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Hematological Malignancy-Derived Small Extracellular Vesicles and Tumor Microenvironment: The Art of Turning Foes into Friends.

Small extracellular vesicles (small EVs) are commonly released by all cells, and are found in all body fluids. They are implicated in cell to cell short- and long-distance communication through the transfer of genetic material and proteins, as well as interactions between target cell membrane receptors and ligands anchored on small EV membrane. Beyond their canonical functions in healthy tissues, small EVs are strategically used by tumors to communicate with the cellular microenvironment and to establish a proper niche which would ultimately allow cancer cell proliferation, escape from the imm

PPAR-γ in Melanoma and Immune Cells: Insights into Disease Pathogenesis and Therapeutic Implications.

Changes in skin pigmentation, like hyperpigmentation or moles, can affect appearance and social life. Unlike locally containable moles, malignant melanomas are aggressive and can spread rapidly, disproportionately affecting younger individuals with a high potential for metastasis. Research has shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) and its ligands exhibit protective effects against melanoma. As a transcription factor, PPAR-γ is crucial in functions like fatty acid storage and glucose metabolism. Activation of PPAR-γ promotes lipid uptake and enhances sensitivi

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… The transcriptional activity of PPAR-γ is modulated by various post-translational modifications, including SUMOylation and O-GlcNAcylation. … As demonstrated by Shimizu et al., SUMOylation of Lys107 negatively regulates the transcription of PPAR-γ target genes by repressing the ligand-independent transactivation function of the A/B domain, thereby reducing the overall transactivating competence of PPAR-γ [ 184 ]. …

Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management.

The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution.

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies.

Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studie

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… Proteasome production and function are also influenced by post-translational modifications, including acetylation, ADP-ribosylation, glycosylation, methylation, myristoylation, oxidation, phosphorylation, SUMOylation, ubiquitylation, and proteolytic processing [ 24 , 29 ]. … A similar mode of action is exerted by arsenic trioxide (As 2 O 3 ) with covalent modification of PML-RARα and its sumoylation. Both compounds can induce degradation by autophagy of PML-RARα via the mTOR pathway, and that process is responsible for its basal turnover [ 41 ]. …

Proceedings of International Conference on Cell Death in Cancer and Toxicology. February 20-22, 2018. Guest Editors: Kausar M. Ansari, CSIR-IITR, India and Dhyan Chandra, Roswell Park, USA.

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… We show for the first time that the human coactivator protein hADA3 is posttranslationally modified by SUMOylation and HPV16E6 stimulates hADA3 degradation by enhancing its SUMOylation. … In another study, we also demonstrate the involvement of HPV16 E7 in modulating SUMOylation of FoxM1b by impairing its interaction with Ubc9. These findings provide important insight on SUMOylation as a novel mechanism related to HPV mediated transformation of cervical cancer cells. …

Sp140L функционирует как фактор ограничения герпесвируса, подавляющий вирусную транскрипцию и активирующий интерферонально-стимулированные гены.

Герпесвирусы, включая вирус Эпштейн-Барр (ЭБВ), - человеческий онкогенный вирус и важнейший пусковой механизм множественного склероза, - должны обходить механизмы ДНК-разведки, чтобы установить пожизненную скрытую инфекцию. Поэтому герпесвирусы кодируют вирусные белки, чтобы разрушить ключевые факторы, связанные с зондированием ДНК и вирусным ограничением. Первый вирусный белок латентности, выраженный EBNA-LP, крайне важен для преобразования наивных клеток B и установления вирусного генного экспрессии, однако его роль в уклонении от защиты хостов остается неясной. Используя одноклеточную после

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… Sp140L lacks the exons that in Sp100 encode SUMOylation and HP1 binding motifs but retains the exons for binding the high mobility group protein HMGB2. …

Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib.

One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulati

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… SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma. Blood Adv. 2023;7:469–481. doi: 10.1182/bloodadvances.2022007875. 56. Luo X., Kraus W.L. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. …

A Systematic Review and Meta-Analysis of Cancer Patients Affected by a Novel Coronavirus.

BackgroundCancer patients with coronavirus disease 2019 (COVID-19) have been reported to have double the case fatality rate of the general population.MethodsA systematic search of PubMed, Embase, and Cochrane Central was done for studies on cancer patients with COVID-19. Pooled proportions were calculated for categorical variables. Odds ratio (OR) and forest plots (random-effects model) were constructed for both primary and secondary outcomes.ResultsThis systematic review of 38 studies and meta-analysis of 181 323 patients from 26 studies included 23 736 cancer patients. Our meta-analysis show

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… The interventions being assessed include the chloroquine analog (GNS561), an anti PD-1 antibody (nivolumab); an anti-interleukin-6 receptor (tocilizumab); an anti-interleukin-8 (BMS-986253), a SUMOylation inhibitor (TAK-981), ivermectin with losartan, lopinavir/ritonavir, rintatolimod and IFN alpha-2b …

Структурное и механистическое профилирование модулятуры Hurr1 vidofludimus позволяет проектировать лиганд на основе структуры.

В центре биомедицинских исследований находится фактор нейрозащиты, связанный с ядерным рецептором 1 (Nurr1, NR4A2) для его многообещающей нейрозащитной роли в болезни Паркинсона, болезни Альцгеймера и множественном склерозе. Его деятельность может контролироваться лигандами, предлагающими доступ к фармакологической модуляции Hurr1. Вместе с тем связующие эпитопы и механизмы молекулярной активации синтетических активаторов Hurr1 по-прежнему остаются труднодостижимыми, но имеют важное значение для продвижения к новым лекарствам лигандов Hurr1. Здесь мы охарактеризовали диссоциацию Hurr1 димера и

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… I506 (site 3) neighbors a SUMOylation site which could also be affected by mutation and thus alter the response to ligands. …

Nucleo-cytoplasmic transport as a therapeutic target of cancer.

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins s

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… Santiago A, Li D, Zhao LY, Godsey A, Liao D. p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1. Mol Biol Cell. 2013;24:2739–2752. doi: 10.1091/mbc.E12-10-0771. 17. …

miR-708-5p: a microRNA with emerging roles in cancer.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression post-transcriptionally. They are crucial for normal development and maintaining homeostasis. Researchers have discovered that dysregulated miRNA expression contributes to many pathological conditions, including cancer. miRNAs can augment or suppress tumorigenesis based on their expression and transcribed targetome in various cell types. In recent years, researchers have begun to identify miRNAs commonly dysregulated in cancer. One recently identified miRNA, miR-708-5p, has been shown to have profound roles in

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… The authors determined that miR-708-5p was not transcriptionally downregulated; rather sumoylation of DICER resulted in decreased pre-miR-708 processing, resulting in lower mature miR-708-5p levels [ 202 ]. …

Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.

Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, an

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… also regulate phase behavior; acetylation of the autophagy-related protein RB1CC1 modulates its phase separation and influences autophagosome formation. 71 Arginine methylation alters cation-pi interaction capacity and can reduce hnRNPA2 phase separation by disrupting arginine-mediated contacts. 72 SUMOylation …

Epigenetic Regulation of Autophagy in Bone Metabolism.

The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's i

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… Other histone modifications, such as histone phosphorylation, 261 ADP-ribosylation, 262 ubiquitination, 263 SUMOylation, 264 glutamylation, 265 glycosylation, 266 hydroxylation, 267 and isomerization, 268 are also covalent modifications that potentially regulate gene expression by altering chromatin …

Inflammasomes in Cancer Progression and Anti-Tumor Immunity.

The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-i

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… NLRP3 activation also requires several post-translational modifications, i.e. ubiquitination, phosphorylation and sumoylation and the binding of NIMA-related kinase 7 (NEK7) to its LRRs (reviewed in ( Swanson et al., 2019 )). …

Семья гистона деацетилазы в здравии и болезни.

Классические деацетилазы, включая классы I, II и IV, в зависимости от цинка, повсеместно присутствуют у млекопитающих и играют жизненно важную роль в многочисленных биологических процессах. На сегодняшний день eleven Были выявлены члены < < хисттон деацетилаза > > , а именно < < хиттон деацетилаза > > . 1 через гистонную деацетилазу 11. Растущий объем данных подчеркивает важнейшую роль этих гистоновых деацетилазов как в физиологических, так и патологических условиях. В частности, эти гистонные деацетилазы участвуют в различных клеточных процессах, включая воспаление, ме

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… Additionally, PTMs such as phosphorylation and SUMOylation can impact their enzymatic activity and, consequently, their effect on p53-mediated apoptosis. HDAC6 and HDAC5 also regulate apoptosis by modulating p53 acetylation. … HDAC2 has been shown to suppress apoptosis by inhibiting p53 transcriptional activity through modulation of p53-DNA binding activity. 113 Additionally, Brandl et al. revealed that sumoylation of HDAC2 at K462 facilitates its binding to p53, which subsequently mediates deacetylation of p53 at K320, ultimately …

Emerging roles for the IL-6 family of cytokines in pancreatic cancer.

Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the exp

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… The pathway is inhibited by SOCS3, PIAS3, and PTPs via dephosphorylation, ubiquitin-mediated proteasomal degradation, and SUMOylation (right). … PIAS3 preferentially binds pSTAT3 and inhibits activity either by preventing STAT3 interaction with DNA, by recruiting transcriptional repressors to STAT3 target genes, or by SUMOylating STAT3 to prevent its activity [ 150 , 151 ] ( Figure 2 B). …

Additive Pharmacological Interaction between Cisplatin (CDDP) and Histone Deacetylase Inhibitors (HDIs) in MDA-MB-231 Triple Negative Breast Cancer (TNBC) Cells with Altered Notch1 Activity-An Isobolographic Analysis.

The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)-valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast cancer (BC) cell lines with increased and decreased activity of Notch1 were generated using a transfection method. The type of interaction between CDDP and the HDIs was determined by isobolographic analysis of cell proliferation in MDA-MB-231 cells with differential levels of Notch1 activity in vitro.

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… NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. Oncogene. 2015;34:3780–3790. doi: 10.1038/onc.2014.319. 22. Wawruszak A., Kalafut J., Okon E., Czapinski J., Halasa M., Przybyszewska A., Miziak P., Okla K., Rivero-Muller A., Stepulak A. …

Anthracycline-induced cardiotoxicity and renin-angiotensin-aldosterone system-from molecular mechanisms to therapeutic applications.

Few millions of new cancer cases are diagnosed worldwide every year. Due to significant progress in understanding cancer biology and developing new therapies, the mortality rates are decreasing with many of patients that can be completely cured. However, vast majority of them require chemotherapy which comes with high medical costs in terms of adverse events, of which cardiotoxicity is one of the most serious and challenging. Anthracyclines (doxorubicin, epirubicin) are a class of cytotoxic agents used in treatment of breast cancer, sarcomas, or hematological malignancies that are associated w

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… Moreover, DOX, in the unknown manner, decreases HSF2 SUMOylation that normally prevents it from binding to HSE [ 74 ]. Additionally, DOX increases the MAPK-ERK signaling and lead to further activation of HSF2 and upregulation of AT1R [ 72 ]. …

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer.

The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer

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… Sam68 is regulated at the post-translational level by phosphorylation [ 99 ], acetylation [ 100 ], methylation [ 101 ], and SUMO (small ubiquitin-like modifier) modification (SUMOylation, a post-translational modification analogous to ubiquitylation and involving the addition of SUMOs to proteins instead …

Потеря NOR1 связана с воспалением и биологическим старением в коре склероза.

Кортикальное нейродегенерирование и глиальная активация являются основными движущими силами развития инвалидности при множественном склерозе, однако молекулярные механизмы, лежащие в основе этих процессов, по-прежнему плохо определены. Членами семейства ядерных рецепторов NR4A являются реагирующие на стресс факторы транскрипции, которые регулируют нейронное выживание, воспалительную сигнализацию и клеточную адаптацию к метаболическому и окислительному стрессу. В частности, сиротский рецептор нейронного происхождения 1 (NR4A3) был замешан в нейрозащитных и реадаптивных реакциях на стресс в друг

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… SUMOylation of nuclear receptor Nor1/NR4A3 coordinates microtubule cytoskeletal dynamics and stability in neuronal cells . Cell Biosci . 2024 ; 14 ( 1 ): 91 . 38997783 10.1186/s13578-024-01273-x PMC11245793 17 Pu S , Wang Q , Liu Q , Zhao H , Zhou Z , Wu Q . …