Результаты поиска

Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.

Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotyp…

BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma.

Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobul … mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.

MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation.

Recently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse lar … no acid exchanges, thus potentially altering gene function. Expression levels of activation-induced cytidine deaminase (AID), an enzyme essential for somatic hypermutation (SHM), was associated with the mutational load. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding s …

Treatment of advanced hepatocellular carcinoma with biweekly high-dose gemcitabine.

INTRODUCTION: Until today, an optimal palliative treatment regimen has not been defined for patients with advanced hepatocellular carcinoma. Since the novel cytidine analog gemcitabine has shown strong antitumor effects in vitro in a human hepatoma cell line and its therapeutic potential seems well established in several different tumors including gastrointestinal adenocarcinomas, the present phase II trial using a dose-intensified biweekly administration schedule was initiated. PATIENTS AND METHODS: 17 patients with histologically confirmed unresectable advanced or metastatic hepatoma were t…

DNA methylation and globin gene expression in patients treated with 5-azacytidine.

5-Azacytidine, a cytidine analog, stimulated fetal hemoglobin synthesis in five patients who had either severe beta-thalassemia or sickle cell anemia. After treatment, a reduction in the frequency of methylated cytosine residues was observed at all Hpa II sites examined. Despite causing "global" hypomethylation, 5-azacytidine augmented the synthesis of gamma-globin only. Although gamma-gene hypomethylation and increased gamma-gene expression seem to be linked, hypomethylation near other genes was not sufficient to activate transcription. These data suggest that the gamma genes lie in a unique …

Hemolytic anemia in hereditary pyrimidine 5'-nucleotidase deficiency: nucleotide inhibition of G6PD and the pentose phosphate shunt.

We evaluated the erythrocytes of two patients with hereditary pyrimidine 5'-nucleotidase deficiency. Significant findings included an increased reduced glutathione content, increased incubated Heinz body formation, a positive ascorbate cyanide test, and decreased intraerythrocytic pH. The pentose phosphate shunt activity of the patients' red cells as measured by the release of 14CO2 from 14C-1-glucose was decreased compared to high reticulocyte controls. Glucose-6-phosphate dehydrogenase (G6PD) activity in hemolysates from control erythrocytes was inhibited 43% by 5.5 mM cytidine 5'-triphospha…

Effects of high-dose cytarabine.

Plasma, urine, cerebrospinal fluid, and tear concentrations of cytarabine (ara-C) were measured in 15 patients receiving 3 gm/m2 IV ara-C given as a 1 hr infusion every 12 hr for 6 days. The two assay methods used for measuring ara-C concentrations (high-pressure liquid chromatography and radioimmunoassay) gave much the same results. Peak plasma ara-C concentrations (2.0 microM) after high-dose therapy were 50 times those achieved with more conventional (100 to 300 mg/m2) doses. High doses of ara-C were not sufficient to saturate cytidine deaminase; plasma ara-C half-lifes (t1/2) after high-do…

Defective Bcl-2 expression in memory B cells from common variable immunodeficiency patients.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and different degrees of B cell compartment alteration. Memory B cell differentiation requires the orchestrated activation of several intracellular signaling pathways that lead to the activation of a number of factors, such as nuclear factor kappa B (NF-κB) which, in turn, promote transcriptional programs required for long-term survival. The aim of this study was to determine if disrupted B cell differentiation, survival and activation in B cells in CVID patients could be related to def

Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics.

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associate … ed the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-) …

Multi-omics analyses reveal cellular responses to biosynthesis of the non-natural cofactor nicotinamide cytosine dinucleotide.

The ubiquitous cofactors nicotinamide adenine dinucleotide (NAD) and its reduced form play pivotal roles in energy metabolism and redox home … roteins or isozymes. By combining omics data and flux analysis, we identified fructose 6-phosphate, cytidine triphosphate, aspartate and glutamate as key branch nodes in the perturbation network. Importantly, we constructed several lines of E. coli cells capable of synthesizing NCD at different levels and confirmed that these cells grew similarly to their …

Antibiotic-drug conjugates: Enhancing chemo-immunotherapy of gemcitabine for pancreatic cancer by eliminating intratumoral bacteria.

Pancreatic cancer has a dismal five-year survival rate of only ∼13%, owing to its insidious onset, rapid progression, and frequent primary or acquired resistance to gemcitabine (Gm). Moreover, intratumoral bacteria capable of expressing cytidine deaminase (CDD) can undermine the therapeutic efficacy of Gm and contribute to chemoresistance. To address this challenge, antibiotic-drug conjugates (AiDCs, Tob-SS-Gm NPs) were developed by covalently linking tobramycin (Tob) and Gm via disulfide bonds. Tob-SS-Gm NPs retained antibacterial activity against E. coli and chemotherapeutic activity in Panc…

Design of base editing systems with tunable editing hotspots within a defined window through sgRNA engineering.

Base editors (BEs) enable efficient A-to-G or C-to-T conversions without double-stranded DNA cleavage, but their editing windows remain difficult to tune, limiting genome engineering flexibility. Here, we engineered CRISPR/Cas12b sgRNA by introducing MS2 hairpins to recruit an MS2-N55K-cytidine deaminase-UGI complex, enabling programmable control of the editing window. Three modified sgRNAs were generated by replacing two loop regions, each producing distinct editing hotspots in E. coli. The AID*Δ-MSBE system (sgRNA1.1) generated a window near the PAM with peak activity at C7-C9, while the CDA…

Fluorescence polarization-based fragment screen identifies inhibitors of APOBEC3A and APOBEC3B.

APOBEC3A and APOBEC3B are antiviral cytidine deaminases found to drive cancer-associated mutagenesis, contributing to tumor evolution and therapeutic resistance across multiple cancer types. Inhibiting these enzymes holds promise for prolonging response to a wide range of cancer therapies by delaying development of resistance. However, APOBEC3A and APOBEC3B remain challenging drug targets, with no potent and selective small molecule inhibitors reported. Here, we use a fluorescence polarization-based assay to identify small molecules inhibitors of the APOBEC3A-single-stranded DNA interaction. F…

Microdialysis-based metabolomic and proteomic profiling reveals signature variations for disease severity in psoriasis.

Psoriasis is a common chronic inflammatory skin disease characterized by epidermal hyperproliferation and immune dysregulation. However, loc … tory proteins (SERPINB3/4, FABP5), purine and pyrimidine metabolites (adenosine-5-monophosphate, 5'-cytidine monophosphate) and polyamines (spermidine and spermine). Pathway analysis confirmed upregulated nucleotide metabolism and polyamine biosynthesis alongside reduced histidine metabolism, consistent with hyperproliferation, immune activation, and barri …

RNA-Binding Peptide Influences Epitranscriptomic Regulation by Preferentially Binding to Unmodified RNAs Targeted by NSUN2.

5-Methylcytosine (m5C) is a widespread mRNA modification that regulates gene expression and is frequently dysregulated in cancer. Here, we used phage display to identify peptides that bind an NSUN2 consensus RNA sequence in either its unmodified (UN2-RNA) or m5C-modified (MN2-RNA) form. A single peptide, un2p1 (TDYSTHRLSHSL), was selectively enriched against both targets. Biophysical analyses demonstrated that un2p1 binds this RNA sequence with high affinity and that m5C incorporation reduces binding by approximately ninefold, indicating that cytidine methylation acts as a biochemical switch f…

Novel β-L-2'-deoxribonucleoside Revery Fleximers with Inhibitory Activity Against HBV, BKV и другие вирусы.

Со времени их обнаружения в качестве потенциальных антивирусных агентов в начале 1990-х годов L-нуклеозиды были разработаны в качестве средства лечения различных вирусов, включая вирус гепатита В (ВБВ), в силу их эффективности и более низкой токсичности по сравнению с их D-энантиомерами. Одним из известных L-nucleoside является телбивудин (LdT), известный также как L-thymidine, и используется для лечения хронических инфекций ВИЧ. Однако телбивудин, как и многие другие L-нуклеозиды, подвержен развитию резистентности к лекарственным препаратам из-за часто встречающихся точечных мутации. Кроме то

Совпадение в аннотации оригинала
Since their discovery as potential antiviral agents in the early 1990s, L-nucleosides have been developed as treatments for various viruses … nt of drug resistance due to commonly occurring point mutations. Additionally, for both LdT and its cytidine analogue, antiviral activity has only been reported against HBV. Looking to improve upon this scaffold, a series of novel β-L-2'-deoxyribonucleoside reverse fleximer nucleoside analogues were synthesized, and several were found to exhibit antiviral …

Differential characteristics of meat flavor compounds, colonic microbiome and metabolome between Duroc × Landrace × Yorkshire pigs with high and low intramuscular fat of longissimus dorsi muscles.

Pork flavor has received widespread attention from consumers and producers, but the flavor differences and microbial differences in pigs wit … bolites were mainly enriched in nucleotide and pyrimidine metabolic pathways. Dorea and metabolites cytidine, 2'-deoxycytidine-5'-monophosphate, and 2'-deoxythymidine-5'-monophosphate participated in nucleotide and pyrimidine metabolic pathways and potentially influenced the production of flavor compounds. Overall, the results imply that IMF influences por …

Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer.

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDDL) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDDS) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC…

Discovery of Potential Tyrosinase Inhibitors via Machine Learning and Molecular Docking with Experimental Validation of Activity and Skin Permeation.

Tyrosinase, a copper-dependent oxidase, plays a critical role in melanin biosynthesis and is a target in skin-whitening cosmetics. Conventio … selection. We identified three top-ranking inhibitors, rhodanine-3-propionic acid, lodoxamide, and cytidine 5'-(dihydrogen phosphate), with strong binding affinities mediated by metal ion coordination and π-π interactions at the enzyme's active site. In vitro assays revealed that all three compounds exhibited higher inhibitory activity against mushroom ty …

Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 an … tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.