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Резюме 18th Неевромускульная научно-исследовательская конференция Соединенного Королевства 15th и 16th апрель 2025.

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JAK inhibition in PD-1 immunotherapy and tumor microenvironment.

Targeting the programmed cell death 1 (PD-1)/PD-L1 axis has revolutionized cancer therapy; however, the durability of clinical responses is frequently compromised by chronic inflammation and an immunosuppressive tumor microenvironment (TME). The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway serves as a central intracellular node integrating cytokine signals that drive these resistance mechanisms. While physiological JAK/STAT signaling is essential for antitumor immunity, its persistent aberrant activation promotes malignant progression, upregulates

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… Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability . Nat Cell Biol . ( 2008 ) 10 : 489–96 . doi: 10.1038/ncb1713 , PMID: 18344984 PMC3083919 25 Ogawa H Ishiguro K-I Gaubatz S Livingston DM Nakatani Y . …

Polyphyllin I Inhibits the Metastasis of Cervical Cancer Through the Regulation of the β-Catenin Signaling Pathway.

Cervical cancer ranks as the fourth most prevalent cancer and cause of cancer-related mortality among women globally. It exhibits a recurrence/metastasis rate of approximately 30% and a dismal 5-year survival of only 17% in metastatic cases. Despite significant advancements in surgical techniques, chemoradiotherapy, and targeted therapies, effective treatment options for metastatic cervical cancer remain limited. This study explored Polyphyllin I (PPI), which is a monomeric compound derived from the Rhizoma of Paris Polyphyllin, as a potential inhibitor of cervical cancer metastasis. Mechanist

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… E3 ligase Cul2 mediates Drosophila early germ cell differentiation through targeting Bam Dev. Biol. 2023 493 103 108 10.1016/j.ydbio.2022.11.005 36423673 61. Yang L.Q. Yu S.P. Yang Y.T. Zhao Y.S. Wang F.Y. Chen Y. Li Q.H. Tian P. Zhu Y.Y. Zhang J.G. …

Ранние синапсовые изменения фоторецептора Mitochondria в модели мыши Множественного склероза EAE

Множественный склероз (MS) — воспалительное аутоиммунное заболевание центральной нервной системы (CNS), связанное со многими неврологическими нарушениями. Взгляд на систему часто нарушается в MS. В предыдущих исследованиях мы наблюдали ранние синусосы фоторецепторовых лент в модели мыши EAE MS, которые включали изменения в цикле синаптического везикла и нарушения предсинаптического ка2+ гомеостаза. Поскольку эти преднаптические события требуют очень много энергии, мы проанализировали, может ли синаптическая митохондрия, играющая важную роль в синаптическом энергетическом метаболизме, быть заде

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… Since MIC60 is important for the MICOS contact sites in mitochondria [ 95 , 103 ], we analyzed the mitochondria at higher magnifications to identify possible mitochondrial cristae defects, as they were observed in MIC60-deficient yeasts and drosophila [ 103 , 104 ]. …

Естественные соединения серы в состоянии психического здоровья и неврологических расстройств: наблюдения и исследования.

За прошедшие годы глобальное бремя неврологических и психических расстройств значительно возросло, в результате чего они стали одной из наиболее серьезных проблем и вызовов для здоровья человека. В рамках новых методов лечения от болезней и болезней все больше внимания уделяется вопросам питания и здравоохранения. Питание серы, главным образом полученное из различных природных источников, играет решающую роль в многочисленных физиологических процессах, включая функцию мозга. В настоящем обзоре содержится обзор химического состава ряда естественных источников таких богатых серой веществ, как из

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… Another study shows that urate administration elevated its levels in the SOD1G85R-expressing Drosophila model of familial amyotrophic lateral sclerosis (fALS) by activating the Akt signaling pathway and the catalytic subunit of glutamate-cysteine ligase ( 64 ). …

Ubiquitylomics: An Emerging Approach for Profiling Protein Ubiquitylation in Skeletal Muscle.

