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Aging Oct 2022Ribonucleotide reductase (RNR) small subunit M2 (RRM2) levels are known to regulate the activity of RNR, a rate-limiting enzyme in the synthesis of deoxyribonucleotide...
Ribonucleotide reductase (RNR) small subunit M2 (RRM2) levels are known to regulate the activity of RNR, a rate-limiting enzyme in the synthesis of deoxyribonucleotide triphosphates (dNTPs) and essential for both DNA replication and repair. The high expression of RRM2 enhances the proliferation of cancer cells, thereby implicating its role as an anti-cancer agent. However, little research has been performed on its role in the prognosis of different types of cancers. This pan-cancer study aimed to evaluate the effect of high expression of RRM2 the tumor prognosis based on clinical information collected from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found RRM2 gene was highly expressed in 30 types of cancers. And we performed a pan-cancer analysis of the genetic alteration status and methylation of RRM2. Results indicated that RRM2 existed hypermethylation, associated with m6A, m1A, and m5C related genes. Subsequently, we explored the microRNAs (miRNA), long non-coding RNAs (lncRNA), and the transcription factors responsible for the high expression of RRM2 in cancer cells. Results indicated that has-miR-125b-5p and has-miR-30a-5p regulated the expression of RRM2 along with transcription factors, such as CBFB, E2F1, and FOXM. Besides, we established the competing endogenous RNA (ceRNA) diagram of lncRNAs-miRNAs-circular RNAs (circRNA) involved in the regulation of RRM2 expression. Meanwhile, our study demonstrated that high-RRM2 levels correlated with patients' worse prognosis survival and immunotherapy effects through the consensus clustering and risk scores analysis. Finally, we found RRM2 regulated the resistance of immune checkpoint inhibitors through the PI3K-AKT single pathways. Collectively, our findings elucidated that high expression of RRM2 correlates with prognosis and tumor immunotherapy in pan-cancer. Moreover, these findings may provide insights for further investigation of the RRM2 gene as a biomarker in predicting immunotherapy's response and therapeutic target.
Topics: Humans; Ribonucleoside Diphosphate Reductase; RNA, Long Noncoding; RNA, Circular; Computational Biology; Immune Checkpoint Inhibitors; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Prognosis; MicroRNAs; Neoplasms; Immunotherapy; Transcription Factors; Deoxyribonucleotides; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 36202136
DOI: 10.18632/aging.204315 -
Aging Sep 2022The expression of deoxythymidylate kinase (DTYMK) is up-regulated in liver cancer. However, the underlying biological function and potential mechanisms of DTYMK driving...
The expression of deoxythymidylate kinase (DTYMK) is up-regulated in liver cancer. However, the underlying biological function and potential mechanisms of DTYMK driving the progression of lung adenocarcinoma remains unclear. In this study, we investigated the role of DTYMK in lung adenocarcinoma and found that the expression of DTYMK in LUAD tissues was significantly higher than that of DTYMK expression in adjacent normal tissues. Kaplan-Meier survival analysis showed that patients with higher DTYMK expression correlated with adverse prognosis. ROC curve analysis showed that the AUC value of DTYMK was 0.914. Correlation analysis showed that DTYMK expression was associated with immune infiltration in LUAD. Finally, we determine that DTYMK regulated cell proliferation, cell migration, and cell cycle of lung adenocarcinoma . In conclusion, our data demonstrated that DTYMK was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for lung adenocarcinoma.
