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Article: Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder.

Azevedo, Márcia / Martinho, Raquel / Oliveira, Ana / Correia-de-Sá, Paulo / Moreira-Rodrigues, Mónica

2024 Volume 16, Page(s) 1332348

Abstract: The sympathoadrenal medullary system and the hypothalamic-pituitary-adrenal axis are both activated upon stressful events. The release of catecholamines, such as dopamine, norepinephrine (NE), and epinephrine (EPI), from sympathetic autonomic nerves ... ...

Abstract	The sympathoadrenal medullary system and the hypothalamic-pituitary-adrenal axis are both activated upon stressful events. The release of catecholamines, such as dopamine, norepinephrine (NE), and epinephrine (EPI), from sympathetic autonomic nerves participate in the adaptive responses to acute stress. Most theories suggest that activation of peripheral β-adrenoceptors (β-ARs) mediates catecholamines-induced memory enhancement. These include direct activation of β-ARs in the vagus nerve, as well as indirect responses to catecholamine-induced glucose changes in the brain. Excessive sympathetic activity is deeply associated with memories experienced during strong emotional stressful conditions, with catecholamines playing relevant roles in fear and traumatic memories consolidation. Recent findings suggest that EPI is implicated in fear and traumatic contextual memories associated with post-traumatic stress disorder (PTSD) by increasing hippocampal gene transcription (e.g.,
Language	English
Publishing date	2024-01-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2023.1332348
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Article: Editorial: Cellular and molecular targets in epileptogenesis focusing on disease prevention.

Cunha-Reis, Diana / Vaz, Sandra Henriques / Correia-de-Sá, Paulo

Frontiers in cellular neuroscience

2023 Volume 17, Page(s) 1251038

Language	English
Publishing date	2023-07-12
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2023.1251038
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Article ; Online: Purinergic Tuning of the Tripartite Neuromuscular Synapse.

Sousa-Soares, Carlos / Noronha-Matos, José Bernardo / Correia-de-Sá, Paulo

Molecular neurobiology

2023 Volume 60, Issue 7, Page(s) 4084–4104

Abstract: The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal muscle fiber, leading to muscle contraction. Typically, the NMJ is a tripartite ... ...

Abstract	The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal muscle fiber, leading to muscle contraction. Typically, the NMJ is a tripartite synapse comprising (a) a presynaptic region represented by the motor nerve ending, (b) a postsynaptic skeletal motor endplate area, and (c) perisynaptic Schwann cells (PSCs) that shield the motor nerve terminal. Increasing evidence points towards the role of PSCs in the maintenance and control of neuromuscular integrity, transmission, and plasticity. Acetylcholine (ACh) is the main neurotransmitter at the vertebrate skeletal NMJ, and its role is fine-tuned by co-released purinergic neuromodulators, like adenosine 5'-triphosphate (ATP) and its metabolite adenosine (ADO). Adenine nucleotides modulate transmitter release and expression of postsynaptic ACh receptors at motor synapses via the activation of P2Y and P2X receptors. Endogenously generated ADO modulates ACh release by acting via co-localised inhibitory A
MeSH term(s)	Synapses/metabolism ; Neuromuscular Junction/metabolism ; Adenosine/metabolism ; Adenosine Triphosphate/metabolism ; Motor Neurons/metabolism ; Acetylcholine/metabolism
Chemical Substances	Adenosine (K72T3FS567) ; Adenosine Triphosphate (8L70Q75FXE) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-023-03317-8
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Article ; Online: Could hypoxia rehabilitate the osteochondral diseased interface? Lessons from the interplay of hypoxia and purinergic signals elsewhere.

Pinto-Cardoso, Rui / Bessa-Andrês, Catarina / Correia-de-Sá, Paulo / Bernardo Noronha-Matos, José

Biochemical pharmacology

2023 Volume 214, Page(s) 115646

Abstract: The osteochondral unit comprises the articular cartilage (90%), subchondral bone (5%) and calcified cartilage (5%). All cells present at the osteochondral unit that is ultimately responsible for matrix production and osteochondral homeostasis, such as ... ...