Skeletal muscle is a highly adaptable tissue, finely tuned by various physiological and pathological factors. Whilst the pivotal role of skeletal muscle in overall health is widely acknowledged, unravelling the underlying molecular mechanisms poses ongoing challenges. Protein ubiquitylation, a crucial post-translational modification, is involved in regulating most biological processes. This widespread impact is achieved through a diverse set of enzymes capable of generating structurally and functionally distinct ubiquitin modifications on proteins. The complexity of protein ubiquitylation has

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… When combined with stable isotope labelling, ubiquitylomics analysis revealed an age‐related increase of long‐lived ubiquitylated proteins in Drosophila muscle [ 82 ]. …

Targeting Proteasomes in Cancer and Infectious Disease: A Parallel Strategy to Treat Malignancies and Microbes.

Essential core pathways of cellular biology are preserved throughout evolution, highlighting the importance of these pathways for both bacteria and human cancer cells alike. Cell viability requires a proper balance between protein synthesis and degradation in order to maintain integrity of the proteome. Proteasomes are highly intricate, tightly regulated multisubunit complexes that are critical to achieve protein homeostasis (proteostasis) through the selective degradation of misfolded, redundant and damaged proteins. Proteasomes function as the catalytic core of the ubiquitin-proteasome pathw

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… Drosophila Small Cytoplasmic 19S Ribonucleoprotein is Homologous to the Rat Multicatalytic Proteinase . Nature 331 ( 6152 ), 190 – 192 . doi: 10.1038/331190a0 3123994 Finley D. ( 2009 ). Recognition and Processing of Ubiquitin-Protein Conjugates by the Proteasome . Annu. Rev. …

Molecular Approaches To Target GPCRs in Cancer Therapy

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… Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome Cell 1996 85 841 851 8681379 10.1016/s0092-8674(00)81268-4 30. Von Hoff D.D. LoRusso P.M. Rudin C.M. Reddy J.C. Yauch R.L. Tibes R. Weiss G.J. Borad M.J. Hann C.L. Brahmer J.R. Mackey H.M. …

Targeting Oncoproteins for Molecular Cancer Therapy

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Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familia

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… Finally, in addition to murine models, in vivo drug screens are performed with transgenic Caenorhabditis elegans , Drosophila melanogaster , and zebrafish (please see reference for review of animal models used in ALS drug discovery [ 198 ]). …

Specific epigenetic regulators serve as potential therapeutic targets in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a disorder observed mostly in older human beings, is characterised by chronic and progressive lung scarring leading to an irreversible decline in lung function. This health condition has a dismal prognosis and the currently available drugs only delay but fail to reverse the progression of lung damage. Consequently, it becomes imperative to discover improved therapeutic compounds and their cellular targets to cure IPF. In this regard, a number of recent studies have targeted the epigenetic regulation by histone deacetylases (HDACs) to develop and categorise

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… The abbreviation of SMAD/Smad is expanded as follows: Acronym from the fusion of Caenorhabditis elegans SMA ("small" worm phenotype) and MAD ("Mothers against Decapentaplegic") proteins in Drosophila melanogaster . … The abbreviation of SMAD/Smad is expanded as follows: Acronym from the fusion of Caenorhabditis elegans SMA ("small" worm phenotype) and MAD ("Mothers against Decapentaplegic") proteins in Drosophila melanogaster . …

Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.

Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate the expression of a wide range of target genes in response to endogenous and exogenous ligands, including steroid hormones, thyroid hormone, vitamin D, retinoic acid, fatty acids, and oxidative steroids. Upon ligand binding, nuclear receptors form dimer complexes with transcriptional cofactors, which interact with specific DNA sequences in the promoter or enhancer regions of target genes to modulate gene expression. This process plays a crucial role in many physiological processes such as reprodu

Development Trends of Janus Kinase Inhibitors (JAKi) Over Three Decades: From Common to Rare Diseases.

