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1.
Talanta ; 236: 122867, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34635249

RESUMO

Carcinoembryonic antigen (CEA) is one of the most widely used tumor marker around the world, it mainly used for gastrointestinal cancers, especially in colorectal malignancy. At present, the detection methods of CEA are mostly based on antigen-antibody binding, whereas these methods were limited by the high costs and long waiting times in massive population tumor screening. During the experiments, we interestingly found that the fluorescence signal would be dramatically altered when the secondary structure of fluorescent modified guanine-rich DNA changed. Then we explored the reasons and established a new method for CEA detection, this method brings a simple, fast and cheap sensing platform for detection of biomarkers. It has great potential in screening of tumors among the group and is expected to provide prospective effects for tumor treatment.


Assuntos
Aptâmeros de Nucleotídeos , Neoplasias Colorretais , Antígeno Carcinoembrionário , Neoplasias Colorretais/diagnóstico , Fluorescência , Guanina , Humanos
2.
Anal Chem ; 93(46): 15445-15451, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34775754

RESUMO

Albeit with low content, 5-formyluracil has been an important modification in genomic DNA. 5-formyluracil was found to be widely distributed among living bodies. Due to the equilibrium of keto-enol form, 5-formyluracil could be base-paired with guanine, thus inducing mutations in DNA. The highly reactive aldehyde group of 5-formyluracil could also cross-link with proteins nearby, preventing gene replication and expression. In certain cancerous tissues, the content of 5-formyluracil was found to be higher than the normal tissues adjacent to the tumor, and 5-formyluracil might be an important potential epigenetic mark. Nevertheless, the lack of a higher resolution sequencing technique has hampered the studies of 5-formyluracil. We adjusted the base-pairing of 5-formyluracil during the PCR amplification by changing the pH. Hence, we adopted the Alkaline Modulated 5-formyluracil Sequencing (AMfU-Seq), a single-base resolution analysis method, to profile 5-formyluracil at the genome scale. We analyzed the distribution of 5-formyluracil in the human thyroid carcinoma cells using AMfU-Seq. This technique can be used in the future investigations of 5-formyluracil.


Assuntos
DNA , Uracila , DNA/genética , Genômica , Guanina , Humanos , Uracila/análogos & derivados
3.
PLoS One ; 16(10): e0258229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34610052

RESUMO

BACKGROUND/AIMS: We measured the association between underlying chronic hepatitis B (CHB) and antiviral use with infection rates among patients who underwent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. METHODS: In total, 204,418 patients who were tested for SARS-CoV-2 between January and June 2020 were included. For each case patient (n = 7,723) with a positive SARS-CoV-2 test, random controls (n = 46,231) were selected from the target population who had been exposed to someone with coronavirus disease 2019 (COVID-19) but had a negative SARS-CoV-2 test result. We merged claim-based data from the Korean National Health Insurance Service database collected. Primary endpoints were SARS-CoV-2 infection and severe clinical outcomes of COVID-19. RESULTS: The proportion of underlying CHB was lower in COVID-19 positive patients (n = 267, 3.5%) than in COVID-19 negative controls (n = 2482, 5.4%). Underlying CHB was associated with a lower SARS-CoV-2 positivity rate, after adjusting for comorbidities (adjusted odds ratio [aOR] 0.65; 95% confidence interval [CI], 0.57-0.74). Among patients with confirmed COVID-19, underlying CHB tended to confer a 66% greater risk of severe clinical outcomes of COVID-19, although this value was statistically insignificant. Antiviral treatment including tenofovir and entecavir was associated with a reduced SARS-CoV-2 positivity rate (aOR 0.49; 95% CI, 0.37-0.66), while treatment was not associated with severe clinical outcomes of COVID-19. CONCLUSIONS: Underlying CHB and antiviral agents including tenofovir decreased susceptibility to SARS-CoV-2 infection. HBV coinfection did not increase the risk of disease severity or lead to a worse prognosis in COVID-19.


