Nucleosides, Nucleotides & Nucleic Acids最新文献

Cancer cell characteristics are determined by gene expression, influenced by genomic, epigenetic, and transcriptional modifications. Genomic rearrangements and transcriptional splicing can result in the formation of fusion genes. BCR-ABL1 is an established fusion gene employed as a biomarker in leukemia. A single gene can amalgamate with several other genes and may impact cellular fate. Ethnicity-specific variants of fusion genes have been identified, such as the TMPRSS2-ERG variation observed in prostate malignancies among African-American, Caucasian, and Japanese populations in research studies. Next-generation sequencing has provided a new method for predicting genomic and transcriptomic changes. We aim to identify fusion genes in the Indian population using cancer samples to enhance diagnostic outcomes. This study performed a meta-analysis of tumor-specific RNA sequencing data for liver, tongue, and ovarian cancers, which are available online. It identified known fusion genes, including TRO-MAGED2, KRT14-S100A9, RNASE10-CD38, ACTN4-ACTN1, RGPD1-RANBP2, CTSC-RAB38, C15orf57-CBX3, AMBRA1-CKAP5, ATP2B3-ATP2B4, CNKSR3-IPCEF1, E2F4-RPL14, and MZT2A-MZT2B, along with 101 novel fusion genes. Novel fusion genes GABRP_SCGB3A2 and WWOX_FUT1 were identified in all three tumor tissues. GABRP acts as a tumor inducer, whereas SCGB3A2 functions as a tumor suppressor. WWOX2 serves as a tumor suppressor, whereas FUT1 functions as a promoter of malignancy. The interplay between tumor inducers and suppressors may serve as a survival mechanism for cancer cells, a subject that has received limited research attention.

We developed pH-responsive lipids, LIPIDs-1 and LIPIDs-2, which feature an N,N-dimethylaminopropyl head and 2 hydrophobic tails connected by carbonate esters. These lipids are metabolizable owing to acetyl ester structures that can be cleaved by esterases, reducing their affinity for biological membranes after hydrolysis of the esters. We evaluated both lipids in vivo using siRNA-loaded lipid nanoparticles (LNPs) targeting Factor VII, which resulted in significant knockdown activity for up to 6 days. Toxicological studies of LNPs using LIPIDs-1 and LIPIDs-2 in rats indicated minimal liver toxicity and rapid metabolism of the lipids, confirming their safety. Moreover, we tested LNPs using LIPIDs-1 as an mRNA vaccine carrier, which resulted in strong immune responses against both ovalbumin and SARS-CoV-2 antigens with a notable Th1-biased profile. These findings suggest that LNPs made using LIPIDs-1 and LIPIDs-2 are promising candidates for drug delivery and vaccine applications.

Via Dr. Bernhard Witkop, I generated the interest of Dr. Paul F. Torrence to evaluate the requirements of synthetic polynucleotides to induce interferon. His interest, akin to mine, then shifted to 5-substituted 2'-deoxyuridines, which we first evaluated for their activity against herpes simplex virus (HSV) replication and later as tumor cell inhibitors targeted at thymidylate synthetase. The major interest of Dr. Torrence then shifted to the 2'-5'-oligoadenylate (2-5A), which, concomitantly with its target enzyme, RNase L, effected marked antiviral activity, that is, against respiratory syncytial virus (RSV). As the hope(s) for an effective 2-5A therapeutic for RSV or any other virus infection was not realized, Paul Torrence returned to nucleoside analogues, now targeted at poxviruses.

Background: Long non-coding RNAs (lncRNAs) perform critical functions in tumorigenesis and the development of malignancy. Dysregulation of LINC00885 has been associated with intricate biological processes in diverse cancer types. However, the functional significance of LINC00885 in gastric cancer (GC) and the mechanistic underpinnings governing its activity have yet to be thoroughly investigated.

Methods: LINC00885 expression levels were assessed in serum specimens obtained from both healthy donors and GC patients, as well as across various GC cell lines, employing quantitative reverse transcription polymerase chain reaction (RT-qPCR). The diagnostic efficacy of LINC00885 was determined through receiver operating characteristic (ROC) curve analysis. Cellular functions (proliferation, migration, invasion) and the nature of miRNA interactions were elucidated via functional assays and rescue experiments.

