key: cord-0833813-62slwhla
authors: Bergantin, Leandro Bueno
title: Diabetes and inflammatory diseases: An overview from the perspective of Ca(2+)/3'-5'-cyclic adenosine monophosphate signaling
date: 2021-06-15
journal: World J Diabetes
DOI: 10.4239/wjd.v12.i6.767
sha: 3ab685c7605216dbad9cea7267516adc4b41829e
doc_id: 833813
cord_uid: 62slwhla

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 Ca(2+ )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 Ca(2+) and cAMP, inflammation, diabetes, dementia, cancer, and hypertension (alone or combined) were collected by searching PubMed and EMBASE. Both signaling pathways, Ca(2+) and cAMP signaling, control the release of neurotransmitters and hormones, in addition to neurodegeneration, and tumor growth. Furthermore, there is a clear relationship between Ca(2+) signaling, e.g., increased Ca(2+) 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 Ca(2+) 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 Ca(2+)/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 Ca(2+) channel blockers for preventing Ca(2+) signaling disruption due to COVID-19, including the correlation between COVID-19 and diabetes.

The concept of a complex clinical link between diabetes and inflammatory diseases, e.g., cancer, dementia, and hypertension, has been described in several reports [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] . Observational reports provided the first evidence for the link between inflammation and diabetes [11] . An interesting study correlated inflammation and diabetes by showing, in animal models, that tumor necrosis factor-alpha is correlated with both obesity and insulin resistance [13] . In addition, an epidemiologic link between inflammation and diabetes was made when circulating concentrations of markers, and mediators, of inflammation were demonstrated to be increased in these diseases [14] [15] [16] [17] , e.g., white cells, interleukin (IL)-6, fibrinogen, C-reactive protein, plasminogen activator inhibitor-1, and sialic acid. Besides diabetes, the link between cancer and inflammation was proposed in 1863 by Virchow, which postulated that the etiology of cancer is related to chronic inflammation [18] . It is now clear that persistent cell proliferation at sites that are abundant in inflammatory cells, DNA-damage-promoting agents, growth factors, and activated stroma, actually increases the risk of neoplasia [19] . Inflammation also plays a central role in dementia, e.g., Alzheimer's disease (AD) [20] . For instance, persistent stimulation of immune cells, and macrophages in the brain (microglia), has been shown to aggravate both amyloid and tau pathology, which then may operate as a link in the etiology of the disease [20] . Finally, recent interest has focused on studying the avenues, and inflammatory mediators, through which immune cells operate to lead to hypertension and end-organ injury [21] .

Currently, it is also well-known that dyshomