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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(8): 1250-1255, 2022 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-36073226

RESUMO

OBJECTIVE: To investigate the value of HBV RNA for predicting the therapeutic effect of long-term entecavir (ETV) antiviral therapy in patients with chronic hepatitis B (CHB). METHODS: Serum samples were collected from 59 CHB patients treated with ETV for 96 or 108 months. HBV RNA levels, HBV DNA levels, and serological marker (HBeAg) levels were measured at baseline and 3, 6, 9, 12, 36, 72, and 96 (or 108) months during the therapy. RESULTS: Although HBV RNA level decreased after 12 and 36 months of ETV antiviral therapy, no significance changes occurred in HBV RNA negative conversion rate (P>0.05). After 72 months of treatment or longer, 33 patients had HBV RNA levels lower than 100 copies/mL, and among them 29 patients had HBV RNA levels lower than the detection limit, and HBV RNA negative conversion rate was statistically significant (P < 0.05). A lower HBV RNA level was associated with a higher HBeAg negative conversion rate (P < 0.05). Age and HBV RNA level were positively correlated with HBeAg negative conversion rate (P < 0.05). CONCLUSION: Prolonged ETV antiviral therapy results in better clearance of HBV RNA and a higher negative conversion rate in CHB patients. The length of antiviral therapy and age are positively correlated with the negative conversion rate of HBV RNA, and earlier administration of the antiviral treatment achieves better therapeutic effect. Serum HBV RNA level can be used as an indicator for predicting conversion to negative HBeAg in CHB patients receiving ETV therapy.


Assuntos
Antígenos E da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Guanina/análogos & derivados , Vírus da Hepatite B/genética , Humanos , RNA
2.
J Phys Chem B ; 126(37): 7077-7087, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36083211

RESUMO

The remarkable photostability of canonical nucleobases makes them ideal building blocks for DNA and RNA. Even minor structural changes are expected to lead to drastic alteration of their subpicosecond excited state lifetimes. However, it is interesting to note that while the 9H- and 7H-amino tautomers of adenine possess drastically different lifetimes, 9H- and 7H-keto guanine possess similar excited state lifetimes. With an aim to explain this unexpected difference in sensitivity of lifetimes to tautomerization, we have investigated the excited state relaxation mechanism of UV-excited adenine and guanine tautomers using surface hopping based nonadiabatic molecular dynamics. We find that internal conversion in both guanine tautomers is almost barrierless while both adenine tautomers encounter significant barriers before they can deactivate. Moreover, the major deactivation channel (C2-puckering) in 9H-amino adenine is overall more efficient than the one (C6-puckering) in the 7H-amino form. We trace this difference to the frequent rotation of the amino group which disrupts its conjugation with the heterocyclic ring thereby reducing the strength of nonadiabatic coupling and, hence, delaying internal conversion.


Assuntos
Adenina , Simulação de Dinâmica Molecular , Adenina/química , Guanina/química , RNA
3.
Biosens Bioelectron ; 216: 114660, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36099835

RESUMO

The overexpression of specific biomarkers in serum is closely related to diseases, and accurate and sensitive detection of them is beneficial for the early diagnosis and treatment of cancer. In this study, we developed a novel surface-enhanced Raman spectroscopy (SERS)-based aptasensor to detect the prostate-specific antigen biomarkers, consisting of total prostate-specific antigen (PSA) and free prostate-specific antigen (f-PSA). A composite structure containing arrays of polystyrene colloidal sphere @Ag shell (PS@Ag) was fabricated as a SERS-active chip. A complementary DNA probe (SH-DNA) and PSA aptamer (Apt) were immobilised stepwise on the chip, followed by the binding of a Raman reporter methylene blue (MB) to the guanine base of the aptamer. PSA-Apt recognition causes the release of MB-Apt and a decrease in the SERS intensity of MB on the chip, which correlates with the PSA concentration. The proposed biosensor has high spectral reproducibility, selectivity, and sensitivity and successfully determines the PSA levels in serum samples collected from prostate cancer patients, demonstrating great potential for clinical diagnosis.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Nanopartículas Metálicas , Neoplasias da Próstata , Aptâmeros de Nucleotídeos/química , Biomarcadores Tumorais , Técnicas Biossensoriais/métodos , DNA Complementar , Dimaprit/análogos & derivados , Ouro/química , Guanina , Humanos , Limite de Detecção , Masculino , Nanopartículas Metálicas/química , Azul de Metileno , Poliestirenos , Próstata , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico , Reprodutibilidade dos Testes , Análise Espectral Raman/métodos
4.
Acc Chem Res ; 55(18): 2628-2646, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36054116

