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Нейтрофильные внеклеточные ловушки в расстройствах центральной нервной системы: механизмы, последствия и новые перспективы.

Нейтрофильные внеклеточные ловушки (НЕТ) в качестве важнейшего защитного механизма нейтрофилов в последние годы привлекли все большее внимание к их роли в расстройствах центральной нервной системы (КНС). В настоящем обзоре содержится исчерпывающая краткая информация об основных характеристиках и механизмах формирования ННО, а также освещаются последние результаты исследований, касающихся их участия в различных заболеваниях НКЦ. Обсуждаются конкретные механистические идеи, в том числе то, как НЕТ усугубляют ишемический инсульт в результате иммунотромбоза, способствуют нарушению кровеносных барь

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… Wang et al. ( 36 ) found that NETs could aggravate tissue plasminogen activator (tPA)-induced brain damage in stroke patients by inhibiting cyclic GMP-AMP synthase (cGAS) ( 36 ). …

Microbiota-derived metabolites as modulators of cancer immunotherapy response.

The microbiome is a key regulator of host homeostasis and immune activity, in part through the production of metabolites. These microbiota-derived metabolites can modulate both the innate and adaptive immune system, as well as directly target tumour cells, thereby regulating anti-tumour immunity and response to immunotherapy. Here, we describe the current mechanistic knowledge on how these metabolites exert their effects and outline the methodologies used to detect and assess these metabolites. Finally, we summarize microbiota-targeted therapies capable of improving microbial functionality to

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… GMP-AMP synthase, MDSC myeloid-derived suppressor cell. … EZH2, in turn, binds the promoter of cyclic GMP-Amp synthase (cGAS), thereby silencing its expression. …

ADMET-Guided Design and In Silico Planning of Boron Delivery Systems for BNCT: From Transport and Biodistribution to PBPK-Informed Irradiation Windows.

BNCT (Boron Neutron Capture Therapy) is a binary radiotherapeutic modality in which high LET (Linear Energy Transfer) particles are generated from 10B(n,α)7Li reaction, ideally within boron-loaded tumour cells, so the therapeutic outcome depends critically on the pharmacokinetics and biodistribution of boron carriers. In this review, boron-containing agents for BNCT, with a focus on ADMET (absorption, distribution, metabolism, excretion and toxicity) and model-informed design, were examined. Low-MW (low-molecular-weight) compounds, peptide conjugates, polymeric and nanostructured platforms and

Targeting signaling pathways in lymphoma: From molecular mechanisms to clinical breakthroughs.

AbstractThe treatment paradigm for lymphoma, a highly heterogeneous group of hematologic malignancies, has been revolutionized by the development of therapies targeting oncogenic signaling pathways. This shift from conventional chemotherapy to precision medicine is driven by a deep molecular understanding of the pathways that govern lymphoma cell survival and proliferation. This review comprehensively surveys the landscape of these targeted therapies, from fundamental molecular mechanisms to clinical breakthroughs. We first dissect the molecular architecture of key oncogenic drivers, covering

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… GMP-AMP; cGAS: Cyclic GMP-AMP synthase; cyt c: Cytochrome c; DDR: DNA damage response; DNMTs: DNA methyltransferases; dsDNA: Double-stranded DNA; ER: Endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; ERK: Extracellular signal-regulated kinase; EZH2: Enhancer of zeste homolog 2; GMP-AMP … GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) innate immunity pathway cGAS–STING pathway as a central sensor for innate immunity The cGAS-STING pathway is a critical component of the innate immune system that functions as a primary sensor for cytosolic double-stranded DNA (dsDNA). [ …

ENPP1/CD203a-targeting heavy-chain antibody reveals cell-specific expression on human immune cells.

ENPP1/CD203a is a membrane-bound ectonucleotidase capable of hydrolyzing ATP, cGAMP and other substrates. Its enzymatic activity plays an important role in the balance of extracellular adenine nucleotides and the modulation of purinergic signaling, in soft tissue calcification, and in the regulation of the cGAS/STING pathway. However, a detailed analysis of ENPP1 surface expression on human immune cells has not been performed. Here, we selected VHH domains from human ENPP1-immunized alpacas to generate heavy-chain antibodies targeting ENPP1, and analyzed cell surface expression on all circulat

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… In addition, the purinergic enzymes CD38, ENPP1 and ENPP3 can modulate type I interferon response by regulating extracellular cGAMP levels [ 18 – 20 ]. cGAMP is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic double-stranded DNA, a danger signal indicative of intracellular pathogens …

Recent Advances in Cancer Vaccines: Challenges, Achievements, and Futuristic Prospects.

