The Connections between Inflammaging and Ca2+/cAMP Signalling: A Unified Theory.

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The Interactions among Hypertension, Cancer, and COVID-19: Perspective with Regard to Ca2+/cAMP Signalling.

BACKGROUND: The hypothesis that hypertension is clinically associated with an enhanced risk of developing cancer has been highlighted. However, the working principles involved in this link are still under intensive discussion. A correlation among inflammation, hypertension, and cancer could accurately describe the clinical link between these diseases. In addition, dyshomeostasis of Ca2+ has been considered to be involved in both cancer and hypertension, and inflammation. There is a strong link between Ca2+ signalling, e.g. enhanced Ca2+ signals, and inflammatory outcomes. cAMP also modulates pro- and anti-inflammatory outcomes; pharmaceuticals, which increase intracellular cAMP levels, can decrease the production of proinflammatory mediators and enhance the production of antiinflammatory outcomes. OBJECTIVE: This article highlights the participation of Ca2+/cAMP signalling in the clinical association among inflammation, hypertension, and an enhanced risk for the development of cancer. In addition, considering that research on coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviews recent reports related to the role of Ca2+ channel blockers in restoring Ca2+ signalling disruption due to COVID-19, including the relationship among COVID-19, cancer, and hypertension. CONCLUSION: An understanding of the association among these diseases could expand current pharmacotherapy, involving Ca2+ channel blockers and pharmaceuticals that facilitate a rise in cAMP levels.

Neuroinflammation, Diabetes and COVID-19: Perspectives Coming from Ca2+/cAMP Signalling.

A link between inflammatory diseases, e.g., epilepsy, dementia, diabetes, and COVID-19, has been established. For instance, observational studies involving several individuals reported that people with epilepsy show an enhanced incidence of manifesting dysfunctions related to cognition, e.g., dementia, while people with dementia have a higher incidence of manifesting epilepsy, thus an evident bidirectional relationship between epilepsy and dementia might occur. In addition, epilepsy commonly cooccurs in patients with diabetes, indicating an association between these two disorders. Intriguingly, some reports have also observed a poor prognosis of people with both diabetes and COVID-19. It is recognized that a dyshomeostasis of both Ca2+ and cAMP signalling pathways could be a molecular connection for these disorders. Therefore, clarifying this clinical relationship among epilepsy, dementia, diabetes, and COVID-19 may outcome in novel hypotheses for identifying the etiology of these disorders.

Diabetes and inflammatory diseases: An overview from the perspective of Ca2+/3'-5'-cyclic adenosine monophosphate signaling.

A large amount of evidence has supported a clinical link between diabetes and inflammatory diseases, e.g., cancer, dementia, and hypertension. In addition, it is also suggested that dysregulations related to Ca2+ signaling could link these diseases, in addition to 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways. Thus, revealing this interplay between diabetes and inflammatory diseases may provide novel insights into the pathogenesis of these diseases. Publications involving signaling pathways related to Ca2+ and cAMP, inflammation, diabetes, dementia, cancer, and hypertension (alone or combined) were collected by searching PubMed and EMBASE. Both signaling pathways, Ca2+ and cAMP signaling, control the release of neurotransmitters and hormones, in addition to neurodegeneration, and tumor growth. Furthermore, there is a clear relationship between Ca2+ signaling, e.g., increased Ca2+ signals, and inflammatory responses. cAMP also regulates pro- and anti-inflammatory responses. Due to the experience of our group in this field, this article discusses the role of Ca2+ and cAMP signaling in the correlation between diabetes and inflammatory diseases, including its pharmacological implications. As a novelty, this article also includes: (1) A timeline of the major events in Ca2+/cAMP signaling; and (2) As coronavirus disease 2019 (COVID-19) is an emerging and rapidly evolving situation, this article also discusses recent reports on the role of Ca2+ channel blockers for preventing Ca2+ signaling disruption due to COVID-19, including the correlation between COVID-19 and diabetes.

Common Issues Among Asthma, Epilepsy, and Schizophrenia: From Inflammation to Ca2+/cAMP Signalling.

BACKGROUND: A large amount of evidence has described that asthma may be associated with a high epilepsy risk, and epilepsy may be linked with high asthma risk, especially among children and individuals in their 30s. Curiously, asthma has also been associated with an increased risk for schizophrenia. Most interestingly, a bidirectional link between schizophrenia and epilepsy has also been established and has been of interest for many years. OBJECTIVE: Bearing in mind the experience of our group in the field of Ca2+/cAMP signalling pathways, this article discussed, beyond inflammation, the role of these signalling pathways in this link among epilepsy, asthma, and schizophrenia. METHODS: Publications involving these signalling pathways, asthma, epilepsy, and schizophrenia (alone or combined) were collected by searching PubMed and EMBASE. RESULTS AND CONCLUSION: There is a clear relationship between Ca2+ signalling, e.g. increased Ca2+ signals and inflammatory responses. In addition to Ca2+, cAMP regulates pro- and anti-inflammatory responses. Then, beyond inflammation, the comprehension of the link among epilepsy, asthma, and schizophrenia could improve the drug therapy.

A link among schizophrenia, diabetes, and asthma: Role of Ca2+/cAMP signaling.

Asthma has been associated with an increased risk for developing schizophrenia. In addition, schizophrenia has been associated with an increased risk for developing type 2 diabetes mellitus, resulting in an elevated cardiovascular risk and in a limited life expectancy. It is well discussed that dysregulations related to Ca2+ signaling could link these diseases, in addition to cAMP signaling pathways. Thus, revealing this interplay among schizophrenia, diabetes, and asthma may provide novel insights into the pathogenesis of these diseases. Publications involving Ca2+ and cAMP signaling pathways, schizophrenia, diabetes, and asthma (alone or combined) were collected by searching PubMed and EMBASE. Both Ca2+ and cAMP signaling pathways (Ca2+/cAMP signaling) control the release of neurotransmitters and hormones, in addition to airway smooth muscle contractility, then dysregulations of these cellular processes may be involved in these diseases. Taking into consideration, the experience of our group in this field, this narrative review debated the involvement of Ca2+/cAMP signaling in this link among schizophrenia, diabetes, and asthma, including its pharmacological implications.

The clinical link between depression and obesity: Role of Ca2+/cAMP signalling.

A link between depression and obesity has been established by several reports. Consistent data support a bidirectional link between depression and obesity, e.g. obese people have demonstrated an increased risk of developing depression in their lifetime, whereas depressed people have shown an increased risk of becoming obese. An intensive debate in the field is that a Ca2+ signalling dysregulation may be an upstream issue which could link obesity and depression. In fact, Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) control the release of both neurotransmitters and hormones, in addition to neuronal death and lipogenesis. Then, I herein discussed the putative contribution of Ca2+/cAMP signalling in this link between depression and obesity.

The Interactions Between Alzheimer's Disease and Major Depression: Role of Ca2+ Channel Blockers and Ca2+/cAMP Signalling.

BACKGROUND: The interactions between Alzheimer's Disease (AD) and major depression can be translated into clinical data showing that depressive patients have had an enhanced risk for developing AD (later in life). The cellular mechanisms involved in these interactions remain under intensive debate in the literature. In addition, the role of a Ca2+ homeostasis dysregulation in the pathogenesis of neurodegenerative diseases, like AD, and major depression has been under intensive discussion. OBJECTIVE: Thus, revealing the interplay between AD and major depression may provide novel insights into the pathogenesis of these diseases. METHODS: Publications involving Ca2+ signalling pathways, AD, and major depression (alone or combined) were collected by searching multiple databases to find the maximum number of relevant citations (using a search strategy with high sensitivity for studies of etiology). RESULTS: Ca2+ Channel Blockers (CCBs), classically prescribed for hypertensive patients, have been demonstrating neuroprotective effects, such as decreasing the incidence of AD in hypertensive patients, including alleviating major depression symptoms. A mechanism under debate is focused on the restoration of the Ca2+ homeostasis. Indeed, previous studies of our own have correlated Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) in controlling both the neurotransmitter release and neuronal death. These studies also observed that CCBs can affect Ca2+/cAMP signalling. CONCLUSION: This review discussed the plausible role of Ca2+/cAMP signalling in the neuroprotective effects of CCBs, including the participation of Ca2+/cAMP signalling in the interactions between major depression and AD. Considering both AD and major depression have become highly prevalent medical problems in the world, the comprehension of the interactions between these diseases could improve drug development.