Abstract	The osteochondral unit comprises the articular cartilage (90%), subchondral bone (5%) and calcified cartilage (5%). All cells present at the osteochondral unit that is ultimately responsible for matrix production and osteochondral homeostasis, such as chondrocytes, osteoblasts, osteoclasts and osteocytes, can release adenine and/or uracil nucleotides to the local microenvironment. Nucleotides are released by these cells either constitutively or upon plasma membrane damage, mechanical stress or hypoxia conditions. Once in the extracellular space, endogenously released nucleotides can activate membrane-bound purinoceptors. Activation of these receptors is fine-tuning regulated by nucleotides' breakdown by enzymes of the ecto-nucleotidase cascade. Depending on the pathophysiological conditions, both the avascular cartilage and the subchondral bone subsist to significant changes in oxygen tension, which has a tremendous impact on tissue homeostasis. Cell stress due to hypoxic conditions directly influences the expression and activity of several purinergic signalling players, namely nucleotide release channels (e.g. Cx43), NTPDase enzymes and purinoceptors. This review gathers experimental evidence concerning the interplay between hypoxia and the purinergic signalling cascade contributing to osteochondral unit homeostasis. Reporting deviations to this relationship resulting from pathological alterations of articular joints may ultimately unravel novel therapeutic targets for osteochondral rehabilitation. At this point, one can only hypothesize how hypoxia mimetic conditions can be beneficial to the ex vivo expansion and differentiation of osteo- and chondro-progenitors for auto-transplantation and tissue regenerative purposes.
MeSH term(s)	Nucleotides/metabolism ; Chondrocytes/metabolism ; Receptors, Purinergic/metabolism ; Cartilage, Articular/metabolism ; Cell Membrane/metabolism
Chemical Substances	Nucleotides ; Receptors, Purinergic
Language	English
Publishing date	2023-06-13
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2023.115646
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Zs.A 19: Show issues

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Article ; Online: Resolving the Ionotropic P2X4 Receptor Mystery Points Towards a New Therapeutic Target for Cardiovascular Diseases.

Bragança, Bruno / Correia-de-Sá, Paulo

International journal of molecular sciences

2020 Volume 21, Issue 14

Abstract: Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main ... ...

Abstract	Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main activators of the P2 and P1 purinoceptor families, respectively. Mounting evidence suggests that the ionotropic P2X4 receptor (P2X4R) plays pivotal roles in the regulation of the cardiovascular system, yet further therapeutic advances have been hampered by the lack of selective P2X4R agonists. In this review, we provide the state of the art of the P2X4R activity in the cardiovascular system. We also discuss the role of P2X4R activation in kidney and lungs vis a vis their interplay to control cardiovascular functions and dysfunctions, including putative adverse effects emerging from P2X4R activation. Gathering this information may prompt further development of selective P2X4R agonists and its translation to the clinical practice.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/physiopathology ; Drug Discovery ; Heart/drug effects ; Heart/physiopathology ; Humans ; Molecular Targeted Therapy ; Purinergic P2X Receptor Agonists/pharmacology ; Purinergic P2X Receptor Agonists/therapeutic use ; Receptors, Purinergic P2X4/metabolism
Chemical Substances	Purinergic P2X Receptor Agonists ; Receptors, Purinergic P2X4 ; Adenosine Triphosphate (8L70Q75FXE)
Keywords	covid19
Language	English
Publishing date	2020-07-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21145005
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Article ; Online: RNA-seq reveals that anti-obesity irisin and triiodothyronine (T3) hormones differentially affect the purinergic signaling transcriptomics in differentiated human adipocytes.

Mathias, Lucas Solla / Herman-de-Sousa, Carina / Cury, Sarah Santiloni / Nogueira, Célia Regina / Correia-de-Sá, Paulo / de Oliveira, Miriane

Biochimica et biophysica acta. Molecular and cell biology of lipids

2023 Volume 1868, Issue 4, Page(s) 159276

Abstract: The anti-obesity thyroid hormone, triiodothyronine (T3), and irisin, an exercise- and/or cold-induced myokine, stimulate thermogenesis and energy consumption while decreasing lipid accumulation. The involvement of ATP signaling in adipocyte cell function ...

