

Coronavirus infections induce the expression of multiple proinflammatory cytokines and chemokines. We have previously shown that in cells infected with gammacoronavirus infectious bronchitis virus (IBV), interleukin 6 (IL-6), and IL-8 were drastically upregulated, and the MAP kinase p38 and the integrated stress response pathways were implicated in this process. In this study, we report that coronavirus infection activates a negative regulatory loop that restricts the upregulation of a number of proinflammatory genes. As revealed by the initial transcriptomic and subsequent validation analyses, the anti-inflammatory adenine-uridine (AU)-rich element (ARE)-binding protein, zinc finger protein 36 (ZFP36), and its related family members were upregulated in cells infected with IBV and three other coronaviruses, alphacoronaviruses porcine epidemic diarrhea virus (PEDV), human coronavirus 229E (HCoV-229E), and betacoronavirus HCoV-OC43, respectively. Characterization of the functional roles of ZFP36 during IBV infection demonstrated that ZFP36 promoted the degradation of transcripts coding for IL-6, IL-8, dual-specificity phosphatase 1 (DUSP1), prostaglandin-endoperoxide synthase 2 (PTGS2) and TNF-α-induced protein 3 (TNFAIP3), through binding to AREs in these transcripts. Consistently, knockdown and inhibition of JNK and p38 kinase activities reduced the expression of ZFP36, as well as the expression of IL-6 and IL-8. On the contrary, overexpression of mitogen-activated protein kinase kinase 3 (MKK3) and MAPKAP kinase-2 (MK2), the upstream and downstream kinases of p38, respectively, increased the expression of ZFP36 and decreased the expression of IL-8. Taken together, this study reveals an important regulatory role of the MKK3-p38-MK2-ZFP36 axis in coronavirus infection-induced proinflammatory response. IMPORTANCE Excessive and uncontrolled induction and release of proinflammatory cytokines and chemokines, the so-called cytokine release syndrome (CRS), would cause life-threatening complications and multiple organ failure in severe coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and COVID-19. This study reveals that coronavirus infection also induces the expression of ZFP36, an anti-inflammatory ARE-binding protein, promoting the degradation of ARE-containing transcripts coding for IL-6 and IL-8 as well as a number of other proteins related to inflammatory response. Furthermore, the p38 MAP kinase, its upstream kinase MKK3 and downstream kinase MK2 were shown to play a regulatory role in upregulation of ZFP36 during coronavirus infection cycles. This MKK3-p38-MK2-ZFP36 axis would constitute a potential therapeutic target for severe coronavirus infections.


Assuntos
Infecções por Coronavirus/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Tristetraprolina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adenina/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Humanos , Vírus da Bronquite Infecciosa/metabolismo , Vírus da Bronquite Infecciosa/patogenicidade , Interleucina-6/genética , Interleucina-8/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosforilação , Ativação Transcricional , Regulação para Cima , Uridina/metabolismo , Células Vero
10.
J Biomol Struct Dyn ; 40(8): 3668-3680, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33297848

RESUMO

Different esters were found potential against microorganisms, and could be a better choice to solve the multidrug resistant (MDR) pathogenic global issue due to their improved biological and pharmacokinetic properties. In this view, several 4-t-butylbenzoyl uridine esters 4-15 with different aliphatic and aromatic groups were synthesized for antimicrobial, physicochemical and biological studies. In vitro antimicrobial tests against nine bacteria and three fungi along with prediction of activity spectra for substances (PASS) indicated promising antifungal functionality of these uridine esters compared to the antibacterial activities. In support of this observation their cytotoxicity and molecular docking studies have been performed against lanosterol 14α-demethylase (CYP51A1) and Aspergillus flavus (1R51). Significant binding affinities were observed against SARS-CoV-2 main protease (7BQY) considering hydroxychloroquine (HCQ) as standard. ADMET predictions were investigated to evaluate their absorption, metabolism and toxic properties. Most of the uridine esters showed better results than that of the HCQ. Overall, the present study might be useful for the development of uridine-based novel MDR antimicrobial and COVID-19 drugs.


