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1.
Clin Oral Investig ; 28(10): 536, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39302523

RESUMO

OBJECTIVE: To investigate the efficacy of ribose-crosslinked collagen (RCLC) matrices functionalized by crosslinked hyaluronic acid (xHya) for reconstructive treatment of class I and III (b-c) peri-implantitis lesions in a transmucosal healing mode. MATERIALS AND METHODS: Thirteen patients presenting with 15 implants were included in this prospective case series. Upon flap reflection, the implants were thoroughly decontaminated employing glycine powder air polishing and adjunctive sodium hypochlorite. For defect augmentation, xHyA was administered to the bony defect walls, exposed implant surfaces, and the RCLC matrix before defect grafting. The full-thickness flap was readapted and sutured around the implant neck for transmucosal healing. Baseline and respective values at the 12 months post-op evaluation were recorded for the clinical parameters peri-implant probing depth (PPD), buccal soft tissue dehiscence (BSTD) and bleeding on probing (BoP). Furthermore, two independent investigators analyzed radiographic changes in the defect area. The mean changes for all variables were analyzed with a paired t-test. RESULTS: The initial mean PPD was 7.2 ± 1.9 mm, and BoP was present in 63% of sites. After 12 months, PPD at the latest visit was 3.2 ± 0.66 mm, which amounted to a respective 3.9 ± 1.85 mm reduction, while the BoP frequency dropped to 10% at all sites. Radiographic bone fill was accomplished for 62.8% of the former defect area, accompanied by a mean MBL gain of 1.02 mm around the treated implants (all p < 0.001). CONCLUSIONS: Within the limits of this case series, we conclude that the proposed treatment sequence substantially improved peri-implant defects and offered a simplified but predictive technique. CLINICAL RELEVANCE: Reconstructive treatment approaches for peri-implantitis are effective but remain non-superior to open flap debridement. Further research on novel biomaterial combinations that may improve reconstructive treatment outcomes are warranted. Ribose-crosslinked collagen matrices biofunctionalized by hyaluronic acid used in this study yield improved clinical and radiographic peri-implant conditions after 12 months.


Assuntos
Colágeno , Ácido Hialurônico , Peri-Implantite , Ribose , Humanos , Estudos Prospectivos , Ácido Hialurônico/química , Masculino , Feminino , Pessoa de Meia-Idade , Ribose/química , Peri-Implantite/cirurgia , Resultado do Tratamento , Retalhos Cirúrgicos , Adulto , Reagentes de Ligações Cruzadas/química , Idoso , Procedimentos de Cirurgia Plástica/métodos , Cicatrização , Implantes Dentários
2.
J Phys Chem B ; 128(35): 8313-8331, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39172066

RESUMO

Over the last few decades, chemically modified sugars have been incorporated into nucleic acid-based therapeutics to improve their pharmacological potential. Chemical modification can influence the sugar conformation, Watson-Crick hydrogen (W-C) bonding, and nucleobase stacking interactions, which play major roles in the structural integrity and dynamic properties of nucleic acid duplexes. In this study, we categorized 33 uridine (U*) and cytidine (C*) sugar modifications and calculated their sugar conformational parameters. We also calculated the Watson-Crick hydrogen bond energies of the modified RNA-type base pairs (U*:A and C*:G) using DFT and sSAPT0 methods. The W-C base pairing energy calculations suggested that the South-type modified sugar strengthens the C*:G base pair and weakens the U*:A base pair compared to the unmodified one. In contrast, the North-type sugar modifications form weaker C*:G base pair and marginally stronger U*:A base pair compared to the South-type modified sugars. Moreover, intrastrand base stacking energies were calculated for 15 modifications incorporated at the fourth position in 7-mer non-self-complementary RNA duplexes [(GCAU*GAC)2 and (GCAC*GAC)2], utilizing molecular dynamics simulation and quantum mechanical (DFT and sSAPT0) methods. The sugar modifications were found to have minimal effect on the intrastrand base-stacking interactions. However, the glycol nucleic acid modification disturbs the intrastrand base-stacking significantly, corroborating the experimental data.