The Interplay Between Depression and Parkinson´s Disease: Learning the Link Through Ca2+/cAMP Signaling.

BACKGROUND: Parkinson´s disease (PD) and depression have an interplay at multiple cellular levels, a phenomenon which is translated into clinical data showing that depressive patients presented an enhanced risk for developing PD. The pathogenesis of both diseases is under intensive debate as correlated to dysregulations related to Ca2+ signaling. OBJECTIVE: Then, revealing this interplay between these diseases may provide novel insights into the pathogenesis of them. METHODS: Publications involving Ca2+ signaling, PD and depression (alone or combined) were collected by searching PubMed and EMBASE. RESULTS: Not surprisingly, calcium (Ca2+) channel blockers (CCBs), classical antihypertensive medicines, have been demonstrated off-label effects, such as alleviating both PD and depression symptoms. DISCUSSION: A mechanism under debate for the antiparkinsonism and antidepressant effects associated to CCBs is focused on the restoration of Ca2+ signaling dysregulations. In addition, previous studies have observed that CCBs can affect Ca2+/cAMP signaling. CONCLUSION: Thus, this article discussed the role of Ca2+/cAMP signaling in the interplay between depression and PD, including the implications for the pharmacotherapy involving CCBs.

Diabetes and cancer: Debating the link through Ca2+/cAMP signalling.

The incidence of both cancer and diabetes is dramatically increasing in worldwide population, costing many millions from governments into expenditures related to medical health systems. Diabetes has been clinically linked to an increased risk for developing several types of cancer. The cellular mechanisms involved in this link are still under intensive debate in literature. In addition, a Ca2+ homeostasis dysregulation has been intensively debated as an issue involved in both cancer and diabetes. Calcium (Ca2+) channel blockers (CCBs), prescribed for treating hypertension, have also been showing anti-cancer effects along with reducing diabetes symptoms. A debated mechanism of action could rest in the fact that CCBs may restore Ca2+ homeostasis dysregulations, involved in both diseases. Our studies about Ca2+/cAMP signalling may add some new light in this field. In this review, I have debated the possible involvement of Ca2+/cAMP signalling in the clinical link between diabetes and a higher risk for the development of several types of cancer, including the plausible involvement in both anti-cancer and anti-diabetic effects of CCBs.

Debating the "bidirectional link" between diabetes and depression through the Ca2+/cAMP signalling: Off-label effects of Ca2+ channel blockers.

Many reports have been demonstrating off-label effects for calcium (Ca2+) channel blockers (CCBs), for example: patients medicated with CCBs have had an improvement of their diabetes status (control of glycemia), along with an improvement of both depression symptoms and cognitive function. Indeed, diabetes and depression are medical problems both with clearly restricted pharmacotherapies, along with a high prevalence around the world, then costing millions and millions for the medical health systems. Furthermore, the incidence of depression is till three times higher in patients with diabetes. In addition, depression may augment the risk of developing type 2 diabetes till 60%. Then, there is a clear "bidirectional link" between depression and diabetes, reflecting substantial interactions in their etiology. But which are the possible cellular mechanisms for this "bidirectional link" between depression and diabetes, and for the off-label effects of CCBs? Considering our previously cited international articles, which demonstrated the role of the Ca2+/cAMP signalling in regulating both the neurotransmitter release and the neuronal death, in this review I have debated the possible involvement of the Ca2+/cAMP signalling in the off-label effects of CCBs, including the role of the Ca2+/cAMP signalling in the "bidirectional link" between diabetes and depression.