Cancer is a chronic disease, and it can be lethal due to limited therapeutic options. The conventional treatment options for cancer have numerous challenges, such as a low blood circulation time as well as poor solubility of anticancer drugs. Therapeutic cancer vaccines emerged to try to improve anticancer drugs' efficiency and to deliver them to the target site. Cancer vaccines are considered a viable therapeutic technique for most solid tumors. Vaccines boost antitumor immunity by delivering tumor antigens, nucleic acids, entire cells, and peptides. Cancer vaccines are designed to induce lon

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… Mn2 + raises the sensitivity of cyclic GMP-AMP synthase and STING, which alerts immune cells to infections. …

Sildenafil, a Type-5 Phosphodiesterase Inhibitor, Fails to Reverse Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression in Cells Isolated From Tuberculosis Patients.

Successful TB treatment is hampered by increasing resistance to the two most effective first-line anti-TB drugs, namely isoniazid and rifampicin, thus innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for increasing treatment efficacy without inducing drug resistance. We assessed the ability of Sildenafil, a type-5 phosphodiesterase inhibitor, as a repurposed compound, to serve as HDT target, by counteracting the suppressive effects of myeloid-derived suppressor cells (MDSC) obtained from active TB cases on T-cell responsivene

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… Effects of Sildenafil, a Type-5 cGMP Phosphodiesterase Inhibitor, and Papaverine on Cyclic GMP and Cyclic AMP Levels in the Rabbit Corpus Cavernosum. vitro Br J Urol (1997) 79:958–63. doi: 10.1046/j.1464-410X.1997.00206.x 23. Prasad S, Wilkinson J, Gatzoulis MA. …

Immune mediated support of metastasis: Implication for bone invasion.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we describe

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… List of abbreviations protein kinase B basic helix loop helix family member e22 bone microenvironment bone matrix protein cancer‐associated fibroblast C‐C motif ligand C‐C‐motif receptor CD137 ligand cyclic GMP‐AMP synthase SicCr2‐encapsulated cationic nanoparticle Collagen Type I Alpha 1 … Zhou et al. [ 237 ] found that osteocytes can transfer mitochondria to tumor cells, triggering cyclic GMP‐AMP synthase/ stimulator of interferon genes (cGAS/STING) signaling, the upregulation of which can cause tumor cells to continue to secrete cytokines such as IFN‐I, NK cells, DCs, macrophages, and …

The 'speck'-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis.

The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death

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… Opposing evidence reported that GSDMD plays protective roles in IBD [ 51 ], since genetic ablation of GSDMD aggravated colitis by boosting cyclic GMP-AMP synthase (cGAS)-dependent inflammation [ 66 , 71 ]. …

Extracellular vesicles in multiple myeloma-bone marrow niche crosstalk: from cellular dialogue to clinical perspectives.

Multiple myeloma (MM) is a haematological neoplasia defined by the clonal expansion of malignant plasma cells within the intricate and dynamic ecosystem of the bone marrow (BM). Although genetic aberrations intrinsic to tumour cells play a critical role in MM initiation, the advancement and aggressiveness of the disease are heavily influenced by ongoing signalling exchanges and persistent interactions with the surrounding microenvironment. Extracellular vesicles (EVs) are increasingly recognized as essential messengers in this reciprocal communication, acting as membrane-encapsulated vehicles

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… In particular, five miRNAs were identified in the MM exosome cargo, including miR-16-5p, miR-146a-5p, miR-197-3p, miR-20b-5p and miR-21-5p, which are responsible for inhibition of the Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) pathway and reduction of type-I Interferon (IFN-I … GMP-AMP Synthase Circular MYC RNA Mesenchymal-Epithelial transition Factor receptor Circulating Tumor Cells Cytotoxic T-Lymphocyte–associated Antigen 4 Chemokine (C-X-C motif) Ligand 1 Dishevelled 3 Endothelial Cells Epidermal Growth Factor Receptor Extracellular Vesicle Magnetic-Levitation …

Exploring neutrophil extracellular traps: mechanisms of immune regulation and future therapeutic potential.