Results: LINC00885 expression was markedly reduced in GC and demonstrated the capacity to differentiate GC patients from healthy controls. Based on the median serum LINC00885 expression level in 218 gastric cancer patients, cases were categorized into high- and low-expression groups. Low serum LINC00885 levels were significantly associated with larger tumor size (p = 0.044) and advanced TNM stage (p = 0.022), but not with other clinicopathological parameters. Ectopic expression of LINC00885 inhibited the proliferative, migratory, and invasive capacities of GC cells. LINC00885 was demonstrated to bind directly to miR-320c and modulate GC cellular behavior. Mechanistically, the tumor-suppressive impact of LINC00885 during GC progression is likely mediated by its function as a competitive endogenous RNA (ceRNA), sequestering miR-320c.

Conclusion: LINC00885 exhibits potential diagnostic value and represents a promising therapeutic target for GC.

Breast cancer is the most common malignancy that affects women. MicroRNAs (miRNAs) play an essential role in cancer therapy and regulate many biological processes such as cisplatin resistance. The study's objective was to determine whether miR-182 dysregulation was the cause of cisplatin resistance in TNBC cell line MDA-MB-231. To determine the expression of miR-182, PCR was performed with primers specific to miR-182, and agarose gel electrophoresis was performed. To reduce the expression of miR-182 in MDA-MB-231 cells, anti-miR-182 oligonucleotides were used. RT-qPCR was used to confirm knockdown. The knockdown and control groups were treated with cisplatin at the same time. Propidium iodide (PI) and Annexin V staining were performed for apoptosis assay. Flow cytometric analysis was used to investigate the effect of miR-182 knockdown on cell cycle arrest. In comparison to untreated control MDA-MB-231 cells with MDA-MB-231 cells treated with anti-miR-182, there was a significant increase in the cisplatin-induced early apoptosis phase (p = 0.023). Also, inhibition of miR-182 significantly increased the cell cycle arrest at the G2/M phase in MDA-MB-231 cells (p = 0.031). Our results revealed that miR-182 inhibition may play a role in the overcoming of cisplatin resistance by inducing apoptosis and, cell cycle arrest in TNBC.

Esophageal squamous cell carcinoma (ESCC), a prevalent malignancy within the digestive tract, is associated with a significantly high mortality rate. MicroRNAs were already demonstrated to work in a wide range of tumors. The objective of the present research was to elucidate the involvement of miR-103 in the pathogenesis of ESCC and to explore its underlying mechanisms of action. Real-time quantitative polymerase chain reaction was used to detect miR-103 expressions in ESCC tissues and cells. The clinical significance of these expressions was assessed by a series of statistical analyses. Transwell assay was used to study the impact of miR-103 on migration and invasion ability of ESCC cells. Furthermore, a dual luciferase reporter gene method was adopted to study the association of miR-103 with the targeting of forkhead box protein 1 (FOXP1). miR-103 was significantly up-regulation in ESCC tissues and cell lines. Clinically, high miR-103 expression was associated with negative prognosis in ESCC. The low miR-103 expression significantly inhibited cell proliferation, migration and invasion in ESCC cell lines. Furthermore, miR-103 regulated the mechanism of action of ESCC by targeting FOXP1. In this study, we found that miR-103 may serve as a biomarker for ESCC prognosis. miR-103 may promote ESCC cell metastasis by targeting FOXP1. These studies may elucidate the potential of miR-103 as a novel target for the treatment of ESCC.

Objective: Type 2 Diabetes Mellitus (T2DM) can lead to long-term vascular complications such as diabetic peripheral neuropathy (DPN). This study aimed to investigate the role of angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) and angiotensin II type 1 receptor (AT1R) A1166C variants in the predisposition to T2DM in the Turkish population and their association with DPN.

Methods: The study included 90 T2DM patients (42 with DPN) and 50 healthy individuals. ACE I/D and ATIR A1166C gene regions were analyzed for the variant. Both the general genotype distribution of these variants and the observed genotype ratios were examined separately.

Results: In the T2DM group, the proportion of individuals with the AA genotype of the AT1R A1166C variant was lower than in the control group, and the proportion of individuals with the AC genotype was higher. There was no significant difference in the genotype distribution between the groups for the ACE I/D variant. There was no significant difference in the genotype distribution of the ACE I/D and ATIR A1166C variants in patients with and without DPN.

Conclusion: In the Turkish population, no significant difference was observed in the overall genotype distribution of ACE I/D and AT1R A1166C variants between T2DM patients and healthy individuals, whereas the AC genotype of the AT1R A1166C variant was more frequent in T2DM patients, and the AA genotype was less frequent. For both variants, no significant difference was observed in the genotype distribution between T2DM patients with and without DPN.

