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Regulation of 90-kilodalton ribosomal S6 kinase phosphorylation in the rat pineal gland.

In this study we investigated diurnal changes in the activation state of the 90-kDa ribosomal S6 kinase (p90RSK) in the rat pineal gland. In animals housed under a lighting regimen with 12 h of light, we found an increase in phosphorylated p90RSK during the dark phase, and this increase was abolished by treatment with propranolol or continuous exposure to light. To determine the intracellular mechanism involved, rat pinealocytes were treated with norepinephrine. Norepinephrine caused a parallel increase in phosphorylated p42/44 MAPK (p42/44(MAPK)) and p90RSK that was reduced by prazosin or pro

Phosphodiesterase type 5 and cancers: progress and challenges.

Cancers are an extraordinarily heterogeneous collection of diseases with distinct genetic profiles and biological features that directly influence response patterns to various treatment strategies as well as clinical outcomes. Nevertheless, our growing understanding of cancer cell biology and tumor progression is gradually leading towards rational, tailored medical treatments designed to destroy cancer cells by exploiting the unique cellular pathways that distinguish them from normal healthy counterparts. Recently, inhibition of the activity of phosphodiesterase type 5 (PDE5) is emerging as a

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… Differential expression of the cyclic GMP-stimulated phosphodiesterase PDE2a in human venous and capillary endothelial cells. J Histochem Cytochem. 1999;47:895–906. doi: 10.1177/002215549904700707. 28. … Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214–222. doi: 10.1038/nm1175. 107. Dunkern TR, Hatzelmann A. …

C-type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor and the most common soft tissue sarcoma in children. Because of several complications associated with intensive multimodal therapies, including growth disturbance and secondary cancer, novel therapies with less toxicity are urgently needed. C-type natriuretic peptide (CNP), an endogenous peptide secreted by endothelial cells, exerts antiproliferative effects in multiple types of mesenchymal cells. Therefore, we investigated whether CNP attenuates proliferation of RMS cells. We examined RMS patient samples and RMS cell lines. All RMS clini

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… Cyclic GMP is quickly degraded to GMP by phosphodiesterases (PDEs). … Cyclic‐GMP‐dependent protein kinase inhibits the Ras/Mitogen‐activated protein kinase pathway. Mol. Cell. Biol. 18:6983–6994. 33. Itoh, T. , Nagaya N., Murakami S., Fujii T., Iwase T., Ishibashi Ueda H., et al. 2004. …

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil.

The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is

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… Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor-positive and -negative breast cancer cell lines . FEBS J ( 2011 ) 278 ( 18 ): 3360–9 . 10.1111/j.1742-4658.2011.08260.x 21777390 39 Lee K Piazza GA . … Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G . …

Nitric oxide-induced inhibition of aortic smooth muscle cell motility: role of PTP-PEST and adaptor proteins p130cas and Crk.

Vascular injury increases nitric oxide (NO) levels, and this effect may play a counterregulatory role in neointima formation, by decreasing vascular smooth muscle cell motility. However, the mechanisms underlying this effect are not well established. We tested the hypothesis that NO decreases cell motility by increasing the activity of a protein tyrosine phosphatase (PTP), PTP-PEST, in cultured rat aortic smooth muscle cells. Two NO donors increased the activity of PTP-PEST. A cGMP analog mimicked the effect of NO, whereas a guanyl cyclase inhibitor blocked it, indicating that elevated cGMP is

Перенос Митохондрии для ремонта миелина.

Обезвоживание является общей характеристикой нейро-воспалительных и дегенеративных заболеваний центральной нервной системы (КНС), таких, как множественный склероз (МС). Часто это связано с нарушениями межклеточной связи, биоэнергетики и метаболического баланса в сочетании с митохондриальной дисфункцией в таких клетках, как олигодендроциты, нейроны, астроциты и микроглиа. Несмотря на то, что нынешние методы лечения MS сосредоточены на иммуномодуляции, они не могут остановить или обратить вспять прогресс демиэлизации. Последние достижения подчеркивают межклеточный митохондриальный обмен в качест

Cyclic nucleotide phosphodiesterases as drug targets.

Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels

Molecular Delivery of Cytotoxic Agents via Integrin Activation.

