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Drugging the efferocytosis process: concepts and opportunities.

The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infe

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… Spermidine is a bioactive polyamine, which has been proven beyond doubt to have beneficial effects in ageing and increasing lifespan in human subjects. … Apoptotic cells synthesize and secrete spermidine, and administration of spermidine in combination with purine nucleotides (GMP and IMP) was demonstrated to improve the pathology in an arthritis model as well as in a lung transplant rejection model 15 . …

Role of mitochondria in physiological activities, diseases, and therapy.

Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of

Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen meta

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… Ornithine Transcarbamylase; CPS1: Carbamoyl Phosphate Synthetase 1; PPAT: Phosphoribosyl Pyrophosphate Amidotransferase; ARG1: Arginase 1; ARG2: Arginase 2; OAT: Ornithine Aminotransferase; GLUL: Glutamine Synthetase; PSAT1: Phosphoserine Aminotransferase 1; CTH: Cystathionine Gamma-lyase; SRM/SMS: Spermidine … Synthase; ODC1: Ornithine Decarboxylase 1; ASNS: Asparagine Synthetase; PHGDH: Phosphoglycerate Dehydrogenase; ATIC: 5-aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase; NOS3: Nitric Oxide Synthase 3; SAT1: Spermidine/Spermine N1-Acetyltransferase 1. …

Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.

Ammonium metabolism represents a critically understudied yet pivotal driver of prostate tumorigenesis and tumor microenvironment (TME) remodeling. The interplay between tumor metabolic reprogramming and the tumor microenvironment has emerged as a critical frontier in oncology research. While previous studies on prostate cancer metabolism have predominantly focused on lipid metabolism and the Warburg effect, the role of ammonium metabolism, particularly the urea cycle in tumor immune regulation remains insufficiently explored. This metabolic reprogramming constitutes a central node connecting c

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… Androgens coordinately induce the enzymatic activities of key polyamine biosynthetic enzymes, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and spermidine synthase (SDS), with predominant expression localized to prostatic glandular epithelial cells ( 59 – 61 ). … HIF, hypoxia inducible factor; GLS, glutaminase; CTP, cytidine triphosphate; CAD, Caspase-activated deoxyribonulease; ACNT, aconitase; ODC, ornithine decarboxylase; ARG, arginase; ADC, arginine decarboxylase; SMS, spermine synthase; SDS, spermidine synthase. …

Доказательства потенциала гуанидов против Leishmania (Viannia) braziliensis: исследование витро эффективности, токсичности и влияния на ответ иммунной системы.

Лейшманиаз — это сложная группа инфекционных и паразитарных заболеваний, которая поражает десятки тысяч людей на пяти континентах. Лечение лейшманиаза остается сложной задачей, так как оно зависит от лекарств, известных своей высокой токсичностью и ограниченной эффективностью, что делает необходимым поиск новых молекул, которые обеспечивали бы большую эффективность и безопасность. Настоящее исследование посвящено изучению влияния семи синтетических гуанидиновых производных (LQOF-G1, LQOF-G2, LQOF-G6, LQOF-G7, LQOF-G32, LQOF-G35 и LQOF-G36) на паразита Leishmania (Viannia) braziliensis и витроп

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… Trypanothione: A Novel Bis(glutathionyl)spermidine Cofactor for Glutathione Reductase in Trypanosomatids. Science. 1985;227:1485–1487. doi: 10.1126/science.3883489. 22. Dumas C. …

Integrating Single-Cell Transcriptome and Network Analysis to Characterize the Therapeutic Response of Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by a unique BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) were developed to target the BCR-ABL oncoprotein, inhibiting its abnormal kinase activity. TKI treatments have significantly improved CML patient outcomes. However, the patients can develop drug resistance and relapse after therapy discontinues largely due to intratumor heterogeneity. It is critical to understand the differences in therapeutic responses among subpopulations of cells. Single-cell RNA sequencing measures the transcriptome of individual c

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… DUSP1 , PROM1 , and SAT1 (spermidine/spermine N1-acetyltransferase 1) had direct TF regulators in all cell groups, while HERC2P7 (hect domain and RLD 2 pseudogene 7) and LOC101928834 were regulated directly by TF only in the cells from good responders. …

Cellular Senescence and Aging: Mechanisms, Disease Convergence, and Therapeutic Frontiers.

