Nucleosides, Nucleotides & Nucleic Acids最新文献

Lipids and glucose are important components of energy metabolism closely linked to each other. Glucose regulates cholesterol uptake via regulating the expression of different membrane transport proteins including NPC1L1, SR-B1 and ATP-binding cassette (ABC) transporters. Here, we explored further the mechanism underlying glucose-mediated regulation of cholesterol absorption and secretion. Caco-2 cells were cultivated in glucose-repletion versus glucose-depletion conditions. Quantitative real-time PCR and western blot were performed to assess mRNA and protein levels of different transporters. The amount of 25-NBD cholesterol uptake and the activity of P-gp (ABCB1) protein were measured by direct fluorometry and Rhodamine 123 efflux assay, respectively. Glucose-depleted Caco-2 cells showed lower NPC1L1 expression accompanied by reduced cholesterol uptake when compared to glucose-repleted cells. This effect was associated with an increase in the apical secretion of cholesterol compared with the basal secretion. In addition, glucose depletion upregulated both the expression level and activity of ABCB1, an apical pole transporter. However, the expression levels of ABCG5/G8, an apical sterol dimer transporter as well as ABCA1, a basal cholesterol transporter, were unchanged. The knockdown of ABCB1 in Caco-2 cells increased the intracellular accumulation of cholesterol. Glucose depletion reduces cholesterol accumulation in intestinal cells upon inducing its apical removal via ABCB1-dependent mechanism.

Objectives: Coronavirus disease 2019 (COVID-19) is the most influential public health emergency worldwide. Controlling viral infection with people's health and reducing the impact on people's freedom is difficult at present. The precise control of COVID-19 in a city may be a suitable solution.

Methods: An anonymous cross-sectional survey was conducted among Hangzhou people between 1 January and 28 February 2022. We organized the classification, incidence rate and mortality of COVID-19. And we introduced the discovery process of Omicron, health code of four colors, the epidemiological investigation and the policies of government in Hangzhou. This paper discusses various measures taken against Omicron in Hangzhou, China, which are effective methods to deal with such public health emergencies.

Conclusions: Hangzhou quickly controlled the epidemic through precise control. As of February 1, Hangzhou had 115 confirmed cases with total population is 12.204 million. The rate of severe and death is 0%. Hangzhou's new model of precise control provides an important reference for the global city's response to COVID-19 and the reduction in losses caused by COVID-19. The COVID-19 Omicron variant outbreak indicates that people will still face unpredictable health risks in the future. Precise control is one of the best ways to effectively manage an epidemic, minimize its severity, and reduce losses in all aspects.

Mitochondrial dysfunction in failing hearts has been described as a driving force for energy deprivation and cardiomyocyte energy supply-demand imbalance. Isoproterenol (ISO), the β1/β2-adrenergic receptor agonist that leads to myocardial stress and mitochondrial damage, is extensively used for in vitro and in vivo studies to test the efficacy of therapeutic strategies in heart failure (HF). This study evaluated the cell morphology, nucleotide concentrations, and mitochondrial function of ISO-treated cardiomyocytes stimulated with the activators of mitochondrial biogenesis and nucleotide precursors. H9c2 rat cardiomyocyte line cells were treated with ISO in the presence of mitochondrial biogenesis stimuli quercetin (Que), rosiglitazone (Ros), S-Nitroso-N-acetyl-DL-penicillamin (SNAP), and NAD⁺ precursor, nicotinamide riboside (NR). The intracellular concentrations of nucleotides were analyzed using high-performance liquid chromato-graphy, and the Seahorse metabolic flux analyzer determined the mitochondrial function. ISO decreased intracellular ATP concentration in H9c2 cells as compared to control. The treatment with SNAP increased ATP concentration compared to ISO-only treated cells, while Que, Ros, and NR had no effect. NR treatment led to the elevation of intracellular NAD⁺ concentration, while the treatment with SNAP, Ros, and NR stimulated the mitochondrial respiration in ISO-pretreated H9c2 cells. In conclusion, mitochondrial biogenesis activators consistently improved cardiomyocyte mitochondrial function, but only selected molecules helped to improve ATP or NAD⁺ concentrations. This information may help to optimize treatment to ameliorate energy imbalance in failing cardiomyocytes.

MicroRNA-134 (miRNA134) has emerged as a critical regulator in the pathogenesis of epilepsy, particularly in intractable cases resistant to conventional therapies. This review explores the multifaceted roles of miRNA134 in epileptogenesis, focusing on its influence on dendritic spine morphology and synaptic plasticity. Through its interactions with proteins such as LIM kinase 1 (LIMK1), Pumilio 2 (PUM2), and Tubby-like protein 1 (TULP1), miRNA134 modulates various molecular pathways implicated in epilepsy development. Preclinical studies have shown pro-mising results in targeting miRNA134 for mitigating seizure activity, highlighting its potential as a therapeutic target. Furthermore, miRNA134 holds promise as a biomarker for epilepsy diagnosis and prognosis, offering opportunities for personalized treatment approaches. However, further research is warranted to elucidate the precise mechanisms underlying miRNA134's effects and to translate these findings into clinical applications.