Janus kinase inhibitors (JAKi) have undergone three decades of research and development, demonstrating substantial therapeutic efficacy and broad clinical applicability in autoimmune diseases, inflammatory disorders, hematopoietic malignancies, and a spectrum of rare diseases. However, their research and development are constrained by three key challenges: the difficulty in target selection and safety concerns arising from their effects on cellular signaling pathways, as well as the challenges in formulating optimal dosing regimens due to interindividual variability in pharmacokinetics. In thi

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… A genetic screen reveals an unexpected role for Yorkie signaling in JAK/STAT-dependent hematopoietic malignancies in Drosophila melanogaster . G3 . 2017 ; 7 ( 8 ): 2427 – 2438 . doi: 10.1534/g3.117.044172 28620086 PMC5555452 80. Gao Q , Liang X , Shaikh AS , et al. …

The Role of the Ubiquitin System in Eye Diseases.

The ubiquitin-proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This system is responsible for the degradation of proteins, while proteasomes play a significant role in mechanisms involved in health and human diseases. The participation of the UPS in immune response is particularly relevant, leading to the involvement of immunoproteasomes. This specialized proteasome is involved in the processing and presentation of antigenic peptides, making it crucial fo

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… In Drosophila Melanogaster, ocular development requires ubiquitination to activate retinal morphogenesis and photoreceptor cells viability [ 72 ]. …

Микроэкология и тренировка: целевое воздействие на ось микробиота-Гут-Брэйна для лечения заболеваний центральной нервной системы.

Кишечная микробиота (ГМ) может играть решающую роль в развитии и развитии заболеваний центральной нервной системы (ЦНС). Микроэкология и упражнение могут влиять на состав и функции ГМ, оказывая тем самым позитивное воздействие на НКЦ. Ожидается, что комбинированные физические упражнения и микроэкология позволят более комплексно и эффективно решать проблемы, связанные с заболеваниями CNS, через ось микробиота-гут-мозгов (MMBA), потенциально превысив результаты отдельных мероприятий. Однако в настоящее время по этой теме не проводится соответствующих обзоров. В этом обзоре мы изучаем взаимосвязь

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… At the same time, it reduces β-amyloid deposition and acetylcholinesterase activity in an AD transgenic human Drosophila model and enhances exercise ability and survival rate [ 173 ]. …

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. Most of the patients of PDAC present at later stages of disease and have a five-year survival rate of less than 10%. About 5-10% PDAC cases are hereditary in nature and have DNA damage repair (DDR) mutations such as BRCA 1 and 2. Besides having implications on screening and prevention strategies, these mutations can confer sensitivity to platinum-based therapies and determine eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). In the presence of DDR mutations and PARPi, the cells are unable to utilize the error-fr

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… Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura Genetics 1946 31 269 290 20985721 10.1093/genetics/31.3.269 PMC1209328 41. Ashworth A. …

Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation.

Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, incl

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… A family of human receptors structurally related to Drosophila toll. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(2):588–593. doi: 10.1073/pnas.95.2.588. 31. Chuang T. H., Ulevitch R. J. …

Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML.

Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment wi

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… In Drosophila , TNF represses tumor growth of scribble (a tumor suppressor) mutant cells by stimulating a JNK-mediated death signal. However, via JNK, TNF promotes tumor progression and metastasis in scribble mutant cells when either oncoprotein RAS or Notch is expressed ( Cordero et al., 2010 ). …

Emerging strategies and therapies for treatment of Paget's disease of bone.

Paget's disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemi

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… Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity. 2009;30(4):588–598. doi: 10.1016/j.immuni.2009.02.009. 81. Seglen PO, Bohley P. Autophagy and other vacuolar protein degradation mechanisms. …

Epigenetic therapy in myeloproliferative neoplasms: evidence and perspectives.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, originate from a stem cell-derived clonal myeloproliferation that manifests itself with variable haematopoietic cell lineage involvement; they are characterized by a high degree of similarities and the chance to transform each to the other and to evolve into acute leukaemia. Their molecular pathogenesis has been associated with recurrent acquired mutations in janus kinase 2 (JAK2) and myeloproliferative leukemia virus oncogene

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… Over-activation of the Hopscotch gene, a JAK homologue gene in Drosophila Melanogaster , led to a global disruption of heterochromatic gene silencing and promoted tumourigenesis, indicating that the JAK/STAT pathway normally regulates cellular epigenetic status [ 117 ]. …