Cellular senescence, a stress-induced, irreversible cell cycle arrest coupled with a proinflammatory secretory phenotype, has emerged as both a central driver of aging and a tractable therapeutic target. Although acute senescence contributes beneficially to tumor suppression and wound healing, chronic accumulation of senescent cells sustains systemic inflammaging and accelerates organ dysfunction. This review synthesizes current progress in aging biology into a unified mechanistic and translational framework. We first examine how primary aging hallmarks, such as genomic instability and epigene

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… . | Spermidine activates AMPK–mTOR signaling, promotes mitophagy, and restores oocyte chromosome alignment [ 216 ]. Rapamycin induces autophagy, clears stress granules, and preserves ovarian function [ 214 ]. …

Emerging Target Discovery Strategies Drive the Decoding of Therapeutic Power of Natural Products and Further Drug Development: A Case Study of Celastrol.

Celastrol (CEL) is a natural pentacyclic triterpenoid demonstrating significant therapeutic properties against various diseases. However, the ambiguity of target information poses a significant challenge in transitioning CEL from a traditional remedy to a modern pharmaceutical agent. Recently, the emerging target discovery approaches of natural products have broadened extensive avenues for uncovering comprehensive target information of CEL and promoting its drug development. Herein, diverse target discovery strategies are overviewed for the pharmacological and toxicological studies of CEL, inc

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… | Pull‐down, CETSA, IF, MD | Covalent bond (Cys13) | Anti‐cancer (hepatocellular carcinoma) | [ 17f ] Chemical proteomics (ABPP) | PDIA3 | Protein disulfide‐isomerase A3 | BV2 cell lysates | Labeling assay, SPR | NT | Anti‐neuroinflammation | [ 23 ] Chemical proteomics (ABPP) | PfSpdsyn, PfEGF1‐α | Spermidine …

Адаптация эукариот-подобных PRS к прокариот-подобным tRNAPro.

Синтеты Проли-ТРНА (ПРОРС) уникальны среди аминоачил-тРНК (ААРС) two различные структурные архитектуры различных организмов: прокариота-подобные (П-тип) и эукариоте/археон-подобные (Е-тип). Интересно, что Бакиллус Тюрингьенси гавань обоих типов, сосуществует P-тип (BtProRS1) и E-тип PRS (BtProRS2). Несмотря на свои различия, оба фермента формально выражаются и функционируют в vivo. По аналогии с BtProRS1, BtPRS2 выборочно заряжает TRNAPro типа P и демонстрирует более высокий допуск к галоугинону, чем каноническая PRS. Однако эти two Изозимы признают основные идентификационные элементы типа P t

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… The in vitro transcription reaction for tRNA Pro was carried out with 0.3 μM T7 RNA polymerase at 37°C for 3 hours in a buffer comprising 20 mM Tris–HCl (pH 8.0), 150 mM NaCl, 20 mM MgCl 2 , 5 mM dithiothreitol (DTT), 1 mM spermidine, and 2 mM of each NTP. …

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers.

Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer's disease or myasthenia gravis will be discuss

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… Sustained decrease of THF-mediated methylation downregulates an accumulation of spermine and spermidine polyamines in the extracellular fluids and lymphocytes of patients with RA [ 58 , 59 ]. These polyamines are essential cellular growth factors among others in lymphocytes. …

Терапевтический потенциал диметилФумарата для обработки высококалорийной/высокосортной диетологической ожиренией.

Ожирение характеризуется несбалансированностью между потреблением энергии и расходами, которая вызывает ненормальный рост жировых тканей. Диметилфумарат (ДМП) и его первичный активный метаболит монометилфумарат (ММФ) являются активаторами Nrf2 и признаны в качестве стратегических антиоксидантов. Цель этого исследования состояла в том, чтобы оценить потенциал MMF и DMF в плане воздействия на адипогенез и ожирение, а также выявить соответствующие молекулярные механизмы. Предадипоциты 3T3-L1 были инкубированы с дифференциальной среды (MIX) и одновременно обработаны различными концентрациями MMF.

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… Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung. Am. J. Physiol. Lung Cell Mol. Physiol. 2020;319:L312–L324. doi: 10.1152/ajplung.00423.2019. 35. …

The Role of Hypoxia-Inducible Factor-1α (HIF-1α) in the Progression of Ovarian Cancer: Perspectives on Female Infertility.

Hypoxia-Inducible Factor-1α (HIF-1α) is crucial in the progression of ovarian cancer, especially in influencing its tumor microenvironment and promoting pathogenic pathways that worsen female infertility. In hypoxic settings, HIF-1α is stabilized and activates the transcription of genes associated with angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal transition, and therapeutic resistance. Angiogenesis and glycolytic reprogramming mediated by HIF-1 tumor proliferation, survival, and metastasis. Its dysfunction concurrently impairs ovarian homeostasis, undermining follicular gro

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… Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase. Cancer Chemother. Pharmacol. 2011;68:405–413. doi: 10.1007/s00280-010-1500-0. 64. …

Молекулярная основа для человеческой митохондриальной модификации tRNA m3C с помощью альтернативной разбрызгивания METTL8.

METTL8 недавно был определен как катализатор метилпереносазы 3-methylcytidine Биогенез на месте 32 (м3С32) митохондриальных tRNA. METTL8 также потенциально участвует в мRNA метилации и R-loop Biogenesis. Как METTL8 играет многообразную роль в разных камерах, и митохондриальное образование митохондриала tRNA m3C остается неясным. Здесь мы обнаружили, что альтернативное скрещивание mRNA вызвало несколько изоформ METTL8. One (изоформ)METTL8-Iso1) был направлен на митохондрию через N-терминальную предпоследнюю последовательность, в то время как другой one (В тыс.METTL8-Iso4) в основном локализован

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… Determination of in vitro m 3 C and i 6 A modification The m 3 C modification reaction was performed at 37 °C in a 40 μl reaction mixture containing 50 mM Tris–HCl (pH 7.5), 20 mM KCl, 10 mM MgCl 2 , 1 mM DTT, 1 mM spermidine, 100 μM [ 3 H] SAM, 5 μM hmtRNAs (or variants) and 1 μM mature METTL8-Iso1 …

Стратегия выбора субстрата, взаимно исключающаяся, у человека m3C RNA трансферазы METTL2A и METTL6.

tRNAs содержат наиболее разнообразные посттранскрипционные модификации. 3-метилцитидин (m3C) широко распределяется на позиции C32 (m3C32) у эукариотических tRNAThr и tRNASer. m3C32 модифицируется единственным метилтрансферазой Trm140 у дрожжей-попыток; однако для его биогенеза участвуют два (Trm140 и Trm141 у деления дрожжей) или три энзима (METTL2A, METTL2B и METTL6 у млекопитающих). До сих пор неизвестно обоснование существования нескольких метилтрансфераз m3C32 и их механизм дифференциации по субстрату. Здесь мы обнаружили, что оба METTL2A и METTL2B выражены в живых организмах. Мы выделили

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… tRNA methylation assay The methylation reactions were performed at 37°C in a reaction mixture containing 50 mM Tris–HCl (pH 7.5), 20 mM KCl, 10 mM MgCl 2 , 10 mM spermidine, 10 mM DTT, 20 μM [ 3 H] SAM, 5 μM transcribed, t 6 A-modified or overexpressed tRNAs, and 1 μM METTL2A, METTL2B or METTL6. …

Rejuvenation Strategy for Inducing and Enhancing Autoimmune Response to Eliminate Senescent Cells.

The process of aging, which involves progressive changes in the body over time, is closely associated with the development of age-related diseases. Cellular senescence is a pivotal hallmark and mechanism of the aging process. The accumulation of senescent cells can significantly contribute to the onset of age-related diseases, thereby compromising overall health. Conversely, the elimination of senescent cells enhances the body's regenerative and reparative capacity, thereby retarding the aging process. Here, we present a brief overview of 12 Hallmarks of aging and subsequently emphasize the po

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… Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ, 22:509-516. [43] Dellorusso PV, Proven MA, Calero-Nieto FJ, Wang X, Mitchell CA, Hartmann F, et al. (2024). Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells. …

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

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… Spermidine mediates degradation of ornithine decarboxylase by a non-lysosomal, ubiquitin-independent mechanism. J Cell Physiol. 1987;130:133–141. doi: 10.1002/jcp.1041300119. Gonzalez AZ, Eksterowicz J, Bartberger MD, Beck HP, Canon J, Chen A, Chow D, Duquette J, Fox BM, Fu J, et al. …

The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.

The cGAS-STING pathway acts as a critical molecular hub connecting genomic instability with cellular senescence. Functioning as a key regulator of the innate immune system, this pathway detects aberrant cytoplasmic DNA to activate downstream inflammatory responses, thereby playing a pivotal role in aging-related diseases. This review systematically explores the core mechanisms by which the cGAS-STING pathway regulates cellular senescence, emphasizing its role in triggering senescence through the recognition of DNA damage signals (e.g., oxidative stress, telomere dysfunction) and promoting para

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… Promisingly, spermidine (SPD) can mitigate this effect by activating mitophagy to suppress STING signaling, thereby enhancing stem cell function and tissue repair [ 240 ]. …

Involvement of Resveratrol against Brain Cancer: A Combination Strategy with a Pharmaceutical Approach.

A brain tumor (BT) is a condition in which there is growth or uncontrolled development of the brain cells, which usually goes unrecognized or is diagnosed at the later stages. Since the mechanism behind BT is not clear, and the various physiological conditions are difficult to diagnose, the success rate of BT is not very high. This is the central issue faced during drug development and clinical trials with almost all types of neurodegenerative disorders. In the first part of this review, we focus on the concept of brain tumors, their barriers, and the types of delivery possible to target the b

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… Spermidine Prevents Heart Injury in Neonatal Rats Exposed to Intrauterine Hypoxia by Inhibiting Oxidative Stress and Mitochondrial Fragmentation. Oxid. Med. Cell. Longev. 2019;2019:5406468. doi: 10.1155/2019/5406468. 27. …

Реконструкция петли антикодона и форма D-стима приводят к конкретному распознаванию ANN-декодирования tRNA для модификации t6A.

N6-threonylcarbamoyladenosine (t6A) — универсальная трансфертная модификация RNA (tRNA), необходимая для перевода. Модификация устанавливается в положение 37 ANN-декодирование tRNAs (N is A, U, G или C) путем переноса треонилкарбамойла из промежуточного пути, катализированного в бактериях комплексом ЦаБД. Несмотря на строгое требование в отношении 36-UAA-38 Последовательность в субстрате tRNS, структурная основа этой специфичности остается неясной. Мы определили крио-эм-структуры "Термотога маритима Т6А" синтазы, связанные с немодифицированной и изначально модифицированной ТRNA с модификацией

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… Transcription reactions were incubated at 37°C for 5 h in 100 mM HEPES (pH 7.5), 2.0 mM spermidine, 25 mM MgCl 2 , 40 mM DTT, 0.01% Triton X-100, 5.0 mM NTPs, 0.15 pM DNA template, 0.5 U/ml inorganic pyrophosphatase, and 80 μg/ml of the Δ(172–173) variant of the T7 RNA polymerase [ 62 ]. …

Immunosenescence: signaling pathways, diseases and therapeutic targets.

Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellul