cAMP Signaling Interaction Research Articles

Network Pharmacology-based Research of Active Components of Albiziae Flos and Mechanisms of Its Antidepressant Effect.

Albiziae Flos (AF) has been experimentally proven to have an antidepressant effect. However, due to the complexity of botanical ingredients, the exact pharmacological mechanism of action of AF in depression has not been completely deciphered. This study used the network pharmacology method to construct a component-target-pathway network to explore the active components and potential mechanisms of action of AF. The methods included collection and screening of chemical components, prediction of depression-associated targets of the active components, gene enrichment, and network construction and analysis. Quercetin and 4 other active components were found to exert antidepressant effects mainly via monoaminergic neurotransmitters and cAMP signaling and neuroactive ligand-receptor interaction pathways. DRD2, HTR1A, and SLC6A4 were identified as important targets of the studied bioactive components of AF. This network pharmacology analysis provides guidance for further study of the antidepressant mechanism of AF.

Hypertension, Diabetes and Neurodegenerative Diseases: Is there a Clinical Link through the Ca2+/cAMP Signalling Interaction?

Hypertension, diabetes and neurodegenerative diseases are among the most prevalent medical problems around the world, costing millions of dollars to the medical health systems. Indeed, hypertension has been associated with higher risk for decline of cognition, as evidenced in patients with Alzheimer´s disease (AD). Furthermore, there is a clear relationship between hypertension and diabetes, reflecting substantial overlap in their etiology. Calcium (Ca2+) channel blockers (CCBs) have been classically prescribed for treating hypertension because of their mechanism of action due to reducing the influx of Ca2+ into the smooth muscles cells. In addition, many clinical and experimental studies have been demonstrating pleiotropic effects for CCBs. For instance, in hypertensive patients treated with CCBs, it can be observed lower incidence of neurodegenerative diseases such as AD. The virtual mechanism of action could be attributed to a restoration and maintenance of Ca2+ homeostasis, which is dysregulated in the neurodegenerative diseases, including also a reduction of neuronal apoptosis as part of these CCBs pleiotropic effects. Similarly, in hypertensive patients treated with CCBs, it can be observed an improvement of diabetes status such as glycemic control. A possible mechanism of action under debate could be attributed to a restoration of insulin secretion, then achieving glycemic control, and reduction of pancreatic β-cell apoptosis. Considering the discovery of our group entitled "calcium paradox" due to Ca2+/cAMP signalling interaction, in this review I discussed the virtual involvement of this interaction in the pleiotropic effects of CCBs, including the possible role of the Ca2+/cAMP signalling interaction in the association between hypertension and higher risk for the decline of cognition, and diabetes.

Ca2+ and Camp: Do these Intracellular Messengers Work’Independently? Of Course Not, and the History Goes Ahead…

Our group has been pioneering in exploring that the pharmacological handling of Ca2+/cAMP signalling interaction could be a better therapeutic method for increasing neurotransmission in psychiatric disorders, and stimulating neuroprotection for combating neurodegenerative diseases, such as Alzheimer´s disease. Indeed, Ca2+ is a classic intracellular second messenger, now well recognized as a ubiquitous molecule that controls several processes, including gene transcription, cell cycle regulation, mobility, apoptosis, neurotransmitter release and muscle contraction. In addition, cAMP, another vital intracellular messenger, modulates since cardiac contraction to neurotransmitter release. Do these intracellular messengers ´work´ independently? Of course not, and we demonstrated it! Through groundbreaking experiments (including one by accident!), our group discovered that the paradoxical effects (e.g. reduction of intracellular Ca2+ concentration, and enhancing of neurotransmitter release?!) produced by L-type Ca2+ channel blockers (CCBs) resulted from interferences on the Ca2+/ cAMP signalling interaction. Considering the widely use of CCBs as antihypertensive drugs, and for combating arrhythmia, the elucidation of these paradoxical effects proved to be very important (specially for clinical reasons). How does this history correlate to cancer field? Considering the notion that Ca2+/cAMP signalling interaction is a fundamental cellular process, which exists in many cell types, whether this interaction may be a novel therapeutic target to alter cancer tumor growth, angiogenesis and metastasis, without affecting normal cell physiology deserves special consideration. Thus, this editorial article highlights the latest advances made by our group in the field of Ca2+/cAMP signalling interaction.