RESUMO

ConspectusDNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important and have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular structures are stabilized by K+ or Na+ and form readily under physiological solution conditions. Moreover, G-quadruplexes are epigenetic features and can alter chromatin structure and function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand the structures and functions of DNA G-quadruplexes formed in key oncogene promoters and human telomeres and their interactions with small molecules. Using high-field NMR spectroscopy, we determined the high-resolution structures of physiologically relevant telomeric G-quadruplexes in K+ solution with a major form (hybrid-2) and a minor form (hybrid-1), as well as a two-tetrad intermediate. The intrinsic structural polymorphism of telomeric DNA may be important for the biology of human telomeres, and we proposed a model for the interconversion. More recently, we have worked on G-quadruplexes of MYC, BCL2, PDGFR-ß, VEGF, and k-RAS oncogene promoters. We determined the structure of the major G-quadruplex formed in the MYC promoter, a prototype for parallel G-quadruplexes. It is the first example of the parallel-stranded G3NG3 structure motif with a 1-nt loop, which is prevalent in promoter sequences and likely evolutionarily selected to initiate folding. Remarkably, the parallel MYC promoter G-quadruplexes are highly stable. Additionally, we determined the molecular structures of G-quadruplexes formed in human BCL2, VEGF, and PDGFR-ß promoters, each adopting a unique structure. For example, the BCL2 promoter contains distinct interchangeable G-quadruplexes in two adjacent regions, suggesting precise regulation by different proteins. The PDGFR-ß promoter adopts unique "broken-strand" and vacancy G-quadruplexes, which can be recognized by cellular guanine metabolites for a potential regulatory role.Structural information on G-quadruplexes in complex with small-molecules is critical for understanding specific recognition and structure-based rational drug design. Our studies show that many G-quadruplexes contain unique structural features such as capping and loop structures, allowing specific recognition by drugs and protein. This represents a paradigm shift in understanding DNA as a drug target: Rather than a uniform, nonselective binding site in duplex DNA, the G-quadruplex is being pursued as a new class of selectively targetable drug receptors. We focus on targeting the biologically relevant MYC promoter G-quadruplex (MycG4) with small molecules and have determined its first and additional drug complex structures. Very recently, we have discovered clinically tested indenoisoquinolines as strong MycG4 binders and potent MYC inhibitors. We have also discovered drugs targeting the unique dGMP-bound-vG4 formed in the PDGFR-ß promoter. Moreover, we determined the complex structures of the first small molecules that specifically recognize the physiologically relevant human telomeric G-quadruplexes. Unlike the previously recognized dogma that the optimal G-quadruplex ligands are large aromatic or cyclic compounds, our results suggest that smaller asymmetric compounds with appropriate functional groups are better choices to specifically bind G-quadruplexes. This body of work lays a strong foundation for future work aimed at understanding the cellular functions of G-quadruplexes and G-quadruplex-targeted drug design.


Assuntos
Quadruplex G , Cromatina , DNA/química , Guanina/química , Humanos , Ligantes , Oncogenes , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Droga/genética , Telômero/genética , Fator A de Crescimento do Endotélio Vascular
5.
Bioorg Med Chem ; 72: 116972, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36057217

RESUMO

The artificial nucleobase 1,3-diaza-2-oxophenoxazine (tCO) and its derivative G-clamp strongly bind to guanine and, when incorporated into double-stranded DNA, significantly increase the stability of the latter. As the phenoxazine skeleton is a constituent of major pharmaceuticals, we hypothesized that oligonucleotides (ONs) containing phenoxazine bases would induce property changes related to intracellular uptake and migration in tissues. In this study, we designed and synthesized a novel G-clamp-linker antisense oligonucleotide (ASO) in which a G-clamp base with a flexible linker was introduced into the 5'-end of an ASO targeting mouse long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (mMALAT1). Compared to unconjugated ASO, the G-clamp-linker ASO induced significantly more effective knockdown of mMALAT1 in mouse skeletal muscle. The ASOs conjugated with 2'-deoxyribonucleotide(s) bearing a tCO nucleobase at the 5'-end exhibited a similar knockdown effect in skeletal muscle. Thus, it may be possible to improve therapeutic effects against skeletal muscle diseases, such as muscular dystrophy, by using ONs with incorporated phenoxazine nucleobases.