Assuntos
COVID-19/patologia , Hepatite B Crônica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/virologia , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Factuais , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , República da Coreia/epidemiologia , Risco , Índice de Gravidade de Doença , Tenofovir/uso terapêutico , Adulto Jovem
4.
Zhonghua Gan Zang Bing Za Zhi ; 29(9): 830-836, 2021 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-34638200

RESUMO

Objective: To mine the signals of adverse drug reaction (ADR) of entecavir and tenofovir by using the US FDA Adverse Event Reporting System (FAERS) database, so as to provide reference for the safe clinical use of these two drugs. Methods: Reporting odds ratio (ROR) and proportion of report ratio (PRR) method were used to conduct data mining on the 26 quarterly reports of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 to the first quarter of 2019. The ADR descriptive terminology in the report were standardized by using the World Health Organization Adverse Reaction Terminology (System-Organ Class). ROR and PRR methods common signals were screened. Results: 104 and 187 signals of ADR of entecavir and tenofovir dipivoxil were obtained by ROR and PRR methods. The main screened system-organ classes affected by signals of ADR of entecavir were systemic damage, hepatobiliary system damage, and urinary system damage. The main screened system-organ classes affected by signals of ADR of tenofovir were urinary system damage, skeletal and musculoskeletal system damage, and metabolic and nutritional disorders. Conclusion: The mining signals of adverse drug reaction of entecavir and tenofovir dipivoxil indicate that these two drugs can cause female reproductive system damage, fetal abnormalities, neonatal and infant abnormalities, and male reproductive system damage. However, in addition to the above-mentioned ADR, the ADR instruction manual excludes entecavir and tenofovir dipivoxil primarily for respiratory and visual system damage, and the tenofovir disoproxil primarily for skin and appendage damage, and hearing and vestibular function damage. Therefore, in clinical medication management, it is suggested to pay close attention to the choice of drugs for special population infected with HBV, monitor possible ADR during medication course, and provide pharmacological monitoring to achieve personalized medication.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Guanina/análogos & derivados , Humanos , Recém-Nascido , Masculino , Tenofovir/efeitos adversos , Estados Unidos/epidemiologia , United States Food and Drug Administration
5.
Phys Chem Chem Phys ; 23(34): 19043-19053, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612442

RESUMO

Reaction pathway of prebiotic reactions for formation of the pteridines: pterin, xanthopterine, isoxanthopterine and leucopterine, as well as the purine nucleobase guanine from pure formamide are presented. In these reactions, formamide or its tautomer, formimidic acid, play the role of proton-carrying catalyst. All required raw materials, such as hydrogen cyanide, ammonia, water, formic acid, urea, 2-aminomalononitrile, glyoxal, glyoxylic acid and oxalic acid needed in the self-catalyzed reactions are obtained by partial decomposition of formamide. We show that the prebiotic formation of nucleobases and pterins is closely linked and they probably coexisted at the beginning of chemical evolution.


Assuntos
Formamidas/química , Guanina/síntese química , Prebióticos , Pterinas/síntese química , Catálise , Teoria da Densidade Funcional , Evolução Química , Guanina/química , Pterinas/química , Temperatura
6.
Medicine (Baltimore) ; 100(39): e27417, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596169

RESUMO

ABSTRACT: This study evaluated the clinical implications of hepatitis B surface antigen quantification (qHBs Ag) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) and identified the association between qHBs Ag and the risk of hepatocellular carcinoma (HCC) in these patients.Between January 2007 and December 2018, the qHBs Ag and clinical data of 183 CHB patients who initially received ETV (n = 45, 24.6%) or TDF (n = 138, 75.4%) were analyzed.The mean follow-up period of the 183 CHB patients was 45.3 months, of which 59 (32.2%) patients showed a reduction in qHBs Ag by >50% after 1 year of antiviral treatment (ETV or TDF). The HCC development (P = .179) or qHBs Ag reduction (P = .524) were similar in the ETV and TDF groups. Patients with a ≥50% decrease in qHBs Ag had a significantly lower incidence of HCC or decompensated cirrhosis complications (P = .005). Multivariate analysis showed that a >50% reduction of qHBs Ag (hazard ratio 0.085, P = .018) and the presence of cirrhosis (hazard ratio 3.32, P = .016) were independent factors predicting the development of HCC.Patients whose qHBs Ag value decreased >50% at 1 year after antiviral treatment for CHB showed a significant decrease in HCC or decompensated cirrhosis events. A reduction in qHBs Ag could be used as a predictive factor of HCC development or critical complications in CHB patients treated with TDF or ETV.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco
7.
Anal Chim Acta ; 1183: 338977, 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34627517

RESUMO

Water contamination due to heavy metal ions has become a major environmental problem worldwide. In this work, "on-off-on" fluorescence switches comprising N,S-doped carbon dots (N,S-CDs) have been developed for selective recognition of Hg2+ and as reversive probes for guanine. N,S-CDs were synthesized in a facile one-step hydrothermal approach using citric acid and methionine as precursors. The synthesized N,S-CDs display fluorescence with excitation/emission maxima of 370/440 nm and a quantum yield of 32.5%. Under the variable pH (2-12), the fluorescent N,S-CDs with a linear range from 0.05 to 100 µM displayed selective discrimination for Hg2+ with the limit of 6.24 nM over several other cations, anions, and neutral analytes resulting in the quenching of fluorescence response. Furthermore, the addition of guanine at the LOD of 6.4 nM can restore N,S-CDs' fluorescence in a reversible manner. For this kind of fluorescence switch, its purposed applications on environmental samples are employed successfully to detect Hg2+ in tap water and river water.