From a “eureka insight” to a novel potential therapeutic target to treat Parkinson´s disease: The Ca2+/camp signalling interaction

From a “eureka insight” to a novel potential therapeutic target to treat Parkinson´s disease: The Ca2+/camp signalling interaction

Revisiting the Clinical Link Between Alzheimer's Disease and Depression Through the Ca2+/Camp Signalling Interaction

Revisiting the Clinical Link Between Alzheimer's Disease and Depression Through the Ca2+/Camp Signalling Interaction

New Therapeutic Perspectives for the Cognitive Deficit in Alzheimer's Disease: Pharmacological Modulation of Ca2+/cAMP Signaling Interaction

Due to the involvement of the imbalance of Ca²⁺ homeostasis in neuronal cells in the pathogenesis of several neurodegenerative disorders such as Alzheimer's Disease (AD), the use of drugs to prevent or attenuate this imbalance emerged as a new therapeutic perspective for this disease.

Pharmaceutical intervention on Ca2+/cAMP signaling interaction: benefits for combating neurodegeneration and diseases related to aging

The pharmaceutical intervention on the interaction between intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) could bring important benefits for combating neurodegeneration and diseases related to aging. This discovery emerged from classical neurotransmission studies using rodent vas deferens as a model. From classical reports using this model, the concept of Ca2+-dependent processes involved in the neurotransmission (Ca2+ influx triggers muscle contraction and neurotransmitter release) is amply accepted. Thus, Ca2+ channel blockers (CCB) due to reduction of Ca2+ influx through L-type voltage-activated Ca2+ channels (VACC) should reduce neurotransmission. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca2+ influx by low concentrations of CCB (verapamil, diltiazem or nifedipine) produced a paradoxical increase of the contractions mediated by sympathetic nerves, a phenomenon known as “calcium paradox”. Recent studies using adrenal chromaffin cells have also demonstrated that CCB caused a paradoxical increase of the catecholamine release. Because these compounds are blocking the L-type VACC, an augmented nerve-mediated response due to increased neurotransmitter release was an unexpected outcome. In 2013, we revealed that the Ca2+/cAMP signaling interaction could properly explain the so-called “calcium paradox”. The original paper published by us in Cell Calcium (2013) has appeared four times in ScienceDirect TOP 25 Hottest Articles lists. In conclusion, these findings may significantly impact on neurodegenerative diseases, thus may stimulate the development of new pharmacological strategies to combat the diseases related to aging.

Examining Contrasting Views from Behaviorism and Psycho- Biological PerspectivesPerspectives of The Pharmacological Modulation of Ca2+/ Camp Signaling Interaction as a New Neuroprotector Therapeutic Strategy for Amyotrophic Lateral Sclerosis (ALS)

Examining Contrasting Views from Behaviorism and Psycho- Biological PerspectivesPerspectives of The Pharmacological Modulation of Ca2+/ Camp Signaling Interaction as a New Neuroprotector Therapeutic Strategy for Amyotrophic Lateral Sclerosis (ALS)

From a "Eureka Insight" to a Novel Potential Therapeutic Target to Treat Alzheimer's Disease

It has been almost 4 years since we revealed the solution for the enigma of the so-called 'calcium paradox'. Our discovery of the involvement of Ca2+/cAMP signaling interaction in the regulation of neurotransmitter release, and neuro protection, was clearly a serendipitous discovery. It has produced new avenues in the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease. Interestingly, this discovery initiated decades ago when numerous clinical studies have reported that use of L-type Ca2+ channel blockers (CCBs) by hypertensive patients decreased arterial pressure, but produced typical symptoms of sympathetic hyperactivity, such as tachycardia and increment of catecholamine plasma levels.

Advances for the Pharmacotherapy of Parkinson's Disease: Pharmacological Handling of the Ca2+/cAMP Signalling Interaction

The sympathetic hyperactivity due to increment of catecholamine plasma levels, and tachycardia, is the main adverse effect reported since 70's by hypertensive patients that use L-type Ca2+ channel blockers (CCBs). Our discovery of the involvement of interaction between the intracellular signalling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP interaction) revealed that the sympathetic hyperactivity was resulting of increase of transmitter release from sympathetic neurons stimulated by CCBs due to its interference on the Ca2+/cAMP interaction. In the pharmacotherapy of Parkinson's disease, this discovery may produce new paths for the understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease. In this way, novel journeys for the development of new pharmacological strategies more effective for the treatment of Parkinson's may be initiated.