Neutrophil extracellular traps (NETs) are complex, web-like structures consisting of DNA intertwined with antimicrobial proteins, which neutrophils release upon immune activation. These structures play a crucial role in pathogen elimination, particularly in infectious diseases. However, their involvement in various pathological conditions is multifaceted and context-dependent, while NETs contribute to host defense against infections, they can also exacerbate sterile inflammation, autoimmune disorders, and tumor progression. This review provides a comprehensive analysis of the molecular mechani

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… It serves as a ligand for the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, which activates innate immune responses and has been linked to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) [ 78 ]. … GMP-AMP synthase/Stimulator of interferon genes Systemic lupus erythematosus 3-Methyladenine Mechanistic target of rapamycin Phosphoinositide 3-kinase Anti-neutrophil cytoplasmic antibodies Ulcerative colitis Regulated in development and DNA damage responses 1 Interleukin Toll-like receptor …

Tumor Targeting with Peptide-Drug Conjugates: Showcasing Key Progress and Hurdles.

Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs' small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circul

Drug repurposing-a promising approach for patients with angina but non-obstructive coronary artery disease (ANOCA).

In today's era of individualized precision medicine drug repurposing represents a promising approach to offer patients fast access to novel treatments. Apart from drug repurposing in cancer treatments, cardiovascular pharmacology is another attractive field for this approach. Patients with angina pectoris without obstructive coronary artery disease (ANOCA) report refractory angina despite standard medications in up to 40% of cases. Drug repurposing also appears to be an auspicious option for this indication. From a pathophysiological point of view ANOCA patients frequently suffer from vasomoto

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… Clinical relevance of cyclic GMP modulators: a translational success story of network pharmacology. Clin Pharmacol Ther. (2016) 99(4):360–2. 10.1002/cpt.336 24. Dang TA, Schunkert H, Kessler T. cGMP signaling in cardiovascular diseases: linking genotype and phenotype. …

Recent advances in drug repositioning for the discovery of new anticancer drugs.

Drug repositioning (also referred to as drug repurposing), the process of finding new uses of existing drugs, has been gaining popularity in recent years. The availability of several established clinical drug libraries and rapid advances in disease biology, genomics and bioinformatics has accelerated the pace of both activity-based and in silico drug repositioning. Drug repositioning has attracted particular attention from the communities engaged in anticancer drug discovery due to the combination of great demand for new anticancer drugs and the availability of a wide variety of cell- and targ

Targeting the CD47-TSP1 Axis in Abdominal Aortic Aneurysm: A Novel Immunotherapeutic Approach.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive dilation and weakening of the abdominal aortic wall. Despite advances in surgical repair, rupture remains associated with mortality rates exceeding 65%, and no effective pharmacological therapy exists to prevent disease progression. Increasing evidence highlights chronic inflammation, extracellular matrix degradation, and immune dysregulation as central drivers of AAA pathogenesis. Among these mechanisms, the thrombospondin-1 (TSP1)-CD47 signaling axis has emerged as a critical upstream regulat

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… Transcriptomic analysis revealed that activation of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) and Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathways induced type I interferon production, driving the differentiation of monocytes/macrophages … GMP-AMP synthase–stimulator of interferon genes cGMP Cyclic guanosine monophosphate CTD Intracellular domain CVD Cardiovascular disease DAMP Damage-associated molecular patterns ECM Extracellular matrix ECD Extracellular domain EGF-like repeat Epidermal Growth Factor-like domain HDAC3 Histone deacetylase …

Наномедицина - мощная терапия CAR-T для множественной миеломы: к программируемой, долговременной и точной иммунотерапии.