The MBL2 gene encodes the mannose-binding lectin protein (MBL), which is secreted by the liver. Several variants of MBL2 have been found to be associated with altered serum levels and susceptibility to various chronic diseases. Defects in MBL protein polymerization that result in functional impairments and/or low serum levels may influence genetic susceptibility to type 2 diabetes (T2D) and its complications. Therefore, the present case-control study was conducted to assess the potential association of six MBL2 gene variants and haplotypes with susceptibility to T2D and its complications in Morocco. The MBL2 gene was genotyped by PCR-sequencing for the promoting, non-coding, and coding regions in 435 individuals. Our findings revealed a significant association between the heterozygous CG and homozygous recessive GG genotypes of the variant at position -221 C > G in the MBL2 gene promoter with an increased risk of T2D. Similarly, for +4 C > T in the non-coding region, statistical analysis indicates a strong association with T2D risk, particularly with the heterozygous CT and homozygous recessive TT genotypes. The LYQC haplotype is also found to be associated with T2D risk. Furthermore, the heterozygous CT genotype, and recessive T allele of the variant at position +4 C > T, and heterozygous GA genotype of codon Gly54Asp of the MBL2 gene, are associated with protection against hypertension in T2D patients. However, no association was observed between MBL2 variants and dyslipidemia in T2D patients. The study concludes that -221 C > G and +4 C > T variants of the MBL2 gene significantly contribute to T2D susceptibility in Morocco.

This article presents a new and facile method for the synthesis of Schiff base compounds with a benzimidazole group using a low-cost and reusable calcium aluminate nanophosphorus catalyst (CaAl₂O₄). This approach avoids harmful solvents and reactants, supporting a more environmentally friendly synthesis process. The catalyst maintained its activity and heterogeneity over four cycles with minimal loss of efficiency. The synthesis process was straightforward and eliminated the need for column chromatography. The Schiff base ligand (HL=(E)-N-((6-(thiophen-2-yl)pyridin-2-yl)methylene)-1H-benzo[d]imidazol-2-amine)) was synthesized by the reaction of 6-(thiophen-2-yl)pyridine-2-carbaldehyde with 1H-benzimidazole-2-amine. Subsequently, metal(II) complexes of Co(II), Ni(II), and Cu(II) were prepared using this ligand. Structural analysis of both the ligand and its metal complexes was carried out using various physicochemical and spectroscopic methods. Ni(II) and Co(II) complexes were found to adopt an octahedral geometry, while the Cu(II) complex exhibited a square-planar structure. Binding studies with calf thymus DNA (CT-DNA) at pH 7.2 were performed using UV-visible spectroscopy, viscosity measurements, and thermal denaturation studies and showed that the metal complexes intercalate into the DNA and produced a distinct binding pattern. Molecular docking simulations with AutoDock Vina provided insights into the interaction of these complexes with the B-DNA dodecamer. Furthermore, the ligand and its metal complexes showed UV-visible photonuclease activity against pUC19 DNA. Agarose gel electrophoresis showed that the metal complexes exhibit photoinduced nuclease activity, confirming their ability to cleave DNA upon exposure to light.

This study introduces a new and simple method for the synthesis of a series of 3-(benzo[d]thiazol-2-yl)-5-phenylisoxazole derivatives 3(a-f), and examines its potential interactions with DNA. The synthesis includes the reaction of 2-aminobenzenethiol (1) with a variety of substituted 5-phenylisoxazole-3-carbaldehydes 2(a-f) in the presence of a cost-effective and reusable nanocatalyst, Calcium-Zincate (CaZnO₂). The CaZnO₂ catalyst showed a consistent and long-lasting catalytic activity over several reaction cycles and retained its unique heterogeneous properties. The resulting compounds were characterized in detail using various spectroscopic and analytical techniques in order to confirm their structures. In addition, the interaction of these synthesized compounds with calf thymus-DNA (CT-DNA) using absorption spectroscopy and viscosity measurements was assessed. In silico docking studies were performed to predict their binding affinity with human DNA (PDB ID: 1G3X). The compounds were further analyzed using the Density Functional Theory (DFT) with the B3LYP functional and the 6-31 G(d) basis set in chloroform, with the results aligning closely with the experimental findings. Furthermore, the compounds ability to cleave PUC19 DNA was assessed, along with their photoinduced nuclease activity under UV-visible light, confirmed by photo-induced cleavage assays.