Novel Concepts for Neurology and Medicine from the Interaction between Signalling Pathways Mediated by Ca2+ and cAMP: An Intriguing History

It is now well-established that the signalling pathways mediated by Ca2+ and cAMP can interact (Ca2+/cAMP signalling interaction), thus playing a vital role in cellular processes of mammalians. In the neurology and medicine, it has opened novel opportunities for the development of pharmaceuticals more efficient, and safer, for treating neurodegenerative diseases. The solution for the so-called “calcium paradox” has been revealed 4 years ago, when we demonstrated the involvement of the Ca2+/cAMP signalling interaction in this enigma. The “calcium paradox” emerged 4 decades ago, when numerous clinical studies have concluded that prescription of L-type Ca2+ channel blockers (CCBs) for hypertensive patients decreased arterial pressure, but produced stimulation of sympathetic hyperactivity. Indeed, initially these adverse effects of CCBs have been attributed to adjust reflex of arterial pressure, but this conclusion remained not completely satisfactory. The year of 2013 would change this history forever! Through an original experiment, we revealed that the "calcium paradox" phenomenon came from increased transmitter release from sympathetic neurons stimulated by CCBs due to its handling on the Ca2+/cAMP signalling interaction. Then, the manipulation of Ca2+/cAMP signalling interaction could improve therapeutic strategies for stimulating synaptic transmission compromised by transmitter release deficit, and attenuating death of neurons.

Clinical Research: Good News Coming from Ca2+/cAMP Signaling Interaction

Clinical research plays an important role in medical sciences by determining the safety and efficiency of medications, devices and diagnostic products for human use. Our discovery of the interactions between intracellular signaling pathways as mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) in neurotransmission could help improve clinical research. This discovery emerged from classical neurotransmission studies using rodent vas deferens as a model. In addition, the concept of Ca2+-dependent muscle contraction (Ca2+ influx triggers muscle contraction) is amply accepted. Thus, Ca2+ channel blockers (CCB) should reduce muscle contraction. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca2+ influx by low concentrations of CCB (verapamil, diltiazem or nifedipine) produced a paradoxical increase of the contractions mediated sympathetic nerves, a phenomenon known as “calcium paradox”. Recent studies using adrenal chromaffin cells have also demonstrated that CCB caused a paradoxical increase of the catecholamine release. Because these compounds are blocking the L-type voltage-activated Ca2+ channels (VACC), an augmented nerve-mediated response due to increased neurotransmitter release was an unexpected outcome. In 2013, we revealed that the Ca2+/cAMP signaling interaction could properly explain the so-called “calcium paradox”. The original paper published by us in Cell Calcium (2013) has appeared four times in ScienceDirect TOP 25 Hottest Articles lists. In conclusion, these findings may significantly impact on cardiovascular and neurodegenerative diseases, cancer, stem cell-based therapies and many other diseases, and may stimulate the development of new pharmacological strategies to combat these diseases.

Sudden Unexpected Death in Parkinson’s Disease and the Pharmacological Modulation of the Ca2+/cAMP Signaling Interaction: A Shot of Good News

This discusses how pharmacological modulation of the Ca2+/cAMP signaling interaction could be an important neuroprotective and cardioprotective strategy to protect the dopaminergic neurons from cell death related to Parkinson’s disease (PD) and at the same time to prevent the cardiac collapse in sudden unexpected death in PD.