Abstract	The anti-obesity thyroid hormone, triiodothyronine (T3), and irisin, an exercise- and/or cold-induced myokine, stimulate thermogenesis and energy consumption while decreasing lipid accumulation. The involvement of ATP signaling in adipocyte cell function and obesity has attracted increasing attention, but the crosstalk between the purinergic signaling cascade and anti-obesity hormones lacks experimental evidence. In this study, we investigated the effects of T3 and irisin in the transcriptomics of membrane-bound purinoceptors, ectonucleotidase enzymes and nucleoside transporters participating in the purinergic signaling in cultured human adipocytes. The RNA-seq analysis revealed that differentiated adipocytes express high amounts of ADORA1, P2RY11, P2RY12, and P2RX6 gene transcripts, along with abundant levels of transcriptional products encoding to purine metabolizing enzymes (ENPP2, ENPP1, NT5E, ADA and ADK) and transporters (SLC29A1, SCL29A2). The transcriptomics of purinergic signaling markers changed in parallel to the upsurge of "browning" adipocyte markers, like UCP1 and P2RX5, after treatment with T3 and irisin. Upregulation of ADORA1, ADORA2A and P2RX4 gene transcription was obtained with irisin, whereas T3 preferentially upregulated NT5E, SLC29A2 and P2RY11 genes. Irisin was more powerful than T3 towards inhibition of the leptin gene transcription, the SCL29A1 gene encoding for the ENT1 transporter, the E-NPP2 (autotaxin) gene, and genes that encode for two ADP-sensitive P2Y receptors, P2RY1 and P2RY12. These findings indicate that anti-obesity irisin and T3 hormones differentially affect the purinergic signaling transcriptomics, which might point towards new directions for the treatment of obesity and related metabolic disorders that are worth to be pursued in future functional studies.
MeSH term(s)	Humans ; Adipocytes/drug effects ; Adipocytes/metabolism ; Fibronectins/genetics ; Fibronectins/metabolism ; Obesity/genetics ; Obesity/metabolism ; RNA-Seq ; Transcriptome ; Triiodothyronine/pharmacology ; Triiodothyronine/metabolism
Chemical Substances	Fibronectins ; Triiodothyronine (06LU7C9H1V) ; FNDC5 protein, human
Language	English
Publishing date	2023-01-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2022.159276
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Article ; Online: 2,4,5-Triaminopyrimidines as blue fluorescent probes for cell viability monitoring: synthesis, photophysical properties, and microscopy applications.

Gonçalves, Jorge M / Gonçalves, João N D / Sousa, Luís F / Rodrigues, Lígia R / Correia-de-Sá, Paulo / Coutinho, Paulo J G / Castanheira, Elisabete M S / Oliveira, Rui / Dias, Alice M

Organic & biomolecular chemistry

2024 Volume 22, Issue 11, Page(s) 2252–2263

Abstract: Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine ... ...

Abstract	Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine derivatives able to discriminate between live and dead cells. To our knowledge, these compounds are the first fluorescent nucleobase analogues (FNAs) with cell viability monitoring potential. These new fluorescent molecules are synthesized using highly efficient and cost-effective methods and feature unprecedented photophysical properties (longer absorption and emission wavelengths, environment-sensitive emission, and unprecedented brightness within FNAs). Using a live-dead
MeSH term(s)	Fluorescent Dyes ; Microscopy ; Cell Survival
Chemical Substances	Fluorescent Dyes
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/d4ob00092g
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Article: Pharmacological Tuning of Adenosine Signal Nuances Underlying Heart Failure With Preserved Ejection Fraction.

Campos-Martins, Alexandrina / Bragança, Bruno / Correia-de-Sá, Paulo / Fontes-Sousa, Ana Patrícia

Frontiers in pharmacology

2021 Volume 12, Page(s) 724320

Abstract: Heart failure with preserved ejection fraction (HFpEF) roughly represents half of the cardiac failure events in developed countries. The proposed 'systemic microvascular paradigm' has been used to explain HFpHF presentation heterogeneity. The lack of ... ...