Topics: Humans; Thymidine Monophosphate; Lung Neoplasms; Adenocarcinoma of Lung; Prognosis; Biomarkers; Tumor Microenvironment
PubMed: 36170019
DOI: 10.18632/aging.204308 -
Nutrients Sep 2022Methionine restriction and selenium supplementation are recommended because of their health benefits. As a major nutrient form in selenium supplementation,... (Comparative Study)
Comparative Study
Methionine restriction and selenium supplementation are recommended because of their health benefits. As a major nutrient form in selenium supplementation, selenomethionine shares a similar biological process to its analog methionine. However, the outcome of selenomethionine supplementation under different methionine statuses and the interplay between these two nutrients remain unclear. Therefore, this study explored the metabolic effects and selenium utilization in HepG2 cells supplemented with selenomethionine under deprived, adequate, and abundant methionine supply conditions by using nuclear magnetic resonance-based metabolomic and molecular biological approaches. Results revealed that selenomethionine promoted the proliferation of HepG2 cells, the transcription of selenoproteins, and the production of most amino acids while decreasing the levels of creatine, aspartate, and nucleoside diphosphate sugar regardless of methionine supply. Selenomethionine substantially disturbed the tricarboxylic acid cycle and choline metabolism in cells under a methionine shortage. With increasing methionine supply, the metabolic disturbance was alleviated, except for changes in lactate, glycine, citrate, and hypoxanthine. The markable selenium accumulation and choline decrease in the cells under methionine shortage imply the potential risk of selenomethionine supplementation. This work revealed the biological effects of selenomethionine under different methionine supply conditions. This study may serve as a guide for controlling methionine and selenomethionine levels in dietary intake.
Topics: Amino Acids; Aspartic Acid; Choline; Citrates; Creatine; Dietary Supplements; Glycine; Hep G2 Cells; Humans; Hypoxanthines; Lactates; Methionine; Nucleoside Diphosphate Sugars; Racemethionine; Selenium; Selenomethionine; Selenoproteins
PubMed: 36145081
DOI: 10.3390/nu14183705 -
Nanomaterials (Basel, Switzerland) Sep 2022The deoxyribonucleotide (DNA) molecule is a stable carrier for large amounts of genetic information and provides an ideal storage medium for next-generation information... (Review)
Review
The deoxyribonucleotide (DNA) molecule is a stable carrier for large amounts of genetic information and provides an ideal storage medium for next-generation information processing technologies. Technologies that process DNA information, representing a cross-disciplinary integration of biology and computer techniques, have become attractive substitutes for technologies that process electronic information alone. The detailed applications of DNA technologies can be divided into three components: storage, computing, and self-assembly. The quality of DNA information processing relies on the accuracy of DNA reading. Nanopore detection allows researchers to accurately sequence nucleotides and is thus widely used to read DNA. In this paper, we introduce the principles and development history of nanopore detection and conduct a systematic review of recent developments and specific applications in DNA information processing involving nanopore detection and nanopore-based storage. We also discuss the potential of artificial intelligence in nanopore detection and DNA information processing. This work not only provides new avenues for future nanopore detection development, but also offers a foundation for the construction of more advanced DNA information processing technologies.
PubMed: 36144924
DOI: 10.3390/nano12183135 -
ACS Infectious Diseases Oct 2022Bacterial glycoconjugates, such as cell surface polysaccharides and glycoproteins, play important roles in cellular interactions and survival. Enzymes called...
Bacterial glycoconjugates, such as cell surface polysaccharides and glycoproteins, play important roles in cellular interactions and survival. Enzymes called nucleotidyltransferases use sugar-1-phosphates and nucleoside triphosphates (NTPs) to produce nucleoside diphosphate sugars (NDP-sugars), which serve as building blocks for most glycoconjugates. Research spanning several decades has shown that some bacterial nucleotidyltransferases have broad substrate tolerance and can be exploited to produce a variety of NDP-sugars . While these enzymes are known to be allosterically regulated by NDP-sugars and their fragments, much work has focused on the effect of active site mutations alone. Here, we show that rational mutations in the allosteric site of the nucleotidyltransferase RmlA lead to expanded substrate tolerance and improvements in catalytic activity that can be explained by subtle changes in quaternary structure and interactions with ligands. These observations will help inform future studies on the directed biosynthesis of diverse bacterial NDP-sugars and downstream glycoconjugates.
