Nucleosides, Nucleotides & Nucleic Acids最新文献

Thiosemicarbazide was used as a key starting material for the building of a diversity of novel heterocyclic moieties. The heterocyclization reaction of thiosemicarbazide derivatives with carbon disulfide in basic conditions afforded novel heterocyclic 1,3,4-thiadiazolethiolate derivatives. 1,3,4-thiadiazole-2-thiol was successfully reacted with protected α-D-gluco- and galacto-pyranosyl bromides in dimethylformamide at room temperature to give the matching 1,3,4-thiadiazole S-glycosides in good yields. The latter compounds were reacted with ammonia-methanol at room temperature for 10 min, and the deprotected derivatives were obtained in good yields. The newly synthesized compounds were characterized by basic analyses and spectral information (IR,¹H NMR, and ¹³C NMR, X-ray). All newly produced compounds were evaluated and screened for their antibacterial activities. Compound 6f proved to be the most active antimicrobial among the investigated heterocycles.

Objective: Circadian rhythmicity has been shown to contribute to the regulation of key physiological and cognitive processes related to performance. The period homolog 3 (PER3) is expressed in a circadian pattern in the suprachiasmatic nucleus. Therefore, in this study, we aimed to evaluate the role of the variable tandem repeat (VNTR) variant of the PER3 gene in athletic performance in the Turkish population.

Methods: This study included 223 subjects, which consisted of 123 athletes and 100 sedentary controls. Blood samples were drawn from all subjects. DNA was extracted from whole-blood samples. The PER3 VNTR variant was genotyped using the polymerase chain reaction-restriction method (PCR). The results of the analyses were evaluated for statistical significance.

Results: The mean ages of athletes and controls were 22 ± 2.814 and 23 ± 3.561, respectively. Endurance athletes in the group were 21.1%, and sprint athletes were 78.9%. There was no statistical significance in terms of PER3 VNTR genotype distribution or allele frequency. In the recessive model, a statistically significant association was observed when the athletes were compared with the controls according to 4/4 + 4/5 versus 5/5 genotype (p = 0.020).

Conclusion: In this case-control study, for the first time in our country, we obtained findings suggesting that the PER3 VNTR variant may affect sports performance in the Turkish population. Results need to be replicated in different ethnic and larger samples.

Interferon-gamma (IFN-γ) has been established to play a pivotal role in the pathogenesis of tuberculosis (TB). Existing evidence suggests a potential association between the genetic poly-morphisms of IFN-γ and the susceptibility to TB. However, this association remains a topic of controversy. To address this knowledge gap, a meta-analysis was conducted to provide more accurate results regarding their relationship. The pooled odds ratio along with its corresponding 95% confidence interval was calculated using four different gene models. This analytical approach served to evaluate the strength of the association between single nucleotide polymorphisms (SNPs) and TB susceptibility. Additionally, we determined whether a fixed effect model or a random effect model should be applied based on the extent of heterogeneity. Egger's test was used to evaluate publication bias. This study included a total of nine studies, involving 4509 patients with TB and 4378 healthy controls. In non-Asian populations, a C > T mutation at polymorphic variant rs2069705 and a T > C mutation at rs2069718 was associated with an increased risk of TB. Conversely, among Asians, the variants rs2069705, rs2069718, and rs1861494 were not significantly associated with the risk of TB. Importantly, our investigation did not reveal any significant publication bias in the pooled results of the four gene models. In conclusion, this meta-analysis suggests that two SNPs in IFN-γ may be associated with TB susceptibility in non-Asian populations. However, for Asians, there is no evidence to support a conclusive relationship between these SNPs and the risk of TB.

RECK plays an important role in the development of cancer. The current study focuses on exploring the clinical significance of RECK expression in cancer by mining public data and also evaluating the relationship between genetic polymorphisms of the RECK gene and cancer risk through meta-analysis. The results showed that RECK expression was not only associated with survival prognosis and immune infiltration in many types of cancers, but also with multiple drug sensitivity in pan-cancer. In addition, the RECK rs10814325 polymorphism was also associated with cancer risk under the homozygote comparison model (CC vs. TT: OR = 1.64, 95%CI = 1.03-2.61, p = 0.04) and the recessive genetic model [CC vs. (CT + TT): OR = 1.55, 95%CI = 1.27-1.89, p < 0.01]. In conclusion, these findings suggest that RECK expression levels may serve as a valuable indicator for assessing cancer prognosis in some cancers as well as drug sensitivity in pan-cancer, and its rs10814325 polymorphism may be used to assess cancer risk.