Assuntos
Anti-Infecciosos , COVID-19 , Antibacterianos , Anti-Infecciosos/química , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus , Ésteres/química , Ésteres/farmacologia , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases , SARS-CoV-2 , Uridina/farmacologia
11.
Chemistry ; 28(6): e202103667, 2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-34875113

RESUMO

N1 -Methylation of pseudouridine (m1 ψ) replaces uridine (Urd) in several therapeutics, including the Moderna and BioNTech-Pfizer COVID-19 vaccines. Importantly, however, it is currently unknown if exposure to electromagnetic radiation can affect the chemical integrity and intrinsic stability of m1 ψ. In this study, the photochemistry of m1 ψ is compared to that of uridine by using photoirradiation at 267 nm, steady-state spectroscopy, and quantum-chemical calculations. Furthermore, femtosecond transient absorption measurements are collected to delineate the electronic relaxation mechanisms for both nucleosides under physiologically relevant conditions. It is shown that m1 ψ exhibits a 12-fold longer 1 ππ* decay lifetime than uridine and a 5-fold higher fluorescence yield. Notably, however, the experimental results also demonstrate that most of the excited state population in both molecules decays back to the ground state in an ultrafast time scale and that m1 ψ is 6.7-fold more photostable than Urd following irradiation at 267 nm.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , SARS-CoV-2 , Uridina , Vacinas Sintéticas
12.
J Integr Plant Biol ; 64(1): 135-148, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34742166

RESUMO

Traditional upland rice generally exhibits insufficient grains resulting from abnormal endosperm development compared to paddy rice. However, the underlying molecular mechanism of this trait is poorly understood. Here, we cloned the uridine 5'-diphospho (UDP)-glucosyltransferase gene EDR1 (Endosperm Development in Rice) responsible for differential endosperm development between upland rice and paddy rice by performing quantitative trait loci analysis and map-based cloning. EDR1 was highly expressed in developing seeds during grain filling. Natural variations in EDR1 significantly reduced the UDP-glucosyltransferase activity of EDR1YZN compared to EDR1YD1 , resulting in abnormal endosperm development in the near-isogenic line, accompanied by insufficient grains and changes in grain quality. By analyzing the distribution of the two alleles EDR1YD1 and EDR1YZN among diverse paddy rice and upland rice varieties, we discovered that EDR1 was conserved in upland rice, but segregated in paddy rice. Further analyses of grain chalkiness in the alleles of EDR1YD1 and EDR1YZN varieties indicated that rice varieties harboring EDR1YZN and EDR1YD1 preferentially showed high chalkiness, and low chalkiness, respectively. Taken together, these results suggest that the UDP-glucosyltransferase gene EDR1 is an important determinant controlling differential endosperm development between upland rice and paddy rice.


Assuntos
Oryza , Alelos , Endosperma/genética , Glucosiltransferases/genética , Oryza/genética , Uridina
13.
Artigo em Inglês | MEDLINE | ID: mdl-34852733

RESUMO

Replacement of a U in an RNA duplex with a pseudouridine (Ψ), in general, stabilize the duplex because of the stronger stacking interaction, even concerning the wobble pair with G. The tRNA species specific to the AUA isoleucine codon in many eukaryotes have a Ψ at the first position of the anticodon. This tRNAIle would cause mistranslation if it could recognize the AUG codon through formation of a Ψ-G base pair. Here, I propose rationales for the minimal promotive effect of the U to Ψ modification on the mistranslation of the AUG codon.