Assuntos
Oligonucleotídeos , RNA Longo não Codificante , Animais , DNA , Desoxirribonucleotídeos , Guanina , Camundongos , Oligonucleotídeos/farmacologia , Oligonucleotídeos Antissenso/genética , Oxazinas , Preparações Farmacêuticas
6.
Genes (Basel) ; 13(9)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36140833

RESUMO

Regulation of the epigenome is critical for healthy cell function but can become disrupted with age, leading to aberrant epigenetic profiles including altered DNA methylation. Recent studies have indicated that DNA methylation homeostasis can be compromised by the formation of DNA secondary structures known as G-quadruplexes (G4s), which form in guanine-rich regions of the genome. G4s can be recognised and bound by certain methylation-regulating enzymes, and in turn perturb the surrounding methylation architecture. However, the effect G4 formation has on DNA methylation at critical epigenetic sites remains elusive and poorly explored. In this work, we investigate the association between G4 sequences and prominent DNA methylation sites, termed 'ageing clocks', that act as bona fide dysregulated regions in aged and cancerous cells. Using a combination of in vitro (G4-seq) and in cellulo (BG4-ChIP) G4 distribution maps, we show that ageing clocks sites are significantly enriched with G4-forming sequences. The observed enrichment also varies across species and cell lines, being least significant in healthy cells and more pronounced in tumorigenic cells. Overall, our results suggest a biological significance of G4s in the realm of DNA methylation, which may be important for further deciphering the driving forces of diseases characterised by epigenetic abnormality, including ageing.


Assuntos
Quadruplex G , Neoplasias , Idoso , Envelhecimento/genética , DNA/genética , Metilação de DNA/genética , Guanina , Humanos , Neoplasias/genética
7.
Int J Mol Sci ; 23(18)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36142283

RESUMO

Epigenetic alterations affect the onset of ischemic stroke, brain injury after stroke, and mechanisms of poststroke recovery. In particular, DNA methylation can be dynamically altered by maintaining normal brain function or inducing abnormal brain damage. DNA methylation is regulated by DNA methyltransferase (DNMT), which promotes methylation, DNA demethylase, which removes methyl groups, and methyl-cytosine-phosphate-guanine-binding domain (MBD) protein, which binds methylated DNA and inhibits gene expression. Investigating the effects of modulating DNMT, TET, and MBD protein expression on neuronal cell death and neurorepair in ischemic stroke and elucidating the underlying mechanisms can facilitate the formulation of therapeutic strategies for neuroprotection and promotion of neuronal recovery after stroke. In this review, we summarize the role of DNA methylation in neuroprotection and neuronal recovery after stroke according to the current knowledge regarding the effects of DNA methylation on excitotoxicity, oxidative stress, apoptosis, neuroinflammation, and recovery after ischemic stroke. This review of the literature regarding the role of DNA methylation in neuroprotection and functional recovery after stroke may contribute to the development and application of novel therapeutic strategies for stroke.


Assuntos
Lesões Encefálicas , AVC Isquêmico , Acidente Vascular Cerebral , Lesões Encefálicas/genética , Citosina , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Guanina , Humanos , AVC Isquêmico/genética , Fosfatos , Acidente Vascular Cerebral/genética
8.
Int J Mol Sci ; 23(18)2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36142479

RESUMO

Oxaliplatin, similar to Cisplatin, exhibits anticancer activity by interacting with DNA and inducing programmed cell death. It is biotransformed through a number of spontaneous and non-enzymatic processes. In this way, several transient reactive species are formed, including dichloro-, monochloro-, and diaqua-DACH platin, which can complex with DNA and other macromolecules. The molecular level suggests that such interactions can also take place with vitamins containing aromatic rings with lone pair orbitals. Theoretical and experimental studies were performed to investigate interactions of vitamins from the B group with Oxaliplatin, and the results were compared with values characterizing native purines. Quantum-chemical simulations were carried out at the B3LYP/6-31G(d,p) level, with the LANL2DZ basis set representing atomic orbitals of platinum atom, and at the MN15/def2-TZVP levels of theory with the use of Polarizable Continuum Model (IEF-PCM formulation) and water as a solvent. Additionally, time-dependent density functional theory (TD-DFT) was employed to study molecular properties in the electronic excited state. Interactions of vitamins and Oxaliplatin were investigated using UV-Vis spectroscopy. Values of the free energy (ΔGr) indicate spontaneous reactions with monoaqua [PtH2OClDACH]+ and diaqua [Pt(H2O)2DACH]2+ derivatives of Oxaliplatin. However, diaqua derivatives were found to be preferable. The free energy (ΔGr) values obtained for vitamins from the B group indicate lower affinity of Oxaliplatin compared with values characterizing complexes formed by guanine, adenine, and cytosine. The exception is the monoaqua form of vitamin B1 (thiamine) at the MN15/def2-TZVP levels of calculations. An application of atoms in molecules (AIM) theory revealed non-covalent interactions present in the complexes studied. The comparison of computed and experimental spectroscopic properties showed a good agreement.