Topics: Bacteria; Glycoconjugates; Ligands; Mutation; Nucleoside Diphosphate Sugars; Nucleosides; Nucleotidyltransferases; Phosphates; Sugars
PubMed: 36106727
DOI: 10.1021/acsinfecdis.2c00402 -
Bioscience Reports Oct 2022Previous documents have reported that the deoxythymidylate kinase (DTYMK) genes were involved in the progression of cancers. However, its significance in the analysis of...
Previous documents have reported that the deoxythymidylate kinase (DTYMK) genes were involved in the progression of cancers. However, its significance in the analysis of pan-cancer and specific molecular mechanism were still poorly understood. In the present study, we conducted a comprehensive study of the DTYMK gene associated with its clinical relevance across a broad-spectrum of human tumors. In addition, association among DTYMK gene and tumor immunogenic features was also explored. Considering the results of pan-cancer analysis, the specific tumor lung adenocarcinoma (LUAD) was chosen to further study the DTYMK-induced signaling pathways and intercellular communications in tumor progression. Our findings demonstrated that DTYMK may be a new biomarker for the prognosis and immunotherapy in various cancers. Importantly, DTYMK was expected to be a guiding marker gene for clinical prognosis and tumor personalized therapy in LUAD.
Topics: Humans; Lung Neoplasms; Thymidine Monophosphate; Adenocarcinoma of Lung; Biomarkers, Tumor
PubMed: 36094557
DOI: 10.1042/BSR20221170 -
Nihon Ronen Igakkai Zasshi. Japanese... 2022To determine the relationship between performance on the Digital Trail Making Peg test (DTMP) and cognitive function in older adults.
AIM
To determine the relationship between performance on the Digital Trail Making Peg test (DTMP) and cognitive function in older adults.
METHODS
A total of 203 community-dwelling older adults (mean age: 76.4±5.1 years old) participated in this study. The five-cog test was used to assess the cognitive function. The DTMP measured completion time, number of errors and intra-individual variability for performance variability (coefficient of variation, CV; inter-elemental variability, IEV). Spearman's rank correlation coefficient (ρ) was calculated to examine the association between each variable. In addition, a multiple regression analysis was performed with the cognitive function score as the dependent variable and the DTMP completion time, number of errors, CV, and IEV as the independent variables, with adjusting for the sex, age, years of education, body mass index, medical history, depression, and physical function.
RESULTS
The rank correlation coefficients with cognitive function scores were as follows: completion time, ρ = -0.479 (P < 0.01), number of errors, ρ = -0.068 (P = 0.332), CV, ρ = 0.085 (P = 0.225), IEV, ρ = -0.316 (P < 0.01). The results of the multiple regression analysis showed that completion time (β = -0.566), CV (β = 0.164), IEV (β = 2.736) were significantly associated with cognitive function scores.
CONCLUSIONS
The shorter the DTMP completion time, the better the overall cognitive function. However, the intra-individual variability of CV and IEV did not show consistent results, with smaller values indicating less intra-individual variability.
Topics: Aged; Aged, 80 and over; Body Mass Index; Cognition; Cognition Disorders; Humans; Independent Living; Thymidine Monophosphate
PubMed: 36070907
DOI: 10.3143/geriatrics.59.331 -
Biochemistry Sep 2022Remdesivir is an adenosine analogue that has a cyano substitution in the C1' position of the ribosyl moiety and a modified base structure to stabilize the linkage of the...