One of the mechanisms responsible for antibiotic resistance in Klebsiella pneumoniae is the enzymes produced by the bacteria; another important mechanism is the ability to form biofilm. In this study, antibiotic resistance, genes associated with virulence, and biofilm-forming properties of K. pneumoniae strains were investigated. A total of 100  K. pneumoniae isolates were obtained from different clinical samples identified by Matrix-Assisted Laser Desorption/Ionization time-of-flight Mass Spectrometry. Antimicrobial susceptibility testing was performed with the Phoenix 100 apparatus. The biofilm forming properties of strains were determined by the microtiter plate method. For molecular analysis, genes encoding the carbapenemase enzyme (bla_OXA-48, bla_NDM-1, bla_IMP, and bla_VIM) and biofilm-related genes (treC, luxS, mrkA, and wza) were investigated by polymerase chain reaction (PCR). While 76% of clinical isolates were resistant to three or more antimicrobials, 24% were classified as non-multidrug resistant (non-MDR). When biofilm-forming capacities of clinical isolates were tested, it was determined that the resistant-isolates produced 59.2% strong biofilm, and susceptible-isolates produced 12.5% strong biofilm. According to PCR results, carbapenemase genes were determined as follows: bla_OXA-48-70%, bla_NDM-49%, and bla_KPC-19%, bla_OXA-48/bla_NDM/bla_KPC-12%, bla_OXA-48/bla_NDM-26%, and bla_OXA-48/bla_KPC-4%. The biofilm-associated genes in bacterial isolates were determined as follows: luxS-98%, treC-94%, mrkA-88%, and wza-15%. In addition, Hierarchical Clustering Tree and Heatmap analysis revealed an association between isolates that lacks resistance genes and isolates lacks biofilm-formation related genes that were included in MDR or non-MDR classes. As a result, biofilm should be considered in the treatment of MDR infections, and therapy should be planned accordingly. In addition, pursuing the data and genes of antibiotic resistance is significant for combating resistance.

Background: Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer treatment.

Methods: LUAD subtypes were identified using unsupervised consensus clustering, and results were subjected to immune and tumor mutation analyses. DEGs between subtypes were identified by differential analysis. Functional enrichment and PPI network analyses were conducted. Patients were classified into high and low expression groups based on the expression of the top 10 hub genes, and survival analysis was performed. Drugs sensitive to feature genes were screened based on the correlation between hub gene expression and drug IC₅₀ value. qRT-PCR and western blot were used for gene expression detection, and CCK-8 and flow cytometry were for cell viability and apoptosis analysis.

Results: Cluster-1 had significantly higher overall survival and a higher degree of immunoinfiltration and immunophenotypic score, but a lower TIDE score, DEPTH score, and TMB. Enrichment analysis showed that pathways and functions of DEGs between two clusters were mainly related to the interaction of receptor ligands with intracellular proteases. High expression of hub genes corresponded to lower patient survival rates. The predicted drugs with high sensitivity to feature genes were CDK1: Ribavirin (0.476), CCNB2: Hydroxyurea (0.474), Chelerythrine (0.470), and KIF11: Ribavirin (0.471). KIF11 and CCNB2 were highly expressed in LUAD cells and promoted cell viability and inhibited cell apoptosis.

Conclusion: This study identified two subtypes of LUAD, with cluster-1 being more suitable for immunotherapy. These results provided a reference for the development of precision immunotherapy for LUAD patients.

In this study, Taguchi optimization method was applied to determine the optimum operating conditions for batch adsorption of Cr(VI) from aqueous solution. Initial pH of solution, adsorbent dose, initial hexavalent chromium concentration, contact time and adsorbent type were selected as the variables, and the removal efficiency of Cr(VI) was chosen for the designated response. L₁₈(3⁵) orthogonal array, signal-to-noise (S/N) ratio and analysis of variance statistical procedures were applied to identify the effect of each operating parameter on the removal of Cr(VI) from aqueous solution. The signal-to-noise (S/N) ratio results showed that the optimal combination for Cr(VI) removal was at pH 1.0, adsorbent dose of 3.6 g.L^-1, Cr(VI) concentration of 30 mg.L^-1, contact time of 95 min and olive leaves as adsorbent type. A removal of 95.09% was obtained at these optimum conditions. The analysis of variance of the data revealed that initial pH of solution was the most dominant parameter affecting Cr(VI) removal efficiency, followed by adsorbent type, adsorbent dose, contact time and initial metal concentration. Under optimal conditions, adsorption kinetic of Cr(VI) was studied and modeled using the pseudo first-order, pseudo-second-order and intraparticle diffusion models. It was found that the pseudo-second-order model fitted the adsorption data most with the highest determination coefficient (R² = 0.996). Freundlich isotherm model, with regression coefficient R² of 0.953, fit well with the equilibrium isotherm data. The Langmuir maximum adsorption capacity was found to be 62.5 mg.g^-1. The experimental values of ΔH°, ΔG° and ΔS° revealed that the adsorption process was spontaneous and endothermic.