Assuntos
Isoleucina , Pseudouridina , Anticódon/genética , Eucariotos , Uridina
14.
Mol Cell ; 82(2): 404-419.e9, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-34798057

RESUMO

The epitranscriptome has emerged as a new fundamental layer of control of gene expression. Nevertheless, the determination of the transcriptome-wide occupancy and function of RNA modifications remains challenging. Here we have developed Rho-seq, an integrated pipeline detecting a range of modifications through differential modification-dependent rhodamine labeling. Using Rho-seq, we confirm that the reduction of uridine to dihydrouridine (D) by the Dus reductase enzymes targets tRNAs in E. coli and fission yeast. We find that the D modification is also present on fission yeast mRNAs, particularly those encoding cytoskeleton-related proteins, which is supported by large-scale proteome analyses and ribosome profiling. We show that the α-tubulin encoding mRNA nda2 undergoes Dus3-dependent dihydrouridylation, which affects its translation. The absence of the modification on nda2 mRNA strongly impacts meiotic chromosome segregation, resulting in low gamete viability. Applying Rho-seq to human cells revealed that tubulin mRNA dihydrouridylation is evolutionarily conserved.


Assuntos
Segregação de Cromossomos , Escherichia coli/genética , Meiose , Processamento Pós-Transcricional do RNA , RNA Bacteriano/genética , RNA Fúngico/genética , RNA Mensageiro/genética , Schizosaccharomyces/genética , Uridina/metabolismo , Cromossomos Bacterianos , Cromossomos Fúngicos , Cromossomos Humanos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Evolução Molecular , Células HCT116 , Humanos , Oxirredução , RNA Bacteriano/metabolismo , RNA Fúngico/metabolismo , RNA Mensageiro/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/metabolismo , Análise de Sequência de RNA , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
15.
Adv Drug Deliv Rev ; 181: 114082, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34923029

RESUMO

Glioblastoma (GBM) is a malignant and aggressive brain tumor with a median survival of ∼15 months. Resistance to treatment arises from the extensive cellular and molecular heterogeneity in the three major components: glioma tumor cells, glioma stem cells, and tumor-associated microglia and macrophages. Within this triad, there is a complex network of intrinsic and secreted factors that promote classic hallmarks of cancer, including angiogenesis, resistance to cell death, proliferation, and immune evasion. A regulatory node connecting these diverse pathways is at the posttranscriptional level as mRNAs encoding many of the key drivers contain adenine- and uridine rich elements (ARE) in the 3' untranslated region. Human antigen R (HuR) binds to ARE-bearing mRNAs and is a major positive regulator at this level. This review focuses on basic concepts of ARE-mediated RNA regulation and how targeting HuR with small molecule inhibitors represents a plausible strategy for a multi-pronged therapeutic attack on GBM.


Assuntos
Adenina/metabolismo , Neoplasias Encefálicas/patologia , Proteína Semelhante a ELAV 1/metabolismo , Glioblastoma/patologia , Uridina/metabolismo , Humanos , Neovascularização Patológica , Interferência de RNA/fisiologia , RNA Mensageiro/metabolismo
16.
J Cell Mol Med ; 26(3): 840-854, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34970843

RESUMO

At present, liver fibrosis is a major challenge of global health. When hepatocyte regeneration cannot compensate for hepatocyte death, it will develop into liver fibrosis in chronic liver disease. Initially, collagen produced by myofibroblasts plays a role in maintaining liver integrity, but excessive collagen accumulation can inhibit the residual liver function, leading to liver failure. At present, many scientists are actively looking for drugs to alleviate liver fibrosis. In the current study, we investigated the potential role of uridine in the treatment of liver fibrosis (uridine is a plant/animal-derived pyrimidine nucleoside, therefore uridine can also be ingested and absorbed by the body, accompanied by the process of food intake). For this, we systematically studied the effect of uridine on CCl4-induced liver fibrosis in vitro and in vivo through a series of technologies, such as Western blot, laser confocal scanning microscope, ELISA and immunohistochemistry. The experimental results showed that uridine can effectively reduce the accumulation of collagen in liver. Furthermore, uridine can improve the activity of liver cells and alleviate CCl4-induced liver injury. Furthermore, uridine can significantly alleviate the risk factors caused by hepatic stellate cell activation, uridine treatment significantly down-regulated the expression of α-SMA, collagen type-I and fibronectin. In conclusion, the current research shows that uridine can alleviate CCl4-induced liver fibrosis, suggesting that uridine can be used as a potential drug to alleviate liver fibrosis.