Assuntos
Mercúrio , Pontos Quânticos , Carbono , Guanina , Nitrogênio , Espectrometria de Fluorescência
8.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(4): 529-536, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34704414

RESUMO

: To establish a high performance liquid chromatography method to simultaneously quantify eight related substances in entecavir film-coated tablets.According to USP40 and YBH33292005 standards, a high performance liquid chromatography (HPLC) method for simultaneous determination of 8 related substance in entecavir film-coated tablets was established and validated. The column was WATERS C18 (250 mm the mobile phase A was water-acetonitrile-trifluoroacetic acid (990∶10∶1), the mobile phase B was water-acetonitrile-trifluoroacetic acid (700∶300∶1) with gradient elution and ultraviolet-visible light detector, detection wavelength at 254 nm and column temperature of The resolution between entecavir and each impurity peak was more than 1.5, and each impurity had a good linear relationship with the peak area in the linear range. The limits of detection and quantification, precision, stability, durability, specificity, met the verification requirements. The HPLC method established in this study can be used for simultaneous determination of 8 related substance in entecavir film-coated tablets.


Assuntos
Guanina , Cromatografia Líquida de Alta Pressão , Guanina/análogos & derivados , Reprodutibilidade dos Testes , Comprimidos
9.
ACS Chem Biol ; 16(9): 1663-1670, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34478263

RESUMO

Many pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid, are potent immunostimulatory molecules and promote the expression of cyclooxygenase 2 (COX-2). While the production of COX-2, and ultimately prostaglandin E2, could be protective, persistent induction of COX-2 leads to inflamed environments that can result in septic shock and death. Bacterial derived cyclic dinucleotides (CDNs), c-di-GMP and c-di-AMP, are also PAMPs and have been shown to produce inflamed environments via the production of pro-inflammatory cytokines such as type I interferons. The well-characterized CDN immunostimulatory mechanism involves binding to stimulator of interferon genes (STING), which ultimately results in the phosphorylation of IRF3 or release of NF-κB to promote expression of type I IFN or pro-inflammatory cytokines. In this study, we sought to investigate if CDNs promote COX-2 expression. Using RAW macrophages as a model system, we reveal that c-di-GMP, but not c-di-AMP or the host-derived 2',3'-cGAMP, promotes COX-2 expression. Using analogues of CDNs, we show that the presence of two guanines and two 3',5'-phosphodiester linkages are requirements for the promotion of COX-2 expression by cyclic dinucleotides. Both c-di-GMP and LPS inductions of COX-2 expression in RAW macrophages are STING-independent and are regulated by Tpl2-MEK-ERK-CREB signaling; inhibitors of Tpl2, MEK, and ERK could attenuate COX-2 expression promoted by c-di-GMP. This work adds to the growing body of evidence that cyclic dinucleotides regulate pathways other than the STING-TBK1-IRF3 axis. Additionally, the differential COX-2 induction by c-di-GMP but not c-di-AMP or cGAMP suggests that the type and level of inflammation could be dictated by the nucleotide signature of the invading pathogen.


Assuntos
GMP Cíclico/análogos & derivados , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Macrófagos/metabolismo , Animais , Proteína Beclina-1/metabolismo , Linhagem Celular , GMP Cíclico/metabolismo , Fosfatos de Dinucleosídeos/metabolismo , Regulação da Expressão Gênica , Guanina/metabolismo , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Camundongos , NF-kappa B/metabolismo , Oligonucleotídeos/metabolismo , Fosforilação , Prostaglandinas/metabolismo , Transdução de Sinais
10.
Analyst ; 146(19): 5866-5872, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570847

RESUMO

DNA-tuned dye assemblies have received considerable attention toward developing various devices. Owing to easy conformation implementation, G-quadruplexes (G4s) have been extensively used as initiators to grow dye assemblies with controllable chiralities. However, programmed chirality regulation of dye assemblies for a given G4 sequence has not been realized in a straightforward manner. In this work, we replaced a middle guanine in the G-tracts of a human telomeric G4 with an apurinic site (AP site) to meet the programmed dye assemblies. Although all of the AP site replacements altered the G4 conformation from the hybrid to the antiparallel folding, the handedness of pinacyanol (PIN) assemblies grown on the AP site-containing G4 was programmably regulated. The G4 with the AP site at the 5'-most G-tract grew right-handed assemblies, while that with the AP site at the 3'-most G-tract grew left-handed assemblies. The handedness of assemblies almost totally mirrored each other within 450-700 nm. Interestingly, we found that the AP site provided a specific binding site for guanosine and guanine, and this binding event sensitively broke the chiral assemblies. Thus, dye assembly-based sensors can be easily established based on the chiral responses with a high selectivity and sensitivity. Our work first demonstrates the AP site programmed chirality regulation of G4-grown dye assemblies and will find wide application in chiral devices.


Assuntos
Quadruplex G , DNA , Guanina , Guanosina , Humanos , Telômero
11.
Anal Methods ; 13(39): 4614-4622, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34528637

RESUMO

Global DNA methylation and hydroxymethylation play an important role in gene expression. They can be connected with several diseases. The modification status could be a biomarker to determine the status of disease. A fast, easy and accurate liquid chromatography - tandem mass spectrometry method has been developed for the precise quantitation of 5-methylcytosine and 5-hydroxymethylcytosine. Formic acid was used for the hydrolysis of the DNA strand resulting in nucleobases. These polar hydrolysis products were separated on a normal phase column using reversed phase eluents in inverse gradient mode. Multiple reaction monitoring was applied to achieve high selectivity and sensitivity for the quantitation. A new relative quantitation model was developed by using guanine, as an internal standard, present in samples. The new method was successfully validated with excellent accuracy and precision values in the range of 0.005-0.5% for 5hmC and 1-15% for 5mC. The main advantages of this quantitation method are that, due to relative quantitation, calibration curves can be used without reacquiring the calibration points and no additional isotope labeled internal standards are required. The method was tested to identify the concentrations of 5mC and 5hmC in various sample types. The lowest level of DNA sample required in the case of 0.005% 5hmC is 0.5 µg.


Assuntos
Metilação de DNA , Guanina , Cromatografia Líquida , DNA , Espectrometria de Massas em Tandem
12.
Talanta ; 235: 122777, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517634

RESUMO

DNA G-quadruplexes (G4s) formed by guanine(G)-rich sequences show diversity of structural topologies. The detection of structural details is of great significance for understanding of their functions and for the target drug design, but is very challenging. Herein, we demonstrate that the surface-enhanced Raman spectroscopy (SERS) via Ag IANPs as substrates is able to identify the numbers of Adenine (A) located on the G-quartet of the G4s. Eight G4s are selected for SERS studies. Besides the detection of series of characteristic bands indicating the formation of G4s, the intensity of the band represented A base ring breath (νA, ~733 cm-1) is observed particularly enhanced when there are A bases coplanar with G-quartet, and which is higher than the intensity of the band corresponding to G base ring breath (νG, ~655 cm-1). Furthermore, the band intensity ratio of νA to νG versus the ratio of the numbers of A on the plane to the sum of numbers of A and G shows very good linear relationship. Thus, based on the band intensities of νA to νG and their ratio in the SERS spectrum, the G-quadruplexes with or without a coplanar A base and numbers of A bases on the plane of G-quartet can be facilely identified. The method is simple, fast, low cost and sensitive to provide particular details of the structure in aqueous solution, therefore, implies widespread applications.


Assuntos
Quadruplex G , Análise Espectral Raman , Adenina , Guanina
13.
BMC Infect Dis ; 21(1): 912, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488678

RESUMO

BACKGROUND: Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue. METHODS: Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups. RESULTS: The rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups. CONCLUSIONS: TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.


Assuntos
Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Farmacorresistência Viral/genética , Quimioterapia Combinada , Guanina/análogos & derivados , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Lamivudina/uso terapêutico , Resultado do Tratamento , Carga Viral
14.
J Phys Chem A ; 125(37): 8196-8204, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34516113

RESUMO

According to the Löwdin model [ Rev. Mod. Phys. 1963, 35, 724-732], the Watson-Crick guanine-cytosine (G-C) base pair is tautomerized (G*-C*) with a small probability and then replication of G*-C* produces G*-thymine (T) and adenine (A)-C* base pairs. On the basis of this model and our previous work [ J. Phys. Chem. B 2020, 124, 1715-1722], we first calculated the intrinsic reaction coordinates from G*-T to G-T* using density functional theory and evaluated the probability of G*-T tautomerization to G-T* by double proton transfer (DPT) on the basis of the transition state theory. Similarly, we calculated the probability of A-C* tautomerization to A*-C by DPT. Then, according to these probabilities, we calculated the probability of transition mutations from G-C to A-T after 2 replications. The calculated probability was 1.31 × 10-8, a value consistent with the mutation rate previously reported by Drake et al. [ Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7160-7164]. Our results suggest that DPT is one cause of the G-C → A-T transition. To investigate differences in the optical properties between G*-T and G-T* and between A-C* and A*-C, we also evaluated the infrared absorption spectra and Raman intensities for these base pairs.


Assuntos
Adenina/química , Citosina/química , Guanina/química , Prótons , Timina/química , Pareamento de Bases , Teoria da Densidade Funcional , Cinética
15.
Nutrients ; 13(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34371907

RESUMO

The effect of coffee and cocoa on oxidative damage to macromolecules has been investigated in several studies, often with controversial results. This study aimed to investigate the effect of one-month consumption of different doses of coffee or cocoa-based products containing coffee on markers of DNA damage and lipid peroxidation in young healthy volunteers. Twenty-one volunteers were randomly assigned into a three-arm, crossover, randomized trial. Subjects were assigned to consume one of the three following treatments: one cup of espresso coffee/day (1C), three cups of espresso coffee/day (3C), and one cup of espresso coffee plus two cocoa-based products containing coffee (PC) twice per day for 1 month. At the end of each treatment, blood samples were collected for the analysis of endogenous and H2O2-induced DNA damage and DNA oxidation catabolites, while urines were used for the analysis of oxylipins. On the whole, four DNA catabolites (cyclic guanosine monophosphate (cGMP), 8-OH-2'-deoxy-guanosine, 8-OH-guanine, and 8-NO2-cGMP) were detected in plasma samples following the one-month intervention. No significant modulation of DNA and lipid damage markers was documented among groups, apart from an effect of time for DNA strand breaks and some markers of lipid peroxidation. In conclusion, the consumption of coffee and cocoa-based confectionery containing coffee was apparently not able to affect oxidative stress markers. More studies are encouraged to better explain the findings obtained and to understand the impact of different dosages of these products on specific target groups.


Assuntos
Biomarcadores/sangue , Chocolate , Café , Dano ao DNA , Peroxidação de Lipídeos , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina/sangue , Chocolate/efeitos adversos , Cromatografia Líquida de Alta Pressão , Café/efeitos adversos , Ensaio Cometa , Estudos Cross-Over , GMP Cíclico/análogos & derivados , GMP Cíclico/sangue , Feminino , Guanina/análogos & derivados , Guanina/sangue , Humanos , Masculino , Espectrometria de Massas em Tandem , Adulto Jovem
16.
Sci Rep ; 11(1): 16251, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376738

RESUMO

Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives-didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen (A5) and other from the substituent attached to nitrogen of imidazole ring (A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Biologia Computacional/métodos , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos/métodos , Guanina/química , Neoplasias/tratamento farmacológico , Descoberta de Drogas , Humanos , Estrutura Molecular , Neoplasias/patologia
17.
Free Radic Biol Med ; 174: 321-328, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34339797

RESUMO

Pterin (Ptr) is a model photosensitizer that acts mainly through type I mechanism and is able to photoinduce the one-electron oxidation of purine and pyrimidine nucleobases. However, under anaerobic conditions Ptr reacts with thymine (T) to form photoadducts (Ptr-T) but does not lead to the photodegradation of guanine (G), which is the nucleobase with the lowest ionization potential. Accordingly, G is thermodynamically able to reduce the radicals of the other nucleobases and has been described in this sense as the "hole sink" of the DNA double helix. Here we analyze by steady-state and time-resolved studies the effect of G in the anaerobic photosensitization of T by Ptr, using nucleotides and oligonucleotides of different sequences. We demonstrated that G is able to reduce T radicals but does not prevent the formation of Ptr-T adducts. Our results suggest that after the encounter between the excited Ptr and T, and completion of the electron transfer step, part of the radicals escape from the solvent cage, to further react with other species. However, a proportion of radicals do not escape and evolve to photoadducts before separation. We provide new evidence that contributes to understand the photosensitizing properties of Ptr in the absence of O2, the mechanism of formation of photoadducts in the DNA and the protective role of G towards the photodamage in other nucleobases.