Remdesivir is an adenosine analogue that has a cyano substitution in the C1' position of the ribosyl moiety and a modified base structure to stabilize the linkage of the base to the C1' atom with its strong electron-withdrawing cyano group. Within the replication-transcription complex (RTC) of SARS-CoV-2, the RNA-dependent RNA polymerase nsp12 selects remdesivir monophosphate (RMP) over adenosine monophosphate (AMP) for nucleotide incorporation but noticeably slows primer extension after the added RMP of the RNA duplex product is translocated by three base pairs. Cryo-EM structures have been determined for the RTC with RMP at the nucleotide-insertion () site or at the + 1, + 2, or + 3 sites after product translocation to provide a structural basis for a delayed-inhibition mechanism by remdesivir. In this study, we applied molecular dynamics (MD) simulations to extend the resolution of structures to the measurable maximum that is intrinsically limited by MD properties of these complexes. Our MD simulations provide (i) a structural basis for nucleotide selectivity of the incoming substrates of remdesivir triphosphate over adenosine triphosphate and of ribonucleotide over deoxyribonucleotide, (ii) new detailed information on hydrogen atoms involved in H-bonding interactions between the enzyme and remdesivir, and (iii) direct information on the catalytically active complex that is not easily captured by experimental methods. Our improved resolution of interatomic interactions at the nucleotide-binding pocket between remedesivir and the polymerase could help to design a new class of anti-SARS-CoV-2 inhibitors.
Topics: Adenosine Monophosphate; Adenosine Triphosphate; Alanine; Antiviral Agents; Coronavirus RNA-Dependent RNA Polymerase; Deoxyribonucleotides; Hydrogen; Nucleotides; RNA, Viral; Ribonucleotides; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 36044776
DOI: 10.1021/acs.biochem.2c00341 -
Molecules (Basel, Switzerland) Aug 2022Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents.... (Review)
Review
Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents. Additionally, they are also valuable for tumor immunotherapy. Thus, studies on the functions and biosynthetic pathways of rhamnose-containing compounds are in progress. In this paper, studies on the biosynthetic pathways of three rhamnose donors, i.e., deoxythymidinediphosphate-L-rhamnose (dTDP-Rha), uridine diphosphate-rhamnose (UDP-Rha), and guanosine diphosphate rhamnose (GDP-Rha), are firstly reviewed, together with the functions and crystal structures of those associated enzymes. Among them, dTDP-Rha is the most common rhamnose donor, and four enzymes, including glucose-1-phosphate thymidylyltransferase RmlA, dTDP-Glc-4,6-dehydratase RmlB, dTDP-4-keto-6-deoxy-Glc-3,5-epimerase RmlC, and dTDP-4-keto-Rha reductase RmlD, are involved in its biosynthesis. Secondly, several known rhamnosyltransferases from , , , , and are discussed. In these studies, however, the functions of rhamnosyltransferases were verified by employing gene knockout and radiolabeled substrates, which were almost impossible to obtain and characterize the products of enzymatic reactions. Finally, the application of rhamnose-containing compounds in disease treatments is briefly described.
Topics: Biosynthetic Pathways; Racemases and Epimerases; Rhamnose; Thymine Nucleotides; Uridine Diphosphate
PubMed: 36014553
DOI: 10.3390/molecules27165315 -
Microorganisms Jul 2022For the molecular diagnosis of Chagas disease by real-time PCR (polymerase chain reaction), optimization of diagnostic accuracy is desirable. The detection limit of...
For the molecular diagnosis of Chagas disease by real-time PCR (polymerase chain reaction), optimization of diagnostic accuracy is desirable. The detection limit of real-time PCR assays for the diagnosis of in human serum is affected by various influences including the choice of the nucleic acid extraction assay. In this study, three nucleic acid extraction assays were compared regarding their influence on the sensitivity of a -specific real-time PCR with 62 reference sera containing target DNA (deoxyribonucleotide acid). More than 95% of the positive sera were correctly identified after all three nucleic acid extraction strategies with a detection rate ranging from 96.8% (60/62) for the worst assay to 100% (62/62) for the best one. A matched pairs analysis for the comparison of the cycle threshold (Ct) values obtained with the 59 reference samples with positive real-time PCR results after all three nucleic acid extraction schemes indicated differences in a range of about 3 Ct steps. Summarized, all three compared nucleic acid extraction schemes were basically suitable for -specific PCR from serum with some minor differences. However, in the case of low quantities of circulating parasite DNA in the serum of a patient with Chagas disease, even minor effects can make a difference in the individual diagnosis.
PubMed: 36013972
DOI: 10.3390/microorganisms10081554