Assuntos
Cisplatino , Platina , Adenina , Cisplatino/farmacologia , Cicloexilaminas , Citosina , DNA , Guanina , Oxaliplatina , Teoria Quântica , Solventes , Tiamina , Vitamina A , Vitaminas , Água
9.
Int J Mol Sci ; 23(18)2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36142522

RESUMO

Outdoor air pollution is a mixture of multiple atmospheric pollutants, among which nitrogen oxide (NOx) stands out due to its association with several diseases. NOx reactivity can conduct to DNA damage as severe as interstrand crosslinks (ICL) formation, that in turn is able to block DNA replication and transcription. Experimental studies have suggested that the ICL formation due to NOx is realized through a diazonium intermediate (DI). In this work, we have modeled the DI structure, including a DNA double-strand composed of two base pairs GC/CG, being diazotized as one of the guanine nucleotides. The structural stability of DNA with DI lesion was essayed through 500 ns molecular dynamics simulations. It was found that the DNA structure of the oligonucleotide is stable when the DI is present since the loss of a Guanine-Cytosine hydrogen bond is replaced by the presence of two cation-π interactions. Additionally, we have studied the mechanism of formation of a crosslink between the two guanine nucleobases from the modeled DI by carrying out DFT calculations at the M06-L/DNP+ level of theory. Our results show that the mechanism is thermodynamically favored by a strong stabilization of the ICL product, and the process is kinetically viable since its limiting stage is accessible.


Assuntos
Poluentes Ambientais , Citosina/química , DNA/química , Dano ao DNA , Guanina/química , Nucleotídeos de Guanina , Óxidos de Nitrogênio , Oligonucleotídeos
10.
Pak J Biol Sci ; 25(8): 732-740, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36098199

RESUMO

<b>Background and Objective:</b> Cytochrome c oxidase gene subunit-I (COI) has conserved and variable regions and along with the 658 nucleotide base pairs at the '5 of these have been used as animal barcode, species identification and evolutionary studies of several vertebrates, especially Anura. This research was conducted to characterize the nucleotides of the COI sequence gene of (<i>Limnonectes cf. grunniens</i>) that live sympatrically with <i>L. modestus</i> on several headwater streams in Kendari, Southeast Sulawesi. <b>Materials and Methods:</b> This research is explorative, samples of frogs were obtained from the Lahundape and Moramo headwater streams. A total of 16 frogs were sampled and the genomic DNA of frog samples was extracted and, then amplified using the PCR method. The next steps are sequencing and analysis using MEGA 7. <b>Results:</b> The result showed nucleotides along 688 to 705 base pairs. There were two haplotypes of <i>L. cf. grunniens</i> and three <i>L. modestus</i>. <i>L. cf. grunniens </i>consist of 32.6% Thymine (Uracil), 32.3% Cytisine, 17.9% Adenine and 17.9% Guanine. While <i>L. modestus</i> is 37.6% Thymine, 26.0% Cytosine, 20.7% Adenine and 15.8% Guanine. Based on Kimura-2 parameter, the genetic distance between genera ranges from 0.25-0.26 while the genetic distance between species is 0.00-0.01. <b>Conclusion:</b> Phylogeny trees based on partial sequences of COI frog genes showed that <i>L. cf. grunniens</i> and <i>L. modestus</i> are monophyletic with bootstrapped values ranging from 86-100% and differentiated between species. There is a genetic variability of COI sequences of <i>Limnonectes cf. grunniens</i> and <i>L. modestus</i> from Kendari, Southeast Sulawesi.