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

BACKGROUND: 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 ß-cell apoptosis. CONCLUSION: 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.

Efeitos de um salgante isento de sódio sobre marcadores sanguíneos bioquímicos hepáticos, renais e cardíacos de ratos normo e hipertensos / Effects of a sodium-free salting agent on blood hepatic, renal and cardiac biochemical markers of normal and hypertensive rats

Introdução: A hipertensão arterial é um dos fatores de risco para doenças cardiovasculares, estando diretamente associada ao elevado consumo de sódio. Objetivo: Avaliar os níveis de marcadores de lesão hepática, renal e cardíaca em ratos hipertensos comparados aos seus controles normotensos, tratados com um salgante isento de sódio, água ou NaCl. Métodos: Ratos hipertensos (SHR) e seus controles normotensos (NWR) foram divididos em 3 grupos (n=7): G1 (água); G2 (solução aquosa contendo NaCl 70 mg/kg/dia); G3 (solução aquosa contendo salgante sem sódio 70 mg/kg/dia). Após 30 dias, o sangue dos animais foi processado. Resultados: Não houve diferença entre os níveis séricos de creatina quinase total, creatina quinase-MB, lactato desidrogenase, ácido úrico, aspartato aminotransferase e fosfatase alcalina tanto nos NWR como nos SHR tratados com NaCl ou Salgante. Houve diminuição da creatinina nos NWR e SHR tratados com NaCl e Salgante em relação aos controles (p<0,005). Conclusões: A suplementação diária com o Salgante e NaCl diminuiu os níveis séricos de creatinina nos grupos NWR e SHR. Contudo, não houve modificação nos níveis séricos de marcadores de lesão cardíaca e hepática. (AU)

Introduction: Hypertension is one of the risk factors for cardiovascular diseases, being directly associated with high consumption of sodium. Objective: To assess the levels of hepatic, renal and cardiac injury markers in hypertensive rats compared to their normotensive controls, treated with a salt free saline solution, water or NaCl. Methods: Hypertensive rats (SHR) and their normotensive controls (NWR) were divided into 3 groups (n = 7): G1 (water); G2 (aqueous solution containing NaCl 70 mg / kg / day); G3 (sodium salt-free aqueous solution 70 mg / kg / day). After 30 days, the animals' blood was processed. Results: There was no difference between serum levels of total creatine kinase, creatine kinase-MB, lactate dehydrogenase, uric acid, aspartate aminotransferase and alkaline phosphatase in both NWR and SHR1 treated NaCl or Salgante. There was a decrease in creatinine in NWR and SHR treated with NaCl and Salgante comparing to controls (p <0.005). Conclusions: Daily supplementation with sodium salt-free aqueous solution and NaCl decreases serum creatinine levels in NWR and SHR groups. However, there was no change in serum levels of cardiac and hepatic injury markers. (AU)

Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction.

In 2013, we discovered that the entitled "calcium paradox" phenomenon, which means a paradoxical sympathetic hyperactivity produced by l-type Ca(2+) channel blockers (CCBs), used in antihypertensive therapy, is due to interaction between the intracellular signalling pathways mediated by Ca(2+) and cAMP (Ca(2+)/cAMP interaction). In 2015, we proposed that the pharmacological manipulation of this interaction could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Besides the paradoxical sympathetic hyperactivity produced by CCBs, several clinical studies have been demonstrating pleiotropic effects of CCBs, including neuroprotective effects. CCBs genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, including Alzheimer's, Parkinson´s disease and others. The molecular mechanisms involved in these pleiotropic effects remain under debate. Our recent discovery that the "calcium paradox" phenomenon is due to Ca(2+)/cAMP interaction may provide new insights for the pharmacological treatment of neurological and psychiatric disorders, including enhancement of current therapies mainly by reducing adverse effects, and improving effectiveness of modern medicines. Whether Ca(2+)/cAMP interaction is involved in CCBs pleiotropic effects also deserves special attention. Then, the pharmacological manipulation of the Ca(2+)/cAMP interaction could be a more efficient therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Thus, in this review we summarize the current knowledge of this field, making new directions and future perspectives.