Assuntos
Pterinas , Timina , Anaerobiose , Guanina , Oxirredução
18.
Can J Gastroenterol Hepatol ; 2021: 3259833, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422709

RESUMO

Aim: Hepatitis B virus (HBV) infection is a major public health concern worldwide. Entecavir (ETV), a first-line nucleos(t)ide analogue (NA) for HBV, has a low risk of resistance. We evaluated the efficacy of ETV monotherapy, ratio of ETV-resistant, and the clinical features of patients with ETV resistance. Methods: A total of 130 patients (72 males, 58 females; mean age, 61 ± 15 years) were divided into a NA-naïve group (n = 108) and NA-experienced group (n = 22). We examined the clinical outcomes of ETV monotherapy and associated factors. We also assessed the clinical features of 15 patients with resistance to ETV (mean, 51.0 ± 27.4 weeks). Results: Among the 130 patients, 94.1% achieved ALT normalization and 63.6% achieved serum HBV DNA negativity after ETV monotherapy for 96 weeks. Of the patients in the NA-naïve group, 93.1% and 60.4% achieved ALT normalization and HBV DNA negativity, respectively. Of the patients in the NA-experienced group, 100% and 74.9% achieved ALT normalization and HBV DNA negativity, respectively. Compared to patients on ETV continuously, 15 ETV-resistant patients had a higher baseline HBV viral load. There was a significant difference in the time to HBV DNA negativity, but not ALT normalization after ETV monotherapy in these groups. Rescue treatment with other NAs led to ALT normalization in all of these patients, but not HBV DNA negativity. Conclusions: ETV monotherapy has a long-term clinical efficacy. While some patients especially with HBV DNA high viral load developed ETV resistance, rescue treatment led to ALT normalization in these patients.


Assuntos
Hepatite B Crônica , Idoso , Antivirais/uso terapêutico , DNA Viral , Farmacorresistência Viral/genética , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
19.
J Phys Chem Lett ; 12(34): 8309-8313, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34428044

RESUMO

Guanine quadruplexes are four-stranded DNA/RNA structures composed of a guanine core (vertically stacked guanine tetrads) and peripheral groups (dangling ends and/or loops). Such a dual structural arrangement of the nucleobases favors their photoionization at energies significantly lower than the guanine ionization potential. This effect is important with respect to the oxidative DNA damage and for applications in the field of optoelectronics. Photoionization quantum yields, determined at 266 nm by nanosecond transient absorption spectroscopy, strongly depend on both the type and position of the peripheral nucleobases. The highest value (1.5 × 10-2) is found for the tetramolecular structure (AG4A)4 in which adenines are intermittently stacked on the adjacent guanine tetrads, as determined by nuclear magnetic resonance spectroscopy. Quantum chemistry calculations show that peripheral nucleobases interfere in a key step preceding electron ejection: charge separation, initiated by the population of charge transfer states during the relaxation of electronic excited states.


Assuntos
Quadruplex G , Guanina/química , Raios Ultravioleta , Modelos Moleculares , Teoria Quântica
20.
PLoS One ; 16(8): e0253216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34379627

RESUMO

Growing evidence suggests that human gut bacteria, which comprise the microbiome, are linked to several neurodegenerative disorders. An imbalance in the bacterial population in the gut of Parkinson's disease (PD) and Alzheimer's disease (AD) patients has been detected in several studies. This dysbiosis very likely decreases or increases microbiome-derived molecules that are protective or detrimental, respectively, to the human body and those changes are communicated to the brain through the so-called 'gut-brain-axis'. The microbiome-derived molecule queuine is a hypermodified nucleobase enriched in the brain and is exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position (position 34) of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation. Queuine depletion leads to protein misfolding and activation of the endoplasmic reticulum stress and unfolded protein response pathways in mice and human cells. Protein aggregation and mitochondrial impairment are often associated with neural dysfunction and neurodegeneration. To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects that lead to proteinopathy, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. After neurons were pretreated with STL-101 we observed a significant decrease in hyperphosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model of synucleinopathy, as well as a decrease in tau hyperphosphorylation in an acute and a chronic model of AD. Additionally, an associated increase in neuronal survival was found in cells pretreated with STL-101 in both AD models as well as in a neurotoxic model of PD. Measurement of queuine in the plasma of 180 neurologically healthy individuals suggests that healthy humans maintain protective levels of queuine. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Guanina/análogos & derivados , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ratos Wistar , alfa-Sinucleína/metabolismo
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