Abstract	Heart failure with preserved ejection fraction (HFpEF) roughly represents half of the cardiac failure events in developed countries. The proposed 'systemic microvascular paradigm' has been used to explain HFpHF presentation heterogeneity. The lack of effective treatments with few evidence-based therapeutic recommendations makes HFpEF one of the greatest unmet clinical necessities worldwide. The endogenous levels of the purine nucleoside, adenosine, increase significantly following cardiovascular events. Adenosine exerts cardioprotective, neuromodulatory, and immunosuppressive effects by activating plasma membrane-bound P1 receptors that are widely expressed in the cardiovascular system. Its proven benefits have been demonstrated in preclinical animal tests. Here, we provide a comprehensive and up-to-date critical review about the main therapeutic advantages of tuning adenosine signalling pathways in HFpEF, without discounting their side effects and how these can be seized.
Language	English
Publishing date	2021-08-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.724320
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Article ; Online: A

Herman-de-Sousa, Carina / Costa, Maria Adelina / Silva, Rafaela Pedro / Ferreirinha, Fátima / Ribeiro, Severino / Correia-de-Sá, Paulo

Life sciences

2022 Volume 310, Page(s) 121080

Abstract: Aims: Disorganization of the subcutaneous tissue due to inflammation and fibrosis is a common feature in patients with myofascial pain. Dermal accumulation of adenosine favours collagen production by human subcutaneous fibroblasts (HSCF) via A: ... ...

Abstract	Aims: Disorganization of the subcutaneous tissue due to inflammation and fibrosis is a common feature in patients with myofascial pain. Dermal accumulation of adenosine favours collagen production by human subcutaneous fibroblasts (HSCF) via A Materials and methods: A Key findings: NECA and CGS21680, two enzymatically-stable A Significance: Adenosine A
MeSH term(s)	Humans ; Adenosine/metabolism ; Adenosine Triphosphate/metabolism ; Collagen/metabolism ; Connexin 43/metabolism ; Connexins/metabolism ; Fibroblasts/metabolism ; Fibrosis ; Histamine/metabolism ; Inflammation/metabolism ; Nerve Tissue Proteins/metabolism ; Pain/metabolism ; Receptor, Adenosine A2A/metabolism ; Subcutaneous Tissue/metabolism
Chemical Substances	Adenosine (K72T3FS567) ; Adenosine Triphosphate (8L70Q75FXE) ; Collagen (9007-34-5) ; Connexin 43 ; Connexins ; Histamine (820484N8I3) ; Nerve Tissue Proteins ; PANX1 protein, human ; Receptor, Adenosine A2A ; ADORA2A protein, human
Language	English
Publishing date	2022-10-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2022.121080
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Uc I Zs.368: Show issues

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Article: Non-genomic Actions of Methylprednisolone Differentially Influence GABA and Glutamate Release From Isolated Nerve Terminals of the Rat Hippocampus.

Neiva, Rafael / Caulino-Rocha, Ana / Ferreirinha, Fátima / Lobo, Maria Graça / Correia-de-Sá, Paulo

Frontiers in molecular neuroscience

2020 Volume 13, Page(s) 146

Abstract: Corticosteroids exert a dual role in eukaryotic cells through their action via (1) intracellular receptors (slow genomic responses), or (2) membrane-bound receptors (fast non-genomic responses). Highly vulnerable regions of the brain, like the ... ...

Abstract	Corticosteroids exert a dual role in eukaryotic cells through their action via (1) intracellular receptors (slow genomic responses), or (2) membrane-bound receptors (fast non-genomic responses). Highly vulnerable regions of the brain, like the hippocampus, express high amounts of corticosteroid receptors, yet their actions on ionic currents and neurotransmitters release are still undefined. Here, we investigated the effect of methylprednisolone (MP) on GABA and glutamate (Glu) release from isolated nerve terminals of the rat hippocampus. MP favored both spontaneous and depolarization-evoked [
Language	English
Publishing date	2020-08-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2020.00146
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