Glutamine amidotransferases (GATs) catalyze the synthesis of nucleotides, amino acids, glycoproteins and an enzyme cofactor, thus serving as key metabolic enzymes for cell proliferation. Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is a multifunctional enzyme of the GAT family and catalyzes the first three steps of the de novo pyrimidine synthesis. Following our findings that cellular GATs are involved in immune evasion during herpesvirus infection, we discovered that CAD reprograms cellular metabolism to fuel aerobic glycolysis and nucleotide synthesis via deamidating RelA. Deamidated RelA activates the expression of key glycolytic enzymes, rather than that of the inflammatory NF-κB-responsive genes. As such, cancer cells prime RelA for deamidation via up-regulating CAD activity or accumulating RelA mutations. Interestingly, the recently emerged SARS-CoV-2 also activates CAD to couple evasion of inflammatory response to activated nucleotide synthesis. A small molecule inhibitor of CAD depletes nucleotide supply and boosts antiviral inflammatory response, thus greatly reducing SARS-CoV-2 replication. Additionally, we also found that CTP synthase 1 (CTPS1) deamidates interferon (IFN) regulatory factor 3 (IRF3) to mute IFN induction. Our previous studies have implicated phosphoribosyl formylglycinamidine synthase (PFAS) and phosphoribosyl pyrophosphate amidotransferase (PPAT) in deamidating retinoic acid-inducible gene I (RIG-I) and evading dsRNA-induced innate immune defense in herpesvirus infection. Overall, these studies have uncovered an unconventional enzymatic activity of cellular GATs in metabolism and immune defense, offering a molecular link intimately coupling these fundamental biological processes.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver disease characterized. The condition ranges from isolated excessive hepatocyte triglyceride accumulation and steatosis (nonalcoholic fatty liver (NAFL), to hepatic triglyceride accumulation plus inflammation and hepatocyte injury (nonalcoholic steatohepatitis (NASH)) and finally to hepatic fibrosis and cirrhosis and/or hepatocellular carcinoma (HCC). However, the mechanism driving this process is not yet clear. Obtain sample microarray from the GEO database. Extract 6 healthy liver samples, 74 nonalcoholic hepatitis samples, 8 liver cirrhosis samples, and 53 liver cancer samples from the GSE164760 dataset. We used the GEO2R tool for differentially expressed genes (DEGs) analysis of disease progression (nonalcoholic hepatitis healthy group, cirrhosis nonalcoholic hepatitis group, and liver cancer cirrhosis group) and necroptosis gene set. Gene set variation analysis (GSVA) is used to evaluate the association between biological pathways and gene features. The STRING database and Cytoscape software were used to establish and visualize protein-protein interaction (PPI) networks and identify the key functional modules of DEGs, drawn factor-target genes regulatory network. Gene Ontology (GO) and KEGG pathway enrichment analyses of DEGs were also performed. Additionally, immune infiltration patterns were analyzed using the cibersort, and the correlation between immune cell-type abundance and DEGs expression was investigated. We further screened and obtained a total of 152 intersecting DEGs from three groups. 23 key genes were obtained through the MCODE plugin. Transcription factors regulating common differentially expressed genes were obtained in the hTFtarget database, and a TF target network diagram was drawn. There are 118 nodes, 251 edges, and 4 clusters in the PPI network. The key genes of the four modules include METAP2, RPL14, SERBP1, EEF2; HR4A1; CANX; ARID1A, UBE2K. METAP2, RPL14, SERBP1 and EEF2 was identified as the key hub genes. CREB1 was identified as the hub TF interacting with those gens by taking the intersection of potential TFs. The types of key gene changes were genetic mutations. It can be seen that the incidence of key gene mutations is 1.7% in EEF2, 0.8% in METAP2, and 0.3% in RPL14, respectively. Finally, We found that the most significant expression differences of the immune infiltrating cells among the three groups, were Tregs and M2, M0 type macrophages. We identified four hub genes METAP2, RPL14, SERBP1 and EEF2 being the most closely with the process from NASH to cirrhosis to HCC. It is beneficial to examine and understand the interaction between hub DEGs and potential regulatory molecules in the process. This knowledge may provide a novel theoretical foundation for the development of diagnostic biomarkers and gene-related therapy targets in the process.