Several studies have reported the relationship between LIN28A gene polymorphisms (rs3811463 T > C and rs34787247 G > A) and cancer susceptibility, but the results are inconsistent and need further clarification. The current study aimed to evaluate their relationship and also to explore the relationship between LIN28A gene expression and immune infiltration, tumor stage, survival prognosis, and drug sensitivity in pan-cancer. The meta-analysis and data mining were completed by STATA software and the GSCA platform, respectively. The meta-analysis showed that the rs3811463 polymorphism was not associated with cancer susceptibility, while the rs34787247 polymorphism was associated with cancer susceptibility in the Chinese population [AA vs. GG: Odd Ratio (OR)=1.98, 95% Confidence Interval (CI)=1.35-2.89, P_Z<0.001; GA vs. GG: OR = 1.17, 95%CI= 1.01-1.36, P_Z=0.04; (AA + GA) vs. GG: OR = 1.24, 95%CI = 1.07-1.43, P_Z=0.004; AA vs. (GA + GG): OR = 1.90, 95%CI = 1.30- 2.78, P_Z=0.001; A vs. G: OR = 1.27, 95%CI = 1.12-1.44, P_Z<0.001]. LIN28A gene expression was associated not only with immune infiltration, pathological stage, and survival prognosis of certain cancers, but also with sensitivity to multiple anticancer drugs, such as cisplatin, pazopanib, olaparib, and selumetinib. In conclusion, the current study suggested that the rs34787247 G > A polymorphism might be used as a cancer risk marker in the Chinese population, and LIN28A might serve as a prognostic marker and therapeutic target for certain cancers.

Damaged 2'-deoxyribonucleotides cause mutations, cancer, cell death, and aging. The Escherichia coli Orf135 (NudG) protein catalyzes the hydrolysis of various 2'-deoxyribonucleotides including an oxidized form of dATP, 2-oxo-1,2-dihydro-2'-deoxyadenosine 5'-triphosphate (dA^OTP, 2-hydroxy-2'-deoxyadenosine 5'-triphosphate). The best substrate is 5-methyl-2'-deoxycytidine 5'-triphosphate (dC^mTP), and the protein prefers dC^mTP over dA^OTP by ∼200-fold in vitro. To make the enzyme specific for the mutagenic nucleotide dA^OTP, a double mutant protein (E33A plus D118E) was designed and produced in E. coli. The purified mutant protein showed one order of magnitude higher dA^OTP preference over dC^mTP. The split protein based on this mutant may potentially be used to detect dA^OTP in living cells.

Leukemia is a cancer affecting the hematopoietic system with an unclear pathogenesis. Recent studies suggest a correlation between several long non-coding RNAs (lncRNAs) and leukemia development. This study focuses on the potential link between H19 (rs2839698 and rs217727) polymorphisms and Acute Lymphoblastic Leukemia (ALL) susceptibility. The study involved 150 patients with clinically confirmed ALL and 150 controls. This research included 150 Iranian patients, who were confirmed to have clinical ALL, and 150 healthy people as the control group. A kit was utilized to extract the DNA of all the samples. After preparing the samples, DNA genotyping was done by using the tetra-primer ARMS-PCR method. After adjusting for age using multivariate logistic regression analysis, individuals carrying the CT genotype of rs2839698 were found to have a significantly 0.32-fold reduced risk of ALL compared with carriers of the CC genotype. Furthermore, a significant 0.48-fold reduction in ALL risk was observed in patients with CT+TT genotype rs2839698 compared with CC. Moreover, the over-dominant model was applied to compare the CT genotype of rs2839698 with its CC+TT genotype, which showed a significant 0.36-fold reduction of ALL risk. Notably, the cases of ALL and the control group were not significantly different in terms of their genotype and allele frequencies of rs217727 polymorphism. Yet, the TT haplotype was significantly associated with ALL risk (OR: 1.64, p = 0.025). Following the findings of this study, it can be concluded that H19 SNP rs2839698, rather than rs217727, might act as an innovative susceptibility marker for ALL leukemia.