Unveiling the potential of purinergic signaling in schistosomiasis treatment

2020 ◽  
Vol 20 ◽  
Author(s):  
Nathália Ferreira Oliveira ◽  
Claudia Lucia Martins Silva
Keyword(s):  
Inflammatory Diseases ◽  
Purinergic Signaling ◽  
P2y Receptors ◽  
Current Data ◽  
Global Public Health ◽  
P2x7 Receptors ◽  
Pharmacological Targets ◽  
Target Organs ◽  
Paracrine Actions ◽  
Molecular Patterns

: Schistosomiasis is a neglected tropical disease. It is related to long-lasting granulomatous fibrosis and inflammation of target organs, and current sub-optimal pharmacological treatment awakens global public health concerns. Intravascular worms and eggs release antigens and extracellular vesicles that target host endothelial cells, modulate the immune system, and stimulate the release of damage-associated molecular patterns (DAMPs). ATP, one of the most studied DAMP, triggers a cascade of autocrine and paracrine actions through purinergic P2X and P2Y receptors, which are shaped by ectonucleotidases (CD39). Both P2 receptor families, and in particular P2Y1, P2Y2, P2Y12, and P2X7 receptors, have been attracting increasing interest in several inflammatory diseases and drug development. Current data obtained in the murine model unveil a CD39-ADP-P2Y1/P2Y12 receptors signaling pathway linked to liver and mesenteric exacerbations of schistosomal inflammation. Therefore, we propose that members of this purinergic signaling could be putative pharmacological targets to reduce schistosomal morbidity.

scholarly journals P2X7 receptors in body temperature, locomotor activity, and brain mRNA and lncRNA responses to sleep deprivation

2016 ◽  
Vol 311 (6) ◽  
pp. R1004-R1012 ◽  
Author(s):  
Christopher J. Davis ◽  
Ping Taishi ◽  
Kimberly A. Honn ◽  
John N. Koberstein ◽  
James M. Krueger
Keyword(s):  
Locomotor Activity ◽  
Body Temperature ◽  
Sleep Deprivation ◽  
Purinergic Signaling ◽  
Core Body Temperature ◽  
Current Data ◽  
Mrna Levels ◽  
Sleep Regulation ◽  
P2x7 Receptors ◽  
Endogenous Rhythms

The ionotropic purine type 2X7 receptor (P2X7R) is a nonspecific cation channel implicated in sleep regulation and brain cytokine release. Many endogenous rhythms covary with sleep, including locomotor activity and core body temperature. Furthermore, brain-hypothalamic cytokines and purines play a role in the regulation of these physiological parameters as well as sleep. We hypothesized that these parameters are also affected by the absence of the P2X7 receptor. Herein, we determine spontaneous expression of body temperature and locomotor activity in wild-type (WT) and P2X7R knockout (KO) mice and how they are affected by sleep deprivation (SD). We also compare hypothalamic, hippocampal, and cortical cytokine- and purine-related receptor and enzyme mRNA expressions before and after SD in WT and P2X7RKO mice. Next, in a hypothesis-generating survey of hypothalamic long noncoding (lnc) RNAs, we compare lncRNA expression levels between strains and after SD. During baseline conditions, P2X7RKO mice had attenuated temperature rhythms compared with WT mice, although locomotor activity patterns were similar in both strains. After 6 h of SD, body temperature and locomotion were enhanced to a greater extent in P2X7RKO mice than in WT mice during the initial 2-3 h after SD. Baseline mRNA levels of cortical TNF-α and P2X4R were higher in the KO mice than WT mice. In response to SD, the KO mice failed to increase hypothalamic adenosine deaminase and P2X4R mRNAs. Further, hypothalamic lncRNA expressions varied by strain, and with SD. Current data are consistent with a role for the P2X7R in thermoregulation and lncRNA involvement in purinergic signaling.

scholarly journals Adenosine diphosphate contributes to wound healing in diabetic mice through P2Y1 and P2Y12 receptors activation

2020 ◽  
Author(s):  
Paula A. Borges ◽  
Ingrid Waclawiak ◽  
Janaína L. Georgii ◽  
Janaína F. Barros ◽  
Vanderlei S. Fraga-Junior ◽  
...  
Keyword(s):  
Wound Healing ◽  
Inflammatory Diseases ◽  
Purinergic Signaling ◽  
Adenosine Diphosphate ◽  
Treg Cells ◽  
Skin Wound ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Keratinocyte Proliferation ◽  
Wound Model