Assuntos
Anuros , Timina , Adenina , Animais , Anuros/genética , Guanina , Indonésia , Nucleotídeos
11.
J Mol Model ; 28(10): 291, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36063245

RESUMO

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs.


Assuntos
Antineoplásicos , Rutênio , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , DNA , Desoxiguanosina , Guanina/farmacologia , Guanosina/farmacologia , Indazóis , Compostos Organometálicos , RNA , Rutênio/farmacologia , Compostos de Rutênio
12.
Biochemistry (Mosc) ; 87(8): 823-831, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36171646

RESUMO

Previously, we have found that a nucleic acid metabolite, 7-methylguanine (7mGua), produced in the body can have an inhibitory effect on the poly(ADP-ribose) polymerase 1 (PARP1) enzyme, an important pharmacological target in anticancer therapy. In this work, using an original method of analysis of PARP1 activity based on monitoring fluorescence anisotropy, we studied inhibitory properties of 7mGua and its metabolite, 8-hydroxy-7-methylguanine (8h7mGua). Both compounds inhibited PARP1 enzymatic activity in a dose-dependent manner, however, 8h7mGua was shown to be a stronger inhibitor. The IC50 values for 8h7mGua at different concentrations of the NAD+ substrate were found to be 4 times lower, on average, than those for 7mGua. The more efficient binding of 8h7mGua in the PARP1 active site is explained by the presence of an additional hydrogen bond with the Glu988 catalytic residue. Experimental and computational studies did not reveal the effect of 7mGua and 8h7mGua on the activity of other DNA repair enzymes, indicating selectivity of their inhibitory action.


Assuntos
NAD , Ácidos Nucleicos , Guanina/análogos & derivados , Humanos
13.
Pol J Vet Sci ; 25(3): 455-462, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36156102

RESUMO

African swine fever (ASF) is an acute, hemorrhagic, and devastating viral infectious disease that causes important economic losses to the swine industry. Currently, there are no effective vaccines or drugs available. Epigenetic mechanisms, especially cytosine methylation of cytosine- -phosphate-guanine (CpG) islands, have a significant impact on the life cycle of several viruses. Hence, drugs targeting DNA methylation may potentially be used for the treatment of ASF. Here, we selected the inner core, core shell, inner membrane, capsid, and external envelope membrane, to analyze the characteristics of CpG islands in the ASF virus (ASFV) genomes. Furthermore, we analyzed the promoters and CpG islands in the upstream regions of these genes. Results showed that the CpG islands of seven genes were conserved in the genomes of two genotype of ASFV strains, whereas the CpG islands of other genes were relatively conserved (ASFV strains differed mainly in the quantity of CpG islands). The different distribution of CpG islands in the genomes of different ASFV strains may affect their methylation status, which may in turn affect the regulation of viral gene expression, leading to different clinical outcomes. In addition, the predicted promoter regions based on the upstream sequences of most genes overlapped with CpG island positions. Methylation of the binding sites of the promoter regions inhibits the binding of the transcription factors to the promoters, thus inhibiting the activation of the promoters and limiting the synthesis of viral proteins. The results of this study provide a basis for exploring new antiviral therapeutic strategies from an epigenetic perspective.


Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Doenças dos Suínos , Vírus da Febre Suína Africana/genética , Animais , Antivirais/farmacologia , Ilhas de CpG , Citosina/metabolismo , Citosina/farmacologia , Genótipo , Guanina/metabolismo , Guanina/farmacologia , Fosfatos , Suínos , Doenças dos Suínos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologia , Proteínas Virais/metabolismo
14.
Proc Natl Acad Sci U S A ; 119(38): e2123529119, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36095201

RESUMO

Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ∼50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of transfer RNA (tRNA) wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human hepatocellular carcinoma cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to demonstrating an epitranscriptomic facet of arsenite toxicity and response, our results highlight the links between environmental exposures, stress tolerance, RNA modifications, and micronutrients.