Assuntos
Pareamento de Bases , Ligação de Hidrogênio , Ribose , Ribose/química , Teoria da Densidade Funcional , Configuração de Carboidratos , Termodinâmica , RNA/química , Citidina/química , Uridina/química , Conformação de Ácido Nucleico , Simulação de Dinâmica Molecular
3.
Nat Commun ; 15(1): 5746, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982056

RESUMO

Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) demonstrates that synergistic lethality is driven by Candida-induced upregulation of functional S. aureus α-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken revealing that zcf13Δ/Δ fails to drive augmented α-toxin or lethal synergism during co-infection. A combination of transcriptional and phenotypic profiling approaches shows that ZCF13 regulates genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments reveal that ribose inhibits the staphylococcal agr quorum sensing system and concomitantly represses toxicity. Unlike wild-type C. albicans, zcf13Δ/Δ did not effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13Δ/Δ mutant fully restores pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.


Assuntos
Candida albicans , Candidíase , Coinfecção , Infecções Intra-Abdominais , Infecções Estafilocócicas , Staphylococcus aureus , Camundongos , Candida albicans/fisiologia , Staphylococcus aureus/fisiologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/patologia , Candidíase/metabolismo , Candidíase/patologia , Coinfecção/metabolismo , Coinfecção/patologia , Toxoide Estafilocócico/metabolismo , Proteínas Fúngicas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/metabolismo , Transativadores/metabolismo , Percepção de Quorum , Infecções Intra-Abdominais/metabolismo , Infecções Intra-Abdominais/microbiologia , Infecções Intra-Abdominais/patologia , Açúcares/metabolismo , Ribose/metabolismo , Modelos Animais de Doenças
4.
Enzyme Microb Technol ; 180: 110482, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39059289

RESUMO

ß-nicotinamide mononucleotide (ß-NMN) is a key precursor of nicotinamide adenine dinucleotide, and becomes attractive in the nutrition and health care fields, but its enzymatic synthesis is expensive. In this study, a six-enzyme cascade catalytic system was constructed to produce ß-NMN. Using D-ribose and nicotinamide as substrates, the ß-NMN yield reached 97.5 % catalyzed by purified enzymes. Then, after knocking out the genes encoding proteins that consume ß-NMN in E. coli BL21(DE3), the similar ß-NMN yield, 97.2 %, using the crude enzymes could be also obtained. After that, ß-NMN synthesis was performed under increased substrate concentration, and 'modular' crude enzymes cascade catalytic reaction system was proposed to reduce the inhibition of polyphosphate on ribose-phosphate diphosphokinase activity, and the ß-NMN yield reached 78.4 % at 10 mM D-ribose, which is 1.82 times of that in 'one-pot' reaction and represents the highest ß-NMN preparation level with phosphoribosylpyrophosphate as the core reported till now.


Assuntos
Escherichia coli , Mononucleotídeo de Nicotinamida , Escherichia coli/genética , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Mononucleotídeo de Nicotinamida/metabolismo , Ribose/metabolismo , Biocatálise , Niacinamida/metabolismo , Niacinamida/química , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/química , Catálise , Especificidade por Substrato
5.
Int J Mol Sci ; 25(12)2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38928433

RESUMO

Prebiotic pre-Darwinian reactions continued throughout biochemical or Darwinian evolution. Early chemical processes could have occurred on Earth between 4.5 and 3.6 billion years ago when cellular life was about to come into being. Pre-Darwinian evolution assumes the development of hereditary elements but does not regard them as self-organizing processes. The presence of biochemical self-organization after the pre-Darwinian evolution did not justify distinguishing between different types of evolution. From the many possible solutions, evolution selected from among those stable reactions that led to catalytic networks, and under gradually changing external conditions produced a reproducible, yet constantly evolving and adaptable, living system. Major abiotic factors included sunlight, precipitation, air, minerals, soil and the Earth's atmosphere, hydrosphere and lithosphere. Abiotic sources of chemicals contributed to the formation of prebiotic RNA, the development of genetic RNA, the RNA World and the initial life forms on Earth and the transition of genRNA to the DNA Empire, and eventually to the multitude of life forms today. The transition from the RNA World to the DNA Empire generated new processes such as oxygenic photosynthesis and the hierarchical arrangement of processes involved in the transfer of genetic information. The objective of this work is to unite earlier work dealing with the formose, the origin and synthesis of ribose and RNA reactions that were published as a series of independent reactions. These reactions are now regarded as the first metabolic pathway.