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 Ca(2+)/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 Ca(2+) 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 Ca(2+)/cAMP signaling pathways. Then, the pharmacological manipulation of the Ca(2+)/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.

Novel model for "calcium paradox" in sympathetic transmission of smooth muscles: role of cyclic AMP pathway.

It is well established that reduction of Ca2+ influx through L-type voltage-dependent Ca2+ channel (L-type VDCC), or increase of cytosolic cAMP concentration ([cAMP]c), inhibit contractile activity of smooth muscles in response to transmitters released from sympathetic nerves. Surprisingly, in this work we observed that simultaneous administration of L-type VDCC blocker (verapamil) and [cAMP]c enhancers (rolipram, IBMX and forskolin) potentiated purinergic contractions evoked by electrical field stimulation of rat vas deferens, instead of inhibiting them. These results, including its role in sympathetic transmission, can be considered as a "calcium paradox". On the other hand, this potentiation was prevented by reduction of [cAMP]c by inhibition of adenylyl cyclase (SQ 22536) or depletion of Ca2+ storage of sarco-endoplasmic reticulum by blockade of Ca2+ reuptake (thapsigargin). In addition, cytosolic Ca2+ concentration ([Ca2+]c) evaluated by fluorescence microscopy in rat adrenal medullary slices was significantly reduced by verapamil or rolipram. In contrast, simultaneous incubation of adrenal slices with these compounds significantly increased [Ca2+]c. This effect was prevented by thapsigargin. Thus, a reduction of [Ca2+]c due to blockade of Ca2+ influx through L-type VDCC could stimulate adenylyl cyclase activity increasing [cAMP]c thereby stimulating Ca2+ release from endoplasmic reticulum, resulting in augmented transmitter release in sympathetic nerves and contraction.

The lumbrical muscle: a novel in situ system to evaluate adult skeletal muscle proteolysis and anticatabolic drugs for therapeutic purposes.

The molecular regulation of skeletal muscle proteolysis and the pharmacological screening of anticatabolic drugs have been addressed by measuring tyrosine release from prepubertal rat skeletal muscles, which are thin enough to allow adequate in vitro diffusion of oxygen and substrates. However, the use of muscle at accelerated prepubertal growth has limited the analysis of adult muscle proteolysis or that associated with aging and neurodegenerative diseases. Here we established the adult rat lumbrical muscle (4/hindpaw; 8/rat) as a new in situ experimental model for dynamic measurement of skeletal muscle proteolysis. By incubating lumbrical muscles attached to their individual metatarsal bones in Tyrode solution, we showed that the muscle proteolysis rate of adult and aged rats (3-4 to 24 mo old) is 45-25% of that in prepubertal animals (1 mo old), which makes questionable the usual extrapolation of proteolysis from prepubertal to adult/senile muscles. While acute mechanical injury or 1- to 7-day denervation increased tyrosine release from adult lumbrical muscle by up to 60%, it was reduced by 20-28% after 2-h incubation with ß-adrenoceptor agonists, forskolin or phosphodiesterase inhibitor IBMX. Using inhibitors of 26S-proteasome (MG132), lysosome (methylamine), or calpain (E64/leupeptin) systems, we showed that ubiquitin-proteasome is accountable for 40-50% of total lumbrical proteolysis of adult, middle-aged, and aged rats. In conclusion, the lumbrical model allows the analysis of muscle proteolysis rate from prepubertal to senile rats. By permitting eight simultaneous matched measurements per rat, the new model improves similar protocols performed in paired extensor digitorum longus (EDL) muscles from prepubertal rats, optimizing the pharmacological screening of drugs for anticatabolic purposes.