second messengers
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2022 ◽  
Vol 177 ◽  
pp. 114525
Author(s):  
Elaheh Samari ◽  
Najmeh Ahmadian Chashmi ◽  
Faezeh Ghanati ◽  
Reza H. Sajedi ◽  
Andrea A. Gust ◽  
...  

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 227
Author(s):  
Laura Camacho ◽  
Alberto Ouro ◽  
Ana Gomez-Larrauri ◽  
Arkaitz Carracedo ◽  
Antonio Gomez-Muñoz

Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination.


2022 ◽  
Author(s):  
Marie-Lise Jobin ◽  
Veronique De Smedt-Peyrusse ◽  
Fabien Ducrocq ◽  
Asma Oummadi ◽  
Rim Baccouch ◽  
...  

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.


2021 ◽  
Vol 23 (1) ◽  
pp. 262
Author(s):  
Patrizia Di Iorio ◽  
Maurizio Ronci ◽  
Patricia Giuliani ◽  
Francesco Caciagli ◽  
Renata Ciccarelli ◽  
...  

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.


2021 ◽  
Vol 23 (1) ◽  
pp. 232
Author(s):  
Wenjing Ren ◽  
Patrizia Rubini ◽  
Yong Tang ◽  
Tobias Engel ◽  
Peter Illes

Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophage-localized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1β (pro-IL-1β)-degrading caspase-1 to lead to IL-1β release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn’s disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences.


2021 ◽  
Vol 22 ◽  
Author(s):  
Idris Zubairu Sadiq

: Free radical contained one or more unpaired electrons in its valence shell, thus making it unstable, short-lived and highly reactive specie. Excessive generation of these free radicals ultimately leads to oxidative stress causing oxidation and damage to significant macromolecules in the living system and essentially disrupting signal transduction pathways and antioxidants equilibrium. At lower concentrations, ROS serves as “second messengers” influencing many physiological processes in the cell. However, at higher concentrations beyond cell capacity causes oxidative stress, which contributes to much human pathology such as diabetes, cancer, Parkinson’s disease, cardiovascular diseases, cataract, asthma, hypertension, atherosclerosis, arthritis and Alzheimer’s disease. Signaling pathways such as NF-κB, MAPKs, PI3K/Akt/ mTOR and Keap1-Nrf2-ARE modulates the detrimental effects of oxidative stress by increasing the expression of cellular antioxidant defenses, phase II detoxification enzymes and decreased production of ROS. Free radicals such as H2O2 are indeed needed for the advancement of cell cycle as these molecules influences DNA, proteins and enzymes in the cell cycle pathway. In the course of cell cycle progression, the cellular redox environment becomes more oxidized moving from G1 phase, becomes higher in G2/M and moderate in S phase. Signals in the form of an increase in cellular pro-oxidant levels are required and these signals are often terminated by a rise in the amount of antioxidants and MnSOD with a decrease in the level of cyclin D1 proteins. Therefore, understanding the mechanism of cell cycle redox regulation will help in therapy of many diseases.


Plants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 14
Author(s):  
Matthew J. Marcec ◽  
Kiwamu Tanaka

Calcium and reactive oxygen species (ROS) are two of the earliest second messengers in response to environmental stresses in plants. The rise and sequestration of these messengers in the cytosol and apoplast are formed by various channels, transporters, and enzymes that are required for proper defense responses. It remains unclear how calcium and ROS signals regulate each other during pattern-triggered immunity (PTI). In the present study, we examined the effects of perturbing one signal on the other in Arabidopsis leaves upon the addition of flg22, a well-studied microbe-associated molecular pattern (MAMP). To this end, a variety of pharmacological agents were used to suppress either calcium or ROS signaling. Our data suggest that cytosolic calcium elevation is required to initiate and regulate apoplastic ROS production generated by respiratory burst oxidase homologs (RBOHs). In contrast, ROS has no effect on the initiation of the calcium signal, but is required for forming a sufficient amplitude of the calcium signal. This finding using pharmacological agents is corroborated by the result of using a genetic double mutant, rbohd rbohf. Our study provides an insight into the mutual interplay of calcium and ROS signals during the MAMP-induced PTI response in plants.


2021 ◽  
Vol 8 (1) ◽  
pp. 23-31
Author(s):  
Jefrin Ahmed ◽  
Judith Mary Lamo ◽  
Baphilinia Jones Mylliemngap

Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. By adding phosphate groups to substrate proteins, they direct the activity, localization and overall function of many proteins, and serve to orchestrate the activity of almost all cellular processes. The main protein kinases consist of protein kinase A (PKA), protein kinase B (PKB), and protein kinase C (PKC) and are distinguished from each other by the different intracellular second messengers involved in their regulation and by the selective substrates they use. They all have a binding site for Mg2+-ATP (phosphate donor) and for substrate protein as well as various regulatory sites. We formulated to compare the binding capacity of protein kinases at the active site to allosteric sites. By comparing the active site and allosteric site of the protein kinases – A, B and C, using molecular docking it was found that in most of the cases the binding energy is high when an inhibitor binds to an active site as compared to the allosteric site. This comparison gave us an understanding of the interaction and inhibition of compounds to protein kinases in order to inhibit the activity of protein kinase A, B and C. It was concluded that for inhibiting the protein kinase function such as cell division and proliferation, binding of inhibitor to the allosteric site will be more effective.


Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1852
Author(s):  
Alexander A. Charbonneau ◽  
Debra M. Eckert ◽  
Colin C. Gauvin ◽  
Nathanael G. Lintner ◽  
C. Martin Lawrence

Csa3 family transcription factors are ancillary CRISPR-associated proteins composed of N-terminal CARF domains and C-terminal winged helix-turn-helix domains. The activity of Csa3 transcription factors is thought to be controlled by cyclic oligoadenyate (cOA) second messengers produced by type III CRISPR-Cas surveillance complexes. Here we show that Saccharolobus solfataricus Csa3a recognizes cyclic tetra-adenylate (cA4) and that Csa3a lacks self-regulating “ring nuclease” activity present in some other CARF domain proteins. The crystal structure of the Csa3a/cA4 complex was also determined and the structural and thermodynamic basis for cA4 recognition are described, as are conformational changes in Csa3a associated with cA4 binding. We also characterized the effect of cA4 on recognition of putative DNA binding sites. Csa3a binds to putative promoter sequences in a nonspecific, cooperative and cA4-independent manner, suggesting a more complex mode of transcriptional regulation. We conclude the Csa3a/cA4 interaction represents a nexus between the type I and type III CRISPR-Cas systems present in S. solfataricus, and discuss the role of the Csa3/cA4 interaction in coordinating different arms of this integrated class 1 immune system to mount a synergistic, highly orchestrated immune response.


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