Assuntos
Tetracloreto de Carbono , Células Estreladas do Fígado , Animais , Tetracloreto de Carbono/efeitos adversos , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Uridina/metabolismo , Uridina/farmacologia , Uridina/uso terapêutico
17.
Carbohydr Res ; 511: 108486, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34915327

RESUMO

TSAO-T and ATSAO-T analogues are molecules of interest that are able to inhibit the reverse transcriptase (RT) of HIV-1 and HCV. We also recently highlighted their antiproliferative properties. In all cases, the spiro cycle was a required group for biological activities, which led chemists to produce many derivatives, especially on this ring. These structures can be accessed through the formation of glycoaminonitriles and glycocyanhydrins using methodologies not always adapted to the synthesis of large quantities. Moreover, these latter are poorly versatile (substrate-dependent), need expensive cyanogenic agents and implies the use of a metal in non-catalytic amounts. For this reason, we report here a new metal-free methodology for the synthesis of glycoaminonitriles and glycocyanhydrins using molecular iodine (I2).


Assuntos
HIV-1 , Compostos de Espiro , Transcriptase Reversa do HIV/metabolismo , Inibidores da Transcriptase Reversa/química , Compostos de Espiro/química , Relação Estrutura-Atividade , Timidina/química , Uridina
18.
Genes Dev ; 36(1-2): 70-83, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34916304

RESUMO

Site-specific pseudouridylation of human ribosomal and spliceosomal RNAs is directed by H/ACA guide RNAs composed of two hairpins carrying internal pseudouridylation guide loops. The distal "antisense" sequences of the pseudouridylation loop base-pair with the target RNA to position two unpaired target nucleotides 5'-UN-3', including the 5' substrate U, under the base of the distal stem topping the guide loop. Therefore, each pseudouridylation loop is expected to direct synthesis of a single pseudouridine (Ψ) in the target sequence. However, in this study, genetic depletion and restoration and RNA mutational analyses demonstrate that at least four human H/ACA RNAs (SNORA53, SNORA57, SCARNA8, and SCARNA1) carry pseudouridylation loops supporting efficient and specific synthesis of two consecutive pseudouridines (ΨΨ or ΨNΨ) in the 28S (Ψ3747/Ψ3749), 18S (Ψ1045/Ψ1046), and U2 (Ψ43/Ψ44 and Ψ89/Ψ91) RNAs, respectively. In order to position two substrate Us for pseudouridylation, the dual guide loops form alternative base-pairing interactions with their target RNAs. This remarkable structural flexibility of dual pseudouridylation loops provides an unexpected versatility for RNA-directed pseudouridylation without compromising its efficiency and accuracy. Besides supporting synthesis of at least 6% of human ribosomal and spliceosomal Ψs, evidence indicates that dual pseudouridylation loops also participate in pseudouridylation of yeast and archaeal rRNAs.


Assuntos
Pseudouridina , RNA Guia , Humanos , Conformação de Ácido Nucleico , Pseudouridina/química , RNA/química , RNA Guia/química , RNA Guia/genética , RNA Ribossômico , Uridina
19.
Hematology Am Soc Hematol Educ Program ; 2021(1): 439-447, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34889435

RESUMO

Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Decitabina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Uridina/análogos & derivados , Administração Oral , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/farmacocinética , Decitabina/administração & dosagem , Decitabina/farmacocinética , Feminino , Humanos , Qualidade de Vida , Uridina/administração & dosagem , Uridina/farmacocinética , Uridina/uso terapêutico
20.
Molecules ; 26(24)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34946540

RESUMO

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics-generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from -4.6 ± 0.14 to -7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP-3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of -25.53 and -7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Acetatos/química , Acetatos/farmacologia , Antivirais/química , Antivirais/farmacologia , Citidina Difosfato Colina/química , Citidina Difosfato Colina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Uridina/análogos & derivados , Uridina/química , Uridina/farmacologia
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