AbstractSeveral studies have shown the importance of purinergic signaling in various inflammatory diseases. In diabetes mellitus, there is an increase in the activity of some nucleotidases suggesting that this signaling may be affected in the diabetic skin. Thus, the aim of our study was to investigate the effect of ADP on wound healing in diabetic skin. Swis and C57BL/6 mice were pharmacologic induced to type 1 diabetes and submitted to a full-thickness excisional wound model to evaluate the effect of ADP as a topic treatment. Adenosine diphosphate accelerated cutaneous wound healing, improved the new tissue formation, and increased collagen deposit by positively modulating P2Y1 and P2Y12 and TGF-β production. In parallel, ADP reduced reactive oxygen species production and TNF-α levels, while increased IFNγ, IL-10 and IL-13 levels in the skin. Also, ADP induced the migration of neutrophils, eosinophils, mast cells, TCRγ4+, and TCRγ5+ cells while reduced Treg cells towards the lesion at day 7. In accordance, ADP increased the proliferation and migration of fibroblast, induced myofibroblast differentiation and keratinocyte proliferation in a P2Y12-dependent manner. We provide the first evidence of ADP acting as a potent mediator on skin wound resolution and a possible therapeutic approach for diabetic patients worldwide.

scholarly journals DNA damage independent inhibition of NF-κB transcription by anthracyclines

2020 ◽  
Author(s):  
Angelo Chora ◽  
Dora Pedroso ◽  
Nadja Pejanovic ◽  
Eleni Kyriakou ◽  
Henrique Colaço ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Anticancer Properties ◽  
Dna Binding Sites ◽  
Immune Mediated ◽  
Life Threatening ◽  
Molecular Patterns

AbstractTranscriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.

The anti-thrombotic effects of vitamin D and their possible relationship with antiphospholipid syndrome

Lupus ◽  
2018 ◽  
Vol 27 (14) ◽  
pp. 2181-2189 ◽  
Author(s):  
M García-Carrasco ◽  
E A Jiménez-Herrera ◽  
J L Gálvez-Romero ◽  
C Mendoza-Pinto ◽  
S Méndez-Martínez ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Antiphospholipid Syndrome ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Serum Levels ◽  
Protective Role ◽  
Current Data ◽  
Current Evidence ◽  
Autoimmune Conditions

The importance of the immunomodulatory effects of vitamin D has recently been associated with autoimmune and chronic inflammatory diseases. Vitamin D deficiency has been linked to the development of autoimmune conditions. Antiphospholipid syndrome is an autoimmune disease characterized by thrombotic events and obstetric complications in patients with antiphospholipid antibodies. Current data show that patients with antiphospholipid syndrome have a high prevalence of vitamin D deficiency even without classic risk factors. Several studies have suggested vitamin D may have anti-thrombotic functions. In antiphospholipid syndrome, low vitamin D serum levels have been associated with thrombotic manifestations, suggesting a possible protective role of vitamin D in antiphospholipid syndrome. This literature review presents current evidence on the haemostatic functions of vitamin D and their possible relationship with the clinical manifestations of antiphospholipid syndrome.

scholarly journals Purinergic signaling, DAMPs, and inflammation

2020 ◽  
Vol 318 (5) ◽  
pp. C832-C835 ◽  
Author(s):  
Francesco Di Virgilio ◽  
Alba Clara Sarti ◽  
Robson Coutinho-Silva
Keyword(s):  
Plasma Membrane ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Extracellular Atp ◽  
Main Metabolite ◽  
P2 Purinergic Receptors ◽  
Evolutionary Features ◽  
Multicellular Organisms ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Danger sensing is one of the most fundamental evolutionary features enabling multicellular organisms to perceive potential threats, escape from risky situations, fight actual intruders, and repair damage. Several endogenous molecules are used to “signal damage,” currently referred to as “alarmins” or “damage-associated molecular patterns” (DAMPs), most being already present within all cells (preformed DAMPs), and thus ready to be released, and others neosynthesized following injury. Over recent years it has become overwhelmingly clear that adenosine 5′-triphosphate (ATP) is a ubiquitous and extremely efficient DAMP (thus promoting inflammation), and its main metabolite, adenosine, is a strong immunosuppressant (thus dampening inflammation). Extracellular ATP ligates and activates the P2 purinergic receptors (P2Rs) and is then degraded by soluble and plasma membrane ecto-nucleotidases to generate adenosine acting at P1 purinergic receptors (P1Rs). Extracellular ATP, P2Rs, ecto-nucleotidases, adenosine, and P1Rs are basic elements of the purinergic signaling network and fundamental pillars of inflammation.