Integrins are cell adhesion receptors overexpressed in tumor cells. A direct inhibition of integrins was investigated, but the best inhibitors performed poorly in clinical trials. A gained attention towards these receptors arouse because they could be target for a selective transport of cytotoxic agents. Several active-targeting systems have been developed to use integrins as a selective cell entrance for some antitumor agents. The aim of this review paper is to report on the most recent results on covalent conjugates between integrin ligands and antitumor drugs. Cytotoxic drugs thus conjugate

Advances in improving cancer immunotherapy with nanotechnology: from smart nanoparticles to synergistic combination strategies.

Cancer immunotherapy has substantially advanced cancer treatment, achieving durable responses in select malignancies. However, its widespread application is limited by significant challenges: low efficacy in many solid tumors, severe side effects, and immune evasion facilitated by the tumor microenvironment (TME). Nanotechnology offers a promising approach to address these obstacles. By employing nanoparticles (NPs), we can precisely deliver therapeutics to tumor sites, ensure controlled release to minimize side effects, and amplify the immune response, thereby substantially boosting the effec

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… One of the most extensively documented signaling routes activated by nanoparticles is the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) axis [ 180 ]. … Nanoparticles engage this pathway through two principal mechanisms: (i) induction of cytosolic double-stranded DNA (dsDNA) via nanoparticle-triggered oxidative stress, DNA damage, or immunogenic cell death, which activates the cytosolic DNA sensor cGAS to produce cyclic GMP-AMP (cGAMP) [ 180 , 181 ]; …

Repurposing drugs in oncology (ReDO)-selective PDE5 inhibitors as anti-cancer agents.

Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of can

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… PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide. Oncotarget. 2017;8(1):1449–1468. doi: 10.18632/oncotarget.13640. 42. Booth L, Roberts JL, Poklepovic A, et al. … The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma. Cancer Lett. 2016;370(2):279–285. doi: 10.1016/j.canlet.2015.10.024. 49. Sponziello M, Verrienti A, Rosignolo F, et al. …

Интерферонские регулятивные факторы как потенциальная терапевтическая цель для нейроинфламмации: фокус на болезни Альцгеймера.

Регулирующие факторы интерферона (ИРФ) являются важнейшими модуляторами иммунной и подстрекательской реакции, однако их роль в болезни Альцгеймера (AD) и других нейродегенеративных расстройствах остается неполной. В то время как IRF признаются за их регулирующие функции в нейроинфламмации, микроглиальной активации и выживании нейронов, их двойная роль как факторов патологического воспаления и посредников нейрозащитных путей подчеркивает сложный нормативный парадокс в нейродегенеративных расстройствах. Цель этого обзора заключается в обобщении текущих данных о нейрофламмации в области АД и связ

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… The first is modulating neuroinflammatory pathways, including pharmacological interventions of pathways such as NF-κB, NLRP3, triggering receptor expressed on myeloid cell 2 (TREM2), and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) [ 13 ]. … Abbreviations AD: Alzheimer’s disease; IRFs: Interferon Regulatory Factors; DBD: DNA-binding domain; ISGs: IFN-stimulated genes; TREM2: triggering receptor expressed on myeloid cell 2; cGAS-STING: cyclic GMP-AMP synthase-stimulator of interferon genes; ER: endoplasmic reticulum; UPR: unfolded protein …

The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors.

Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of the development of virulence inhibitors, inhibition of quorum sensing (QS) is a promising route because various important features in bacterial physiology and virulence are mediated by QS-dependent gene expression. Methods: Forty-five pharmacological agents,

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy.

During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-α and IFN-β, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-α/β share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular p

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… In established melanoma and colorectal cancer cell lines, STING signaling is repressed due, typically, to epigenetic silencing of cyclic GMP-AMP synthase (cGAS) or STING itself. … SUP3 also induced antigen-specific antibodies such as IgM, total IgG and high affinity IgG [ 276 ]. 2 ′ -3 ′ -Cyclic GMP-AMP Several authors have shown that 2′-3′-cyclic GMP-AMP (cGAMP) can be used directly as an adjuvant for antitumor therapy [ 277 ]. cGAS is a major sensor of cytosolic DNA, irrespective …

Ginsenoside-Mediated Ferroptosis Regulation: Bidirectional Effects and Therapeutic Potential in Diseases.

Notably, certain ginsenoside components exhibit distinct bidirectional and context-dependent regulatory effects on ferroptosis depending on the disease setting. In aberrantly proliferating or activated cells, ginsenosides function as ferroptosis inducers, whereas in damaged quiescent cells of normal tissues, they act as ferroptosis inhibitors. The pro-ferroptotic effect is predominantly observed in cells characterized by abnormal proliferation or activation, such as cancer cells and activated hepatic stellate cells in liver fibrosis. In this context, ginsenosides modulate key iron metabolism p

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… LPS: lipopolysaccharide. cGAS: cyclic GMP-AMP Synthase. STING: Stimulator of Interferon Genes. CCl4: carbon tetrachloride. GPX4: glutathione peroxidase 4. DHODH: dihydroorotate dehydrogenase. keap1: Kelch-like ECH-associated protein 1. miR-144-3p: microRNA-144-3p. … FOXO3A: Forkhead Box O3A. p62/SQSTM1: sequestosome 1. cGAS: cyclic GMP-AMP Synthase. STING: Stimulator of Interferon Genes. DHODH: dihydroorotate dehydrogenase. PERK: protein kinase R-like endoplasmic reticulum kinase. ATF4: activating transcription factor 4. …

Meeting abstracts from the 21st European Symposium on Radiopharmacy and Radiopharmaceuticals

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Сверхклеточная везикла в качестве главных регуляторов иммунной модуляции в Мультимиломе.

Множественная миелома (ММ) — генетически и клинически разнородная плазменная порча клеток, характеризующаяся клональным расширением различных клеток В внутри костного мозга (БМ). Пациенты начинают с моноклональной гаммопатии неизвестного значения (MMUS) и переходят на промежуточную стадию под названием Smouldering multieloma (SMM), характеризующуюся несколькими генетическими изменениями, представляющими геномную основу злокачественного клона. Проходы на контрольно-пропускных пунктах иммунной системы играют ключевую роль в формировании иммуноподавляющей ниши BM, что способствует дисфункции Т-кл

Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of PI3K, PKC and PLC pathways.

1. The mechanism(s) by which vascular endothelial growth factor (VEGF) induces endothelial nitric oxide synthase (eNOS) activation remain(s) unclear up to a certain extent. Therefore, we sought to evaluate the contribution of numerous pathways in VEGF-induced nitric oxide (NO) synthesis by measuring cGMP production. In addition, as VEGF induces the synthesis of NO and platelet-activating factor (PAF), we wanted to assess if the induction of PAF and NO is contributing to the synthesis of each other. 2. Herein, we show that a treatment of endothelial cells with a phospholipase C (PLC) inhibitor

Recombinant Oncolytic Viruses: Hexagonal Warriors in the Field of Solid Tumor Immunotherapy.

In the past decade, research on recombinant oncolytic viral agents in the treatment of solid tumors has evolved from the initial stage of simple genetic engineering to the current stage of multiple pipelines of parallel clinical application and combination therapy. Compared with T-VEC, the classical therapeutic agent that only expresses GM-CSF, which was approved in 2015, most new oncolytic virus designs include diverse gene constructs to reduce toxic effects, enhance multiple antitumor immunity, avoid immune clearance, or enhance tumor targeting. The single route of administration that activa

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… The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is the core pathway mediating cytoplasmic DNA-triggered immune responses. Virus DNA released in the tumor cell cytoplasm is activated and activates cGAS to recognize and synthesize GTP after HSV infection. … After oHSV infection, cyclic GMP-AMP synthase (cGAS) recognizes viral dsDNA, activates STING signaling, recruits TBK1, and promotes the phosphorylation of IRF3. These receptors trigger downstream signaling cascades that lead to NF-κB expression and the release of proinflammatory cytokines. …

Молекулярные модели, связанные с ущербом от митохондриала: нейроиммуномодуляторы в патофизиологии центральной нервной системы.

Нейроинфламмация способствует широкому спектру нейродегенеративных заболеваний, включая болезнь Альцгеймера, болезнь Паркинсона, болезнь Хантингтона и множественный склероз. Его движут неевропейские глиальные клетки, главным образом микроглии и астроциты. Микроглии являются постоянными иммунными клетками центральной нервной системы, в то время как астроциты являются основными элементами поддержки нейронных функций, но могут также участвовать в нейроиммунной реакции. Оба этих типа глиальных клеток могут стать реактивными при обнаружении определенных внутриклеточных молекул, которые появляются в

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… Molecules of mtDNA are detected by cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, triggering a signaling cascade that activates the stimulator of IFN genes (STING) pathway in peripheral immune cells. …