Assuntos
Origem da Vida , RNA , Ribose , RNA/química , RNA/genética , RNA/metabolismo , Ribose/química , Ribose/metabolismo , Evolução Molecular
6.
Nucleic Acids Res ; 52(12): 6733-6747, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38828787

RESUMO

Adenosine Deaminases Acting on RNA (ADARs) are enzymes that catalyze the conversion of adenosine to inosine in RNA duplexes. These enzymes can be harnessed to correct disease-causing G-to-A mutations in the transcriptome because inosine is translated as guanosine. Guide RNAs (gRNAs) can be used to direct the ADAR reaction to specific sites. Chemical modification of ADAR guide strands is required to facilitate delivery, increase metabolic stability, and increase the efficiency and selectivity of the editing reaction. Here, we show the ADAR reaction is highly sensitive to ribose modifications (e.g. 4'-C-methylation and Locked Nucleic Acid (LNA) substitution) at specific positions within the guide strand. Our studies were enabled by the synthesis of RNA containing a new, ribose-modified nucleoside analog (4'-C-methyladenosine). Importantly, the ADAR reaction is potently inhibited by LNA or 4'-C-methylation at different positions in the ADAR guide. While LNA at guide strand positions -1 and -2 block the ADAR reaction, 4'-C-methylation only inhibits at the -2 position. These effects are rationalized using high-resolution structures of ADAR-RNA complexes. This work sheds additional light on the mechanism of ADAR deamination and aids in the design of highly selective ADAR guide strands for therapeutic editing using chemically modified RNA.


Assuntos
Adenosina Desaminase , Edição de RNA , Ribose , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/química , Ribose/química , Ribose/metabolismo , Humanos , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/química , Metilação , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/química , Nucleosídeos/química , Nucleosídeos/metabolismo , RNA/metabolismo , RNA/química , Inosina/metabolismo , Inosina/química
7.
J Med Chem ; 67(12): 10490-10507, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38845345

RESUMO

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA2AAR antagonist 2a, we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hA3AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA2AAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA2AAR (Ki,hA2A = 5.0 ± 0.5 nM, Ki,hA3/Ki,hA2A = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of 4a. These findings establish 4a as a viable immune-oncology therapeutic candidate.


Assuntos
Adenina , Antagonistas do Receptor A2 de Adenosina , Nucleosídeos , Receptor A2A de Adenosina , Ribose , Humanos , Relação Estrutura-Atividade , Animais , Adenina/farmacologia , Adenina/química , Adenina/análogos & derivados , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Nucleosídeos/química , Nucleosídeos/farmacologia , Nucleosídeos/síntese química , Ribose/química , Ribose/metabolismo , Receptor A2A de Adenosina/metabolismo , Camundongos , Estrutura Molecular , Ratos , Feminino , Linhagem Celular Tumoral
8.
Astrobiology ; 24(5): 489-497, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38696654

RESUMO

Ribose is the defining sugar in ribonucleic acid (RNA), which is often proposed to have carried the genetic information and catalyzed the biological reactions of the first life on Earth. Thus, abiological processes that yield ribose under prebiotic conditions have been studied for decades. However, aqueous environments required for the formation of ribose from materials available in quantity under geologically reasonable models, where the ribose formed is not immediately destroyed, remain unclear. This is due in large part to the challenge of analysis of carbohydrates formed under a wide range of aqueous conditions. Thus, the formation of ribose on prebiotic Earth has sometimes been questioned. We investigated the quantitative effects of pH, temperature, cation, and the concentrations of formaldehyde and glycolaldehyde on the synthesis of diverse sugars, including ribose. The results suggest a range of conditions that produce ribose and that ribose could have formed in constrained aquifers on prebiotic Earth.


