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α2-3-sialylated Гликосфинголипиды при нейроинфламмации, иммунитете и запрограммированной смерти клеток: механистические доказательства и регулирование в зависимости от контекста: всеобъемлющий обзор.

α2-3-sialylated glycosphingolids (α2)3-GSLs) являются основными составляющими нейронных мембран и липидных плотов, где они формируют сепарацию рецепторов, комплекс сигналов и связь с клетками. Однако их биологическое воздействие варьируется в зависимости от молекулярного подтипа, типа клеток, стадии заболевания, концентрации и местной микроокружающей среды. В настоящем обзоре обобщены данные о перепончатых изменениях в α2-3-GSL профили и их связи с нейроинфламмацией, иммунной реакцией, протеостазом и запрограммированной клеточной смертностью через болезнь Паркинсона, болезнь Альцгеймера, болез

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… Because cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) is inactive in humans, Neu5Gc cannot be synthesized endogenously; however, dietary exposure can induce low-titer natural anti-Neu5Gc antibodies in some individuals ( 142 , 143 ). …

Drug resistance and tumor immune microenvironment: An overview of current understandings (Review).

The use of antitumor drugs represents a reliable strategy for cancer therapy. Unfortunately, drug resistance has become increasingly common and contributes to tumor metastasis and local recurrence. The tumor immune microenvironment (TME) consists of immune cells, cytokines and immunomodulators, and collectively they influence the response to treatment. Epigenetic changes including DNA methylation and histone modification, as well as increased drug exportation have been reported to contribute to the development of drug resistance in cancers. In the past few years, the majority of studies on tum

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… Interestingly, Lurbinectedin (PM01183) enhanced the antitumor of gemcitabine in PDAC by exhibiting a specific depletion of TAMs that downregulated cytidine deaminase expression and increased gemcitabine-mediated DNA damage ( 132 ). …

Emerging therapeutics in the management of COVID-19.

The severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019, COVID-19) pandemic has placed a tremendous burden on healthcare systems globally. Therapeutics for treatment of the virus are extremely inconsistent due to the lack of time evaluating drug efficacy in clinical trials. Currently, there is a deficiency of published literature that comprehensively discusses all therapeutics being considered for the treatment of COVID-19. A review of the literature was performed for articles related to therapeutics and clinical trials in the context of the current COVID-19 pandemic. We

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… Azvudine Chemical composition: Azvudine, also known as FNC, is a cytidine analogue. It is a substrate for deoxycytidine kinase and is phosphorylated to deoxycytidine[ 45 ]. …

Evidence for the use of intravenous immunoglobulins--a review of the literature.

Intravenous immunoglobulins (IVIg) were first introduced in the middle of the twentieth century for the treatment of primary immunodeficiencies. In 1981, Paul Imbach noticed an improvement of immune-mediated thrombocytopenia, in patients receiving IVIg for immunodeficiencies. This opened a new era for the treatment of autoimmune conditions with IVIg. Since then, IVIg has become an important treatment option in a wide spectrum of diseases, including autoimmune and acute inflammatory conditions, most of them off-label (not included in the US Food and Drug Administration recommendation). A panel

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understandi

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… Combination approaches include different epigenetic drugs, such as azacitidine, a chemical analog of cytidine which inhibits DNA methyltransferase, causing hypomethylation of DNA; a phase Ib/II study to assess the effects of everolimus in combination with azacitidine in AML patients has been reported …

Interplay of non-coding RNAs and approved antimetabolites such as gemcitabine and pemetrexed in mesothelioma.

Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to th

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… Resistance factors of gemcitabine treatment include transporter deficiency (reduced hENT1 expression), overexpression of ribonucleotide reductases and of gemcitabine-deactivating cytidine deaminases [ 22 ]. …

Epimutational profile of hematologic malignancies as attractive target for new epigenetic therapies.

In recent years, recurrent somatic mutations in epigenetic regulators have been identified in patients with hematological malignancies. Furthermore, chromosomal translocations in which the fusion protein partners are themselves epigenetic regulators or where epigenetic regulators are recruited/targeted by oncogenic fusion proteins have also been described. Evidence has accumulated showing that "epigenetic drugs" are likely to provide clinical benefits in several hematological malignancies, granting their approval for the treatment of myelodysplastic syndromes and cutaneous T-cell lymphomas. A

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… The metabolic instability of azacitidine and 5-AZA-CdR has prompted the development of modified analogs, including SGI-110, a dinucleotide that includes a deoxyguanosine and is largely resistant to cytidine deaminase activity [ 114 ]. …

HDAC3: A Multifaceted Modulator in Immunotherapy Sensitization.

Histone deacetylase 3 (HDAC3) has emerged as a critical epigenetic regulator in tumor progression and immune modulation, positioning it as a promising target for enhancing cancer immunotherapy. This work comprehensively explores HDAC3's multifaceted roles, focusing on its regulation of key immune-modulatory pathways such as cGAS-STING, ferroptosis, and the Nrf2/HO-1 axis. These pathways are central to tumor immune evasion, antigen presentation, and immune cell activation. Additionally, the distinct effects of HDAC3 on various immune cell types-including its role in enhancing T cell activation,

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… RA significantly up-regulates the expression of B lymphocyte-induced maturation protein 1 (Blimp-1) in germinal center (GC) B lymphocytes and activates the expression of activation-induced cytidine deaminase (AID) in these cells, thereby supporting the normal release of immunoglobulin G (IgG) [ 121 , …

Prospects for Development and Commercialisation of Allogeneic CAR-Based Therapies for Autoimmune Disease.

Chimeric antigen receptor (CAR)-T cell therapies represent a promising therapeutic approach for refractory autoimmune diseases. Although autologous CAR-T cells have achieved success thus far, they require expensive, individualised manufacturing, limiting their commercialisation potential. Allogeneic alternatives could overcome these scalability barriers, providing 'off-the-shelf' treatments, although they raise the issues of graft-vs-host reactions and host-mediated rejection. To mitigate such risks, gene-edited αβ T cells or non-alloreactive host cells (e.g., NK cells, γδ T cells) may be used

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… Base editing instead uses guided cytidine and/or adenine deamination to alter individual nucleotides without introducing a double-stranded DNA break. This represents an attractive solution, with positive clinical trial results showing no likely off-target effects [ 20 ]. …

RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies.

RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes to achieve posttranscriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the US Food and Drug Administration (FDA), several RNAi-based thera

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… TABLE 1 FDA-approved siRNA medications A, adenosine; Af, adenine 2'-F ribonucleoside; Am, adenine 2'-OMe ribonucleoside; C, cytidine; Cf, cytosine 2'-F ribonucleoside; Cm, cytosine 2'-OMe ribonucleoside; dT, thymidine; G, guanosine; Gf, guanine 2'-F ribonucleoside; Gm, guanine 2'-OMe ribonucleoside; …

An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs.

Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as bein

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… Phase III | Plitidepsin | Tunicate | Depsipetide | Anti-cancer | Induces cell cycle arrest or apoptosis | PharmaMar | [ 76 ] Gemcitabine (GEM) (Gemzar) | Sponge | Nucleoside | Anti-cancer | Ribonucleotide reductase inhibitor Replaces cytidine during DNA replication | Eli Lilly and Company | [ 77 ] Phase …

Molecularly targeted therapy and immunotherapy in leukemias.

The advent of next-generation high-throughput sequencing and precision medicine has allowed the identification of recurrent genetic events of vital interest for leukemic cells and for the management of patients with leukemia, since it has a direct impact on prognosis and therapeutic stratification. The precise cytogenetic characterization of these diseases has rapidly enabled the development of innovative therapeutic strategies to improve outcomes and limit toxicities. New targeted therapies, including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug

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… FLT3 inhibitors have also been evaluated in combination with other agents such as venetoclax [ 15 ], in a triplet strategy with venetoclax/azacitidine [ 16 ], venetoclax/decitabine [ 17 ], venetoclax/ASTX727 (decitabine and cedazuridine, a cytidine deaminase inhibitor) [ 18 ], or with histone deacetylase … Azacitidine is a cytidine nucleoside analog that is phosphorylated in cells to its active form. Azacitidine triphosphate reduces both DNA and RNA methylation, inducing activation and expression of genes regulating cancer-suppressing functions and cell differentiation. …

Biologics for bone regeneration: advances in cell, protein, gene, and mRNA therapies.

Bone fractures represent a significant global healthcare burden. Although fractures typically heal on their own, some fail to regenerate properly, leading to nonunion, a condition that causes prolonged disability, morbidity, and mortality. The challenge of treating nonunion fractures is further complicated in patients with underlying bone disorders where systemic and local factors impair bone healing. Traditional treatment approaches, including autografts, allografts, xenografts, and synthetic biomaterials, face limitations such as donor site pain, immune rejection, and insufficient mechanical

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… One common approach to enhance translation is pyrimidine substitution, where uridine and cytidine are partially replaced with for instance 2-thiouridine and 5-methylcytidine. 47 This modification reduces Toll-like receptor (TLR) and RIG-I recognition, minimizing immune activation and inflammation. 142 …

Precision Reprogramming in CAR-T Cell Therapy: Innovations, Challenges, and Future Directions of Advanced Gene Editing.

Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in cancer immunotherapy, demonstrating impressive clinical outcomes, particularly for hematologic malignancies. However, its broader therapeutic application, especially against solid tumors, remains limited. Key challenges include T cell exhaustion, limited persistence, cytokine-mediated toxicities, and logistical hurdles associated with manufacturing autologous products. Emerging gene editing technologies, such as CRISPR/Cas systems, base editing, and prime editing, offer novel approaches to optimize CAR-T cells, aiming

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… Base editors—cytidine or adenine deaminases fused to inactive Cas9—enable direct C→T or A→G conversions, and prime editors (nCas9-reverse transcriptase with pegRNA) install virtually any single-base change without DSBs. …

The emerging role of exosomes in innate immunity, diagnosis and therapy.

Exosomes, which are nano-sized transport bio-vehicles, play a pivotal role in maintaining homeostasis by exchanging genetic or metabolic information between different cells. Exosomes can also play a vital role in transferring virulent factors between the host and parasite, thereby regulating host gene expression and the immune interphase. The association of inflammation with disease development and the potential of exosomes to enhance or mitigate inflammatory pathways support the notion that exosomes have the potential to alter the course of a disease. Clinical trials exploring the role of exo

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… For instance, human cytidine deaminase apolipoprotein B mRNA editing enzyme, catalytic subunit 3G (APOBEC3G) molecules present in exosomes from infected cells cause the deamination of cytosine residues to uracil in the minus strand of viral DNA during reverse transcription. …

Genome Instability in Multiple Myeloma: Facts and Factors.

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete

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… Another model proposes that chromatin bridges formed during cytokinesis are pulverized via concerted action of TREX1 exonuclease and APOBEC3A/B cytidine deaminases [ 658 , 667 , 668 ]. …

Advances in Molecularly Imprinted Polymers for Bone Biomarker Detection and Therapeutic Applications.

This review explores the application of molecularly imprinted polymers (MIPs) in detecting bone turnover biomarkers and advancing osteogenic treatment strategies. MIPs, designed to mimic biological recognition sites, offer innovative solutions for precise molecular recognition in bone health management. Chemical methodologies for MIPs synthesis and their integration into diagnostic systems for detecting bone resorption markers are highlighted. Furthermore, MIP-driven therapeutic advancements, including controlled drug release, cell imprinting for osteogenic differentiation, and functional scaf

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… Once internalized by tumor cells, DFCR is enzymatically converted into toxic 5‐fluorouracil (5‐FU) through a two‐step intracellular cascade involving cytidine deaminase and thymidine phosphorylase, thereby inducing cell death via DNA synthesis inhibition. …

SARS-CoV-2 drug resistance and therapeutic approaches.

In light of the transition of COVID-19 from a pandemic to an endemic phase, there is still a dire need to address challenges associated with drug resistance, particularly among immunocompromised and high-risk populations. This review explores the current state of research on SARS-CoV-2 drug resistance and underscores the ongoing need for effective therapeutic strategies. It critically evaluates existing knowledge on resistance mechanisms and therapeutic options, aiming to consolidate information and highlight areas for future research. By examining the complex interactions between the virus an

Изучение связи между ядерными рецепторами в гематологических галереях.

Гематологические магнации (ГМ) представляют собой подмножество новообразований, затрагивающих кровь, костный мозг и лимфатические системы, которые в основном подразделяются на лейкемию, лимфому и множественную миелому. Их прогнозы значительно отличаются друг от друга, причем, несмотря на текущее лечение, часто возникает опасность рецидива. Несмотря на то, что современные терапевтические стратегии расширили общее выживание пациентов, они не предлагают лечения на продвинутых этапах и часто приводят к таким проблемам, как приобретение лекарственной устойчивости, рецидивы и серьезные побочные эффе

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms.

Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation

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… An inducible JAK2 V617F mouse model (using Mx1-Cre , induced by poly-inosine-cytidine, a.k.a. poly-IC or PIPC) exhibited apoptosis of nestin-expressing mesenchymal stem cells (MSCs) and Schwann cells of sympathetic nerve fibers within the bone marrow, and consequent loss of sympathetic innervation ( …