Novel class of triazine sulfonamide thioglycosides was designed and synthesized. Those novel structures comprising three essential and pharmacological significant moieties such as the triazine, sulfonamide, and thioglycosidic scaffolds. The triazine sulfonamides were furnished via a direct approach starting from potassium cyanocarbonimidodithioate, then the corresponding triazine sulfonamide thioglycosides were generated using the peracylated α-d-gluco- and galacto-pyranosyl bromides. Anti-viral evaluation of compounds in vitro against HCoV-229E virus revealed that some compounds possess promising activity. Compounds 4a, 4b, 4d, 6d and 6e indicate from moderate to low antiviral activity against low pathogenic coronavirus 229E in comparison with remdesivir at a concentration of 100 µg/mL. Additionally their in vitro anti-proliferative effects against NCI 60 cancer cell lines cell lines were also investigated. Compound 4a, the most potent compound among the estimated compounds, revealed remarkably lowest cell growth promotion against CNS cancer SNB-75, and renal cancer UO-31.

To provide a comprehensive account of the association of MMP-9 gene polymorphisms (rs3918242) with susceptibility to cancer. A literature search for eligible candidate gene studies published before May 27, 2022 was conducted in PubMed, Medline, Google Scholar and Web of Science. Potential sources of heterogeneity were sought out across subgroups and sensitivity analysis. Publication bias were also estimated. Overall, a total of 37 articles with 7616 cases and 8165 controls for rs3918242 gene polymorphisms were enrolled. Our meta-analysis suggests that MMP-9 rs3918242 might be associated with breast cancer and gastric cancer susceptibility, and perhaps reduce the risk of lung cancer.

Purpose: Diabetic neuropathy (DN) is a serious complication of diabetes that affects peripheral and autonomic nerves, and it has been linked to irregularities in circadian rhythm. Several studies have demonstrated that disruptions in circadian rhythm and changes in expression of rhythm genes may play a role in the development and progression of diabetes, including the development of DN.

Methods: In this study, the association between the VNTR polymorphism of the PER3 gene and diabetic neuropathy was investigated. The study included 84 patients with diabetes, 220 patients with diabetic neuropathy, and 218 healthy individuals as the control group.

Results: Upon analyzing the data from the study, it was found that there was no significant difference in the PER3 VNTR polymorphism between the diabetic neuropathy patients, diabetes and control groups. However, there was a significant difference observed between the control group and the diabetes group, particularly in terms of the 5/5 genotype and 5 alleles. Moreover, a significant difference was observed between the patient group and the control group (p < 0.05).

Conclusions: In conclusion, first in the world, the relationship between PER3 gene VNTR polymorphism and diabetic neuropathy and diabetes, was investigated. Our results showed that PER3 may be associated with diabetes but not with diabetic neuropathy.

In this work, we developed a series of novel 5-[3-(4-chlorophenyl)-substituted-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives 4(a-e) via a one-pot multicomponent reaction. The structures of the compounds were confirmed using analytical and spectroscopic techniques. Also, the synthesized compounds were screened for their anti-diabetic activity, cytotoxicity and in silico studies. The activity results suggested that the compound 4e exhibited least IC₅₀ values of 0.055 ± 0.002 µM, 0.050 ± 0.002 µM and 0.009 ± 0.001 µM for α-amylase, α-glucosidase and cytotoxicity respectively. Further, in silico molecular docking results revealed that all the obtained compounds effectively interacted with exo-β-D-glucosaminidase and P38 MAP kinase proteins with good binding energies. In that, 4e compound established the least binding energy of -9.6 and -9.1 kcal/mol, respectively. Moreover, our synthesized compounds were subjected to ADME studies, which suggested that all the synthesized compounds obeyed all five rules with good bioavailability and were suitable as drug leads against anti-diabetic and anticancer treatment.