Assuntos
Arsenitos , Epigênese Genética , Guanina , RNA de Transferência , Transcriptoma , Arsenitos/toxicidade , Linhagem Celular Tumoral , Códon/genética , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Oxirredução , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA de Transferência/genética
15.
Phys Chem Chem Phys ; 24(37): 22513-22522, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36106845

RESUMO

The G-quadruplex is a fascinating nucleic acid motif with implications in biology, medicine, and nanotechnologies. G-quadruplexes can form in the telomeres at the edges of chromosomes and in other guanine-rich regions of the genome. They can also be engineered for exploitation as biological materials for nanodevices. Their higher stiffness and higher charge transfer rates make them better candidates in nanodevices than duplex DNA. For the development of molecular nanowires, it is important to optimize electron transport along the wire axis. One powerful basis to do so is by manipulating the structure, based on known effects that structural changes have on electron transport. Here, we investigate such effects, by a combination of classical simulations of the structure and dynamics and quantum calculations of electronic couplings. We find that this structure-function relationship is complex. A single helix shape parameter alone does not embody such complexity, but rather a combination of distances and angles between stacked bases influences charge transfer efficiency. By analyzing linear combinations of shape descriptors for different topologies, we identify the structural features that most affect charge transfer efficiency. We discuss the transferability of the proposed model and the limiting effects of inherent flexibility.


Assuntos
Quadruplex G , DNA/química , Eletrônica , Guanina/química , Conformação de Ácido Nucleico , Telômero
16.
J Labelled Comp Radiopharm ; 65(10-11): 288-291, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35980801

RESUMO

The PET tracer [18 F]F-AraG, an arabinosyl guanine analog, has shown promise for visualizing activated T cells in multiple diseases. Herein, a practitioner's protocol is described, in which the PET tracer is prepared using minimal equipment and manual actions, making it widely accessible for preclinical applications.


Assuntos
Tomografia por Emissão de Pósitrons , Linfócitos T , Guanina , Tomografia por Emissão de Pósitrons/métodos
17.
Hemoglobin ; 46(2): 140-142, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36000573

RESUMO

We report the hematological data of the codon 7 (GAG>TAG (HBB: c.22G>T) mutation for the first time in two Albanian individuals from the region of Elbasan, who underwent genetic testing due to prenatal counseling and diagnosis for ß-thalassemia major (ß-TM) anemia. The phenotype was compatible with a typical ß0-thalassemia (ß0-thal) carrier but the hematological findings of the mutation has not been previously reported. The mutation involves the conversion of codon 7 GAG (Glu) into a translation termination codon (TAG), involving the replacement of guanine by thymine so that no ß chains are produced.


Assuntos
Emigrantes e Imigrantes , Talassemia , Talassemia beta , Códon de Terminação , Análise Mutacional de DNA , Genótipo , Grécia , Guanina , Humanos , Mutação , Talassemia/genética , Timina , Globinas beta/genética , Talassemia beta/diagnóstico , Talassemia beta/genética
18.
J Virol ; 96(18): e0092122, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36040175

RESUMO

The genus Henipavirus (family Paramyxoviridae) currently comprises seven viruses, four of which have demonstrated prior evidence of zoonotic capacity. These include the biosafety level 4 agents Hendra (HeV) and Nipah (NiV) viruses, which circulate naturally in pteropodid fruit bats. Here, we describe and characterize Angavokely virus (AngV), a divergent henipavirus identified in urine samples from wild, Madagascar fruit bats. We report the nearly complete 16,740-nucleotide genome of AngV, which encodes the six major henipavirus structural proteins (nucleocapsid, phosphoprotein, matrix, fusion, glycoprotein, and L polymerase). Within the phosphoprotein (P) gene, we identify an alternative start codon encoding the AngV C protein and a putative mRNA editing site where the insertion of one or two guanine residues encodes, respectively, additional V and W proteins. In other paramyxovirus systems, C, V, and W are accessory proteins involved in antagonism of host immune responses during infection. Phylogenetic analysis suggests that AngV is ancestral to all four previously described bat henipaviruses-HeV, NiV, Cedar virus (CedV), and Ghanaian bat virus (GhV)-but evolved more recently than rodent- and shrew-derived henipaviruses, Mojiang (MojV), Gamak (GAKV), and Daeryong (DARV) viruses. Predictive structure-based alignments suggest that AngV is unlikely to bind ephrin receptors, which mediate cell entry for all other known bat henipaviruses. Identification of the AngV receptor is needed to clarify the virus's potential host range. The presence of V and W proteins in the AngV genome suggest that the virus could be pathogenic following zoonotic spillover. IMPORTANCE Henipaviruses include highly pathogenic emerging zoonotic viruses, derived from bat, rodent, and shrew reservoirs. Bat-borne Hendra (HeV) and Nipah (NiV) are the most well-known henipaviruses, for which no effective antivirals or vaccines for humans have been described. Here, we report the discovery and characterization of a novel henipavirus, Angavokely virus (AngV), isolated from wild fruit bats in Madagascar. Genomic characterization of AngV reveals all major features associated with pathogenicity in other henipaviruses, suggesting that AngV could be pathogenic following spillover to human hosts. Our work suggests that AngV is an ancestral bat henipavirus that likely uses viral entry pathways distinct from those previously described for HeV and NiV. In Madagascar, bats are consumed as a source of human food, presenting opportunities for cross-species transmission. Characterization of novel henipaviruses and documentation of their pathogenic and zoonotic potential are essential to predicting and preventing the emergence of future zoonoses that cause pandemics.