Множественная миелома (ММ) по-прежнему является трудновыполнимой гематологией. Несмотря на то, что терапия против созревания клеток B (BCMA), ориентированная на химерик антигенный рецептор Т-клектор (CAR-T), существенно углубила клиническую реакцию у пациентов с рецидивом/переносом MM, ее более широкое клиническое применение по-прежнему сдерживается рецидивом после лечения, недостаточной устойчивостью реакции, длительными сроками производства и ограниченной доступностью. Растущие данные свидетельствуют о том, что рецидив после лечения CAR-T в MM происходит не из одного механизма, а из конверге

The Effects of Artificial Sweeteners on Intestinal Nutrient-Sensing Receptors: Dr. Jekyll or Mr. Hyde?

The consumption of artificial and low-calorie sweeteners (ASs, LCSs) is an important component of the Western diet. ASs play a role in the pathogenesis of metabolic syndrome, dysbiosis, inflammatory bowel diseases (IBDs), and various inflammatory conditions. Intestinal nutrient-sensing receptors act as a crosstalk between dietary components, the gut microbiota, and the regulation of immune, endocrinological, and neurological responses. This narrative review aimed to summarize the possible effects of ASs and LCSs on intestinal nutrient-sensing receptors and their related functions. Based on the

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… T2R receptor activation enhances the phagocytosis of human macrophages in vitro via the elevation of intracellular calcium release, and endothelial nitric oxide synthase (eNOS) activation via the cyclic GMP (cGMP) pathways [ 27 ]. … Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling Cell. Mol. Life Sci. 2021 78 271 286 10.1007/s00018-020-03494-y 32172302 PMC7492447 28. Sharma P. Yi R. Nayak A.P. Wang N. Tang F. Knight M.J. Pan S. Oliver B. Deshpande D.A. …

Mechanisms and Applications of Manganese-Based Nanomaterials in Tumor Diagnosis and Therapy.

Tumors are the second most common cause of mortality globally, ranking just below heart disease. With continuous advances in diagnostic technology and treatment approaches, the survival rates of some cancers have increased. Nevertheless, due to the complexity of the mechanisms underlying tumors, cancer remains a serious public health issue that threatens the health of the population globally. Manganese (Mn) is an essential trace element for the human body. Its regulatory role in tumor biology has received much attention in recent years. Developments in nanotechnology have led to the emergence

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… Mn influences cell fate via the insulin-IGF1 pathway, the ATM-P53 pathway, autophagy, and the ferroptosis-related pathway, thereby exerting a complex effect on tumor development and progression. cGAS, cyclic GMP-AMP synthase; cGAMP, cyclic GMP-AMP; STING, stimulator of interferon genes; dsDNA, double-stranded … Recent research highlights the pronounced impact of Mn 2+ on the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway, which is essential for immune responses to infections and tumors. …

Piperine: From Green Extraction to Clinical Translation-A Review.

BACKGROUND: Piperine has diverse pharmacological and bioenhancing activities, but poor aqueous solubility, variable exposure, interaction liability, and discontinuity across production, formulation, and clinical evaluation limit translation. This review integrates these frequently separated stages. METHODS: A structured narrative PubMed search covered English-language studies published from 1 January 2021 to 27 April 2026, supplemented by ClinicalTrials.gov records checked through 13 June 2026, backward citation searching, and selected earlier seminal studies. Evidence was synthesized by expe

Иммуномодулирующий и противовоспалительный потенциал S-нитросглутатиона (GSNO) при множественной склерозе: обзор механизмов и терапевтических перспектив.

Многофакторная демиелинизация (МС) — это хроническое аутоиммунное заболевание центральной нервной системы (СНС), характеризующееся длительной нейроинфляминацией, окислительным стрессом, демиелинизацией и прогрессирующей нейродегенерацией. Несмотря на то, что МС остается неизлечимым, современные терапевтические средства (ТМС) помогают снизить частоту обострений и задерживать прогрессирование заболевания. Недавно разработанные инъекционные и инфузийные биологические ТМС обеспечивают целенаправленную иммуномодуляцию, но их клиническая полезность ограничена родственными методами введения и возможн

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… By binding to the heme moiety of soluble guanylyl cyclase (sGC), NO• activates cyclic GMP (cGMP) production, which subsequently stimulates protein kinase G (PKG), cGMP-gated ion channels (CGCs), and phosphodiesterases (PDEs). … The central pathway shows nitric oxide activating guanylyl cyclase and cyclic GMP, producing cardiovascular and endothelial benefits. …