Assuntos
Formaldeído , Ribose , Temperatura , Água , Ribose/química , Concentração de Íons de Hidrogênio , Água/química , Formaldeído/química , Acetaldeído/química , Acetaldeído/análogos & derivados , Planeta Terra , Origem da Vida
9.
Cancer Med ; 13(7): e7149, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572951

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored. METHODS: This retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined. RESULTS: High-grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high-grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non-responders. Furthermore, neutrophil counts were significantly higher among responders than among non-responders. CONCLUSIONS: Inflammation-related blood data, such as neutrophil count, obtained at the initial pre-treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias Ovarianas , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Japão , Ribose/uso terapêutico , Estudos Retrospectivos , Mutação , Antineoplásicos/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Biomarcadores , Poli(ADP-Ribose) Polimerases , Carcinoma/tratamento farmacológico , Ftalazinas/efeitos adversos
10.
Life Sci Alliance ; 7(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38538092

RESUMO

HuR (ElavL1) is one of the main post-transcriptional regulators that determines cell fate. Although the role of HuR in apoptosis is well established, the post-translational modifications that govern this function remain elusive. In this study, we show that PARP1/2-mediated poly(ADP)-ribosylation (PARylation) is instrumental in the pro-apoptotic function of HuR. During apoptosis, a substantial reduction in HuR PARylation is observed. This results in the cytoplasmic accumulation and the cleavage of HuR, both of which are essential events for apoptosis. These effects are mediated by a pADP-ribose-binding motif within the HuR-HNS region (HuR PAR-binding site). Under normal conditions, the association of the HuR PAR-binding site with pADP-ribose is responsible for the nuclear retention of HuR. Mutations within this motif prevent the binding of HuR to its import factor TRN2, leading to its cytoplasmic accumulation and cleavage. Collectively, our findings underscore the role of PARylation in controlling the pro-apoptotic function of HuR, offering insight into the mechanism by which PARP1/2 enzymes regulate cell fate and adaptation to various assaults.


Assuntos
Processamento de Proteína Pós-Traducional , Ribose , Mutação , Diferenciação Celular , Domínios Proteicos
11.
Biotechnol J ; 19(2): e2300748, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38403401

RESUMO

Enzymatic synthesis of ß-nicotinamide mononucleotide (NMN) from D-ribose has garnered widespread attention due to its cheap material, the use of mild reaction conditions, and the ability to produce highly pure products with the desired optical properties. However, the overall NMN yield of this method is impeded by the low activity of rate-limiting enzymes. The ribose-phosphate diphosphokinase (PRS) and nicotinamide phosphoribosyltransferase (NAMPT), that control the rate of the reaction, were engineered to improve the reaction efficacy. The actives of mutants PRS-H150Q and NAMPT-Y15S were 334% and 57% higher than that of their corresponding wild-type enzymes, respectively. Furthermore, by adding pyrophosphatase, the byproduct pyrophosphate which can inhibit the activity of NAMPT was degraded, leading to a 6.72% increase in NMN yield. Following with reaction-process reinforcement, a high yield of 8.10 g L-1 NMN was obtained after 3 h of reaction, which was 56.86-fold higher than that of the stepwise reaction synthesis (0.14 g L-1 ), indicating that the in vitro enzymatic synthesis of NMN from D-ribose and niacinamide is an economical and feasible route.


Assuntos
Mononucleotídeo de Nicotinamida , Ribose , Mononucleotídeo de Nicotinamida/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Niacinamida/metabolismo , Engenharia de Proteínas , NAD/metabolismo
12.
Talanta ; 271: 125728, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38316075

RESUMO

Carbohydrates, in particular the d-enantiomers of ribose, 2-deoxyribose, and glucose, are essential to life's informational biopolymers (RNA/DNA) and for supplying energy to living cells through glycolysis. Considered to be potential biosignatures in the search of past or present life, our capacity to detect and quantify these essential sugars is crucial for future space missions to the Moon, Mars or Titan as well as for sample-return missions. However, the enantioselective analysis of carbohydrates is challenging and both research and routine applications, are lacking efficient methods that combine highly sensitive and reproducible detection with baseline enantioselective resolution and reliable enantiomeric excess (ee) measurements. Here, we present four different derivatization strategies in combination with multidimensional gas chromatography coupled to a reflectron time-of-flight mass spectrometer (GC×GC-TOF-MS) for the enantioselective resolution of C3 to C6 carbohydrates potentially suitable for sample-return analyses. Full mass spectral interpretation and calibration curves for one single-step (cyclic boronate derivatives) and three two-step derivatization protocols (aldononitrile-acetate, hemiacetalization-trifluoroacetylation, and hemiacetalization-permethylation) are presented for concentrations ranging from 1 to 50 pmol µL⁻1 with correlation coefficients R2 > 0.94. We compared several analytical parameters including reproducibility, sensitivity (LOD and LOQ), overall separation, chiral resolution (RS), mass spectrum selectivity, stability during long term storage, and reliability of ee measurements to guide the application-dependent selection of optimal separation and quantification performance.