Assuntos
Quirópteros , Infecções por Henipavirus , Henipavirus , Vírus Nipah , Animais , Antivirais , Quirópteros/genética , Códon de Iniciação , Genômica , Gana , Glicoproteínas/genética , Guanina , Henipavirus/genética , Humanos , Madagáscar , Vírus Nipah/genética , Nucleotídeos , Fosfoproteínas/genética , Filogenia , Receptores da Família Eph/genética , Musaranhos , Zoonoses/genética
19.
Pak J Pharm Sci ; 35(4): 973-983, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36008892

RESUMO

Entecavir is a well-known antiviral drug, commonly prescribed for the treatment of hepatitis B and showed promising therapeutic effects against HBV polymerase. The replication of Hepatitis B Virus requires HBV-DNA polymerase and its natural substrate is deoxyguanosine triphosphate. Entercavir inhibit its activity by phosphorylating into its active metabolite. Furthermore, the efficiency of silver nanoparticles as an antimicrobial or antiviral agent is known for centuries. This study focused on the in-silico stability studies of silver nanoparticles of entecavir. The silver nanoparticles of entecavir synthesized by previously reported method. The stability of drug metal complex was predicted by analysis of variations in internal energies including potential energy, kinetic energy and different non-bonded energies during the simulation run of 4000 picoseconds of different molecular systems. After the simulation run it was concluded that the molecular systems of drug metal complex in aqueous solution at pH 4 showed greater instability as compared to the pH 2 and 6.9. This research gives the idea about the significance of molecular dynamics simulation technique in the field of pharmaceutical sciences for the analysis and characterization of pharmaceutical products and visualizes the effects of different environmental parameters on the structure and physicochemical properties of drug molecules.


Assuntos
Hepatite B Crônica , Nanopartículas Metálicas , Antivirais/uso terapêutico , DNA Viral , Farmacorresistência Viral/genética , Guanina/análogos & derivados , Vírus da Hepatite B/genética , Humanos , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular , Prata/farmacologia
20.
Cells ; 11(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36010587

RESUMO

Queuosine (Q) is a naturally occurring modified nucleoside that occurs in the first position of transfer RNA anticodons such as Asp, Asn, His, and Tyr. As eukaryotes lack pathways to synthesize queuine, the Q nucleobase, they must obtain it from their diet or gut microbiota. Previously, we described the effects of queuine on the physiology of the eukaryotic parasite Entamoeba histolytica and characterized the enzyme EhTGT responsible for queuine incorporation into tRNA. At present, it is unknown how E. histolytica salvages queuine from gut bacteria. We used liquid chromatography-mass spectrometry (LC-MS) and N-acryloyl-3-aminophenylboronic acid (APB) PAGE analysis to demonstrate that E. histolytica trophozoites can salvage queuine from Q or E. coli K12 but not from the modified E. coli QueC strain, which cannot produce queuine. We then examined the role of EhDUF2419, a protein with homology to DNA glycosylase, as a queuine salvage enzyme in E. histolytica. We found that glutathione S-transferase (GST)-EhDUF2419 catalyzed the conversion of Q into queuine. Trophozoites silenced for EhDUF2419 expression are impaired in their ability to form Q-tRNA from Q or from E. coli. We also observed that Q or E. coli K12 partially protects control trophozoites from oxidative stress (OS), but not siEhDUF2419 trophozoites. Overall, our data reveal that EhDUF2419 is central for the direct salvaging of queuine from bacteria and for the resistance of the parasite to OS.


Assuntos
Entamoeba histolytica , Parasitos , Animais , Entamoeba histolytica/metabolismo , Escherichia coli/metabolismo , Guanina/análogos & derivados , Humanos , Parasitos/metabolismo , RNA de Transferência/genética
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