scholarly journals Purinergic Signaling in Endometriosis-Associated Pain

2020 ◽  
Vol 21 (22) ◽  
pp. 8512
Author(s):  
Carla Trapero ◽  
Mireia Martín-Satué
Keyword(s):  
Atp Hydrolysis ◽  
Current Knowledge ◽  
Purinergic Signaling ◽  
Uterine Cavity ◽  
Nucleotide Receptors ◽  
P2x3 Receptor ◽  
P2x7 Receptors ◽  
Pharmacological Management ◽  
Predominant Symptom ◽  
Therapeutic Tools

Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell–nerve and microglia–nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain.

scholarly journals Purinergic Signaling and Related Biomarkers in Depression

2020 ◽  
Vol 10 (3) ◽  
pp. 160 ◽  
Author(s):  
Francesco Bartoli ◽  
Geoffrey Burnstock ◽  
Cristina Crocamo ◽  
Giuseppe Carrà
Keyword(s):  
Purinergic Signaling ◽  
Research Area ◽  
Mood Stabilizers ◽  
P2x7 Receptors ◽  
Purinergic System ◽  
Open Questions ◽  
Antidepressant Effects ◽  
Wide Range ◽  
Adenosine Antagonist

It is established that purinergic signaling can shape a wide range of physiological functions, including neurotransmission and neuromodulation. The purinergic system may play a role in the pathophysiology of mood disorders, influencing neurotransmitter systems and hormonal pathways of the hypothalamic-pituitary-adrenal axis. Treatment with mood stabilizers and antidepressants can lead to changes in purinergic signaling. In this overview, we describe the biological background on the possible link between the purinergic system and depression, possibly involving changes in adenosine- and ATP-mediated signaling at P1 and P2 receptors, respectively. Furthermore, evidence on the possible antidepressive effects of non-selective adenosine antagonist caffeine and other purinergic modulators is reviewed. In particular, A2A and P2X7 receptors have been identified as potential targets for depression treatment. Preclinical studies highlight that both selective A2A and P2X7 antagonists may have antidepressant effects and potentiate responses to antidepressant treatments. Consistently, recent studies feature the possible role of the purinergic system peripheral metabolites as possible biomarkers of depression. In particular, variations of serum uric acid, as the end product of purinergic metabolism, have been found in depression. Although several open questions remain, the purinergic system represents a promising research area for insights into the molecular basis of depression.

scholarly journals Effect of Interleukin-17 in the Activation of Monocyte Subsets in Patients with ST-Segment Elevation Myocardial Infarction

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Montserrat Guadalupe Garza-Reyes ◽  
Mónica Daniela Mora-Ruíz ◽  
Luis Chávez-Sánchez ◽  
Alejandra Madrid-Miller ◽  
Alberto Jose Cabrera-Quintero ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Inflammatory Diseases ◽  
Interleukin 17 ◽  
Monocyte Subsets ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
St Segment ◽  
Molecular Patterns ◽  
First Time ◽  
Circulating Levels

Interleukin- (IL-) 17 is increased in acute myocardial infarction (AMI) and plays a key role in inflammatory diseases through its involvement in the activation of leukocytes. Here, we describe for the first time the effect of IL-17 in the migration and activation of monocyte subsets in patients during ST-segment elevation myocardial infarction (STEMI) and post-STEMI. We analyzed the circulating levels of IL-17 in patient plasma. A gradual increase in IL-17 was found in STEMI and post-STEMI patients. Additionally, IL-17 had a powerful effect on the recruitment of CD14++CD16+/CD14+CD16++ monocytes derived from patients post-STEMI compared with the monocytes from patients with STEMI, suggesting that IL-17 recruits monocytes with inflammatory activity post-STEMI. Furthermore, IL-17 increased the expression of TLR4 on CD14+CD16- and CD14++CD16+/CD14+CD16++ monocytes post-STEMI and might enhance the response to danger-associated molecular patterns post-STEMI. Moreover, IL-17 induced secretion of IL-6 from CD14++CD16− and CD14++CD16+/CD14+CD16++ monocytes both in STEMI and in post-STEMI, which indicates that IL-17 has an effect on the secretion of proinflammatory cytokines from monocytes during STEMI and post-STEMI. Overall, we demonstrate that in STEMI and post-STEMI, IL-17 is increased and induces the migration and activation of monocyte subsets, possibly contributing to the inflammatory response through TLR4 and IL-6 secretion.

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