Emerging A New Strategy for the Antitumor Immunotherapy: Pharmacological Modulation of the Ca2+/Camp Signaling Interaction

Cancer is a major public health problem and the second leading cause of mortality around the world. Antitumor immunotherapy using monoclonal antibodies is considered selective and efficient in the treatment of different types of tumors, but its cost and toxic effects limit its application. Many tumor microenvironments, including lymphoma and carcinoma, are enriched in immune suppressive cells that contribute to immune exhaustion by means expression of inhibitory ligands, suppressive cytokines, and tumor-promoting factors. Antitumor therapies targeted to reduce the induction, recruitment, or suppressive activities of the immune cells have been investigated. New antitumor strategies using drugs targeted to intracellular signaling involved in cell proliferation and survival, angiogenesis, and metastasis have become promising in recent years. Thus, our discovery of the role of functional interaction between intracellular signaling pathways mediated by calcium ions (Ca2+) and cyclic adenosine monophosphate (cAMP) (Ca2+/cAMP signaling interaction) in these cellular responses, opened a great avenue for the development of new antitumor therapeutic strategies. Here, we discuss how the combined use of monoclonal antibodies with drugs that modulate the Ca2+/cAMP signaling interaction to reduce tumor growth could be a potential strategy in the antitumor immunotherapy due to the increment of antitumor efficacy and reduction of adverse effects.

Advances for the pharmacotherapy of depression - Presenting the rising star: Ca2+/camp signaling interaction

Advances for the pharmacotherapy of depression - Presenting the rising star: Ca2+/camp signaling interaction

Insights for the Inhibition of Cancer Progression: Revisiting Ca2+ and Camp Signalling Pathways

This editorial article gives insights for the inhibition of cancer progression. The pharmacological modulation of Ca2+/cAMP signalling interaction is also cited.

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Emerging Concepts for Neuroscience Field from Ca2+/ cAMP Signalling Interaction

Emerging Concepts for Neuroscience Field from Ca2+/ cAMP Signalling Interaction

Pharmacological implications of the Ca(2+)/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders.

In this review, we discussed pharmacological implications of the Ca2+/cAMP signaling interaction in the antihypertensive and neurological/psychiatric disorders therapies. Since 1975, several clinical studies have reported that acute and chronic administration of L-type voltage-activated Ca2+ channels (VACCs) blockers, such as nifedipine, produces reduction in peripheral vascular resistance and arterial pressure associated with an increase in plasma noradrenaline levels and heart rate, typical of sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this apparent sympathomimetic effect of the L-type VACCs blockers remained unclear for decades. In addition, experimental studies using isolated tissues richly innervated by sympathetic nerves (to exclude the influence of adjusting reflex) showed that neurogenic responses were completely inhibited by L-type VACCs blockers in concentrations above 1 μmol/L, but paradoxically potentiated in concentrations below 1 μmol/L. During almost four decades, these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical increase in sympathetic activity produced by L-type VACCs blocker is due to interaction of the Ca2+/cAMP signaling pathways. Then, the pharmacological manipulation of the Ca2+/cAMP interaction produced by combination of the L-type VACCs blockers used in the antihypertensive therapy, and cAMP accumulating compounds used in the antidepressive therapy, could represent a potential cardiovascular risk for hypertensive patients due to increase in sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases.

Effects of granulocyte-macrophage colony-stimulating factor and cyclic AMP interaction on human neutrophil apoptosis.

The current study was undertaken to evaluate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclic AMP (cAMP) signaling interaction on human neutrophil apoptosis, either occurring spontaneously or induced by Fas antigen activation. Results show that GM-CSF, dibutyryl cAMP (a cAMP analog) and forskolin (an adenylate cyclase activator) are all able to suppress spontaneous neutrophil cell death. Of note however, when GM-CSF is used in combination with cAMP-elevating agents, an additive effect on neutrophil survival is observed with dibutyryl cAMP only, whereas supplementation of cell cultures with GM-CSF and forskolin results in a progressive reduction of antiapoptotic effects exerted by the single compounds. Moreover, although dibutyryl cAMP and forskolin do not affect Fas-triggered apoptotic events, they are still able to modulate the GM-CSF capacity to prolong neutrophil survival following anti-Fas IgM cell challenge, with effects similar to those respectively exerted on spontaneous neutrophil apoptosis. The data indicate that GM-CSF may negatively modulate the cAMP-mediated antiapoptotic pathway in human neutrophils, likely via the inhibition of adenylate cyclase activity. This would prevent an abnormal neutrophil survival as a result of cAMP signaling stimulation, which provides a novel insight into the role of GM-CSF as a physiological regulator of myeloid cell turnover.