Assuntos
Glucose , Ribose , Reprodutibilidade dos Testes , Estereoisomerismo , Cromatografia Gasosa
13.
J Cell Sci ; 137(3)2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38345344

RESUMO

The 2'-O-methylation (2'-O-Me) of ribosomal RNA (rRNA) shows plasticity that is potentially associated with cell phenotypes. We used RiboMeth-seq profiling to reveal growth arrest-specific 2'-O-Me patterns in primary human dermal fibroblasts from three different donors. We exposed cells to hydrogen peroxide to induce cellular senescence and to high cell densities to promote quiescence by contact inhibition. We compared both modes of cell cycle arrest to proliferating cells and could indeed distinguish these conditions by their overall 2'-O-Me patterns. Methylation levels at a small fraction of sites showed plasticity and correlated with the expression of specific small nucleolar RNAs (snoRNAs) but not with expression of fibrillarin. Moreover, we observed subtle senescence-associated alterations in ribosome biogenesis. Knockdown of the snoRNA SNORD87, which acts as a guide for modification of a hypermethylated position in non-proliferating cells, was sufficient to boost cell proliferation. Conversely, depletion of SNORD88A, SNORD88B and SNORD88C, which act as guides for modification of a hypomethylated site, caused decreased proliferation without affecting global protein synthesis or apoptosis. Taken together, our findings provide evidence that rRNA modifications can be used to distinguish and potentially influence specific growth phenotypes of primary cells.


Assuntos
RNA Ribossômico , Ribose , Humanos , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Ribose/metabolismo , Ribossomos/metabolismo , Metilação , RNA Nucleolar Pequeno/genética , Fibroblastos/metabolismo
14.
J Phys Chem A ; 128(6): 1109-1123, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38316031

RESUMO

We report a combined experimental and computational study of adenosine cation radicals that were protonated at adenine and furnished with a radical handle in the form of an acetoxyl radical, •CH2COO, that was attached to ribose 5'-O. Radicals were generated by collision-induced dissociation (CID) and characterized by tandem mass spectrometry and UV-vis photodissociation action spectroscopy. The acetoxyl radical was used to probe the kinetics of intramolecular hydrogen transfer from the ribose ring positions that were specifically labeled with deuterium at C1', C2', C3', C4', C5', and in the exchangeable hydroxyl groups. Hydrogen transfer was found to chiefly involve 3'-H with minor contributions by 5'-H and 2'-H, while 4'-H was nonreactive. The hydrogen transfer rates were affected by deuterium isotope effects. Hydrogen transfer triggered ribose ring cleavage by consecutive dissociations of the C4'-O and C1'-C2' bonds, resulting in expulsion of a C6H9O4 radical and forming a 9-formyladenine ion. Rice-Ramsperger-Kassel-Marcus (RRKM) and transition-state theory (TST) calculations of unimolecular constants were carried out using the effective CCSD(T)/6-311++G(3d,2p) and M06-2X/aug-cc-pVTZ potential energy surfaces for major isomerizations and dissociations. The kinetic analysis showed that hydrogen transfer to the acetoxyl radical was the rate-determining step, whereas the following ring-opening reactions in ribose radicals were fast. Using DFT-computed energies, a comparison was made between the thermochemistry of radical reactions in adenosine and 2'-deoxyadenosine cation radicals. The 2'-deoxyribose ring showed lower TS energies for both the rate-determining 3'-H transfer and ring cleavage reactions.


Assuntos
Adenosina , Desoxiadenosinas , Ribose , Cinética , Deutério , Desoxirribose/química , Hidrogênio , Cátions/química , Radicais Livres/química
15.
Drug Resist Updat ; 73: 101028, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38340425

RESUMO

AIMS: The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. METHODS: The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. RESULTS: Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. CONCLUSIONS: The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Ftalazinas , Humanos , Animais , Feminino , Camundongos , Ribose/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias
16.
J Transl Med ; 22(1): 177, 2024 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-38369503

RESUMO

BACKGROUND: Human health is seriously threatened by antibiotic-induced intestinal disorders. Herein, we aimed to determine the effects of Autoinducer-2 (AI-2) combined with Lactobacillus rhamnosus GG (LGG) on the intestinal barrier function of antibiotic-induced intestinal dysbiosis neonatal mice. METHODS: An antibiotic-induced intestinal dysbiosis neonatal mouse model was created using antibiotic cocktails, and the model mice were randomized into the control, AI-2, LGG, and LGG + AI-2 groups. Intestinal short-chain fatty acids and AI-2 concentrations were detected by mass spectrometry and chemiluminescence, respectively. The community composition of the gut microbiota was analyzed using 16S rDNA sequencing, and biofilm thickness and bacterial adhesion in the colon were assessed using scanning electron microscopy. Transcriptome RNA sequencing of intestinal tissues was performed, and the mRNA and protein levels of HCAR2 (hydroxycarboxylic acid receptor 2), claudin3, and claudin4 in intestinal tissues were determined using quantitative real-time reverse transcription PCR and western blotting. The levels of inflammatory factors in intestinal tissues were evaluated using enzyme-linked immunosorbent assays (ELISAs). D-ribose, an inhibitor of AI-2, was used to treat Caco-2 cells in vitro. RESULTS: Compared with the control, AI-2, and LGG groups, the LGG + AI-2 group showed increased levels of intestinal AI-2 and proportions of Firmicutes and Lacticaseibacillus, but a reduced fraction of Proteobacteria. Specifically, the LGG + AI-2 group had considerably more biofilms and LGG on the colon surface than those of other three groups. Meanwhile, the combination of AI-2 and LGG markedly increased the concentration of butyric acid and promoted Hcar2, claudin3 and claudin4 expression levels compared with supplementation with LGG or AI-2 alone. The ELISAs revealed a significantly higher tumor necrosis factor alpha (TNF-α) level in the control group than in the LGG and LGG + AI-2 groups, whereas the interleukin 10 (IL-10) level was significantly higher in the LGG + AI-2 group than in the other three groups. In vitro, D-ribose treatment dramatically suppressed the increased levels of Hcar2, claudin3, and claudin4 in Caco-2 cells induced by AI-2 + LGG. CONCLUSIONS: AI-2 promotes the colonization of LGG and biofilm formation to improve intestinal barrier function in an antibiotic-induced intestinal dysbiosis neonatal mouse model.


Assuntos
Lacticaseibacillus rhamnosus , Probióticos , Camundongos , Humanos , Animais , Animais Recém-Nascidos , Células CACO-2 , Função da Barreira Intestinal , Disbiose , Antibacterianos/farmacologia , Claudina-4/metabolismo , Ribose
17.
Angew Chem Int Ed Engl ; 63(19): e202319235, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38407532

RESUMO

The world in which we live is homochiral. The ribose units that form the backbone of DNA and RNA are all D-configured and the encoded amino acids that comprise the proteins of all living species feature an all-L-configuration at the α-carbon atoms. The homochirality of α-amino acids is essential for folding of the peptides into well-defined and functional 3D structures and the homochirality of D-ribose is crucial for helix formation and base-pairing. The question of why nature uses only encoded L-α-amino acids is not understood. Herein, we show that an RNA-peptide world, in which peptides grow on RNAs constructed from D-ribose, leads to the self-selection of homo-L-peptides, which provides a possible explanation for the homo-D-ribose and homo-L-amino acid combination seen in nature.


Assuntos
Peptídeos , RNA , Peptídeos/química , RNA/química , Ribose/química , Estereoisomerismo , Aminoácidos/química
18.
Mol Biol Rep ; 51(1): 220, 2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38281218

RESUMO

D-ribose, an ubiquitous pentose compound found in all living cells, serves as a vital constituent of numerous essential biomolecules, including RNA, nucleotides, and riboflavin. It plays a crucial role in various fundamental life processes. Within the cellular milieu, exogenously supplied D-ribose can undergo phosphorylation to yield ribose-5-phosphate (R-5-P). This R-5-P compound serves a dual purpose: it not only contributes to adenosine triphosphate (ATP) production through the nonoxidative phase of the pentose phosphate pathway (PPP) but also participates in nucleotide synthesis. Consequently, D-ribose is employed both as a therapeutic agent for enhancing cardiac function in heart failure patients and as a remedy for post-exercise fatigue. Nevertheless, recent clinical studies have suggested a potential link between D-ribose metabolic disturbances and type 2 diabetes mellitus (T2DM) along with its associated complications. Additionally, certain in vitro experiments have indicated that exogenous D-ribose exposure could trigger apoptosis in specific cell lines. This article comprehensively reviews the current advancements in D-ribose's digestion, absorption, transmembrane transport, intracellular metabolic pathways, impact on cellular behaviour, and elevated levels in diabetes mellitus. It also identifies areas requiring further investigation.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Doenças Metabólicas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ribose/metabolismo , Trifosfato de Adenosina
19.
Commun Biol ; 7(1): 69, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195757

RESUMO

Our previous work has shown that D-ribose (RIB)-induced depressive-like behaviors in mice. However, the relationship between variations in RIB levels and depression as well as potential RIB participation in depressive disorder is yet unknown. Here, a reanalysis of metabonomics data from depressed patients and depression model rats is performed to clarify whether the increased RIB level is positively correlated with the severity of depression. Moreover, we characterize intestinal epithelial barrier damage, gut microbial composition and function, and microbiota-gut-brain metabolic signatures in RIB-fed mice using colonic histomorphology, 16 S rRNA gene sequencing, and untargeted metabolomics analysis. The results show that RIB caused intestinal epithelial barrier impairment and microbiota-gut-brain axis dysbiosis. These microbial and metabolic modules are consistently enriched in peripheral (fecal, colon wall, and serum) and central (hippocampus) glycerophospholipid metabolism. In addition, three differential genera (Lachnospiraceae_UCG-006, Turicibacter, and Akkermansia) and two types of glycerophospholipids (phosphatidylcholine and phosphatidylethanolamine) have greater contributions to the overall correlations between differential genera and glycerophospholipids. These findings suggest that the disturbances of gut microbiota by RIB may contribute to the onset of depressive-like behaviors via regulating glycerophospholipid metabolism, and providing new insight for understanding the function of microbiota-gut-brain axis in depression.


Assuntos
Eixo Encéfalo-Intestino , Microbioma Gastrointestinal , Humanos , Animais , Camundongos , Ratos , Ribose , Metabolismo dos Lipídeos , Glicerofosfolipídeos
20.
Reprod Toxicol ; 124: 108550, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38280687

RESUMO

Particulate matter 2.5 (PM2.5) is associated with reproductive health and adverse pregnancy outcomes. However, studies evaluating biological markers of PM2.5 are lacking, and identifying biomarkers for estimating prenatal exposure to prevent pregnancy complications is essential. Therefore, we aimed to explore urine metabolites that are easy to measure as biomarkers of exposure. In this matched case-control study based on the PM2.5 exposure, 30 high PM2.5 group (>15 µg/m3) and 30 low PM2.5 group (<15 µg/m3) were selected from air pollution on pregnancy outcome (APPO) cohort study. We used a time-weighted average model to estimate individual PM exposure, which used indoor PM2.5 and outdoor PM2.5 concentrations by atmospheric measurement network based on residential addresses. Clinical characteristics and urine samples were collected from participants during the second trimester of pregnancy. Urine metabolites were quantitatively measured using gas chromatography-mass spectrometry following multistep chemical derivatization. Statistical analyses were conducted using SPSS version 21 and MetaboAnalyst 5.0. Small for gestational age and gestational diabetes (GDM) were significantly increased in the high PM2.5 group, respectively (P = 0.042, and 0.022). Fifteen metabolites showed significant differences between the two groups (P < 0.05). Subsequent pathway enrichment revealed that four pathways, including pentose and glucuronate interconversion with three pentose sugars (ribose, arabinose, and xylose; P < 0.05). The concentration of ribose increased preterm births (PTB) and GDM (P = 0.044 and 0.049, respectively), and the arabinose concentration showed a tendency to increase in PTB (P = 0.044). Therefore, we identified urinary pentose metabolites as biomarkers of PM2.5 and confirmed the possibility of their relationship with pregnancy complications.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Diabetes Gestacional , Nascimento Prematuro , Recém-Nascido , Feminino , Gravidez , Humanos , Material Particulado/análise , Exposição Materna/efeitos adversos , Poluentes Atmosféricos/análise , Estudos de Coortes , Estudos de Casos e Controles , Arabinose/análise , Ribose/análise , Poluição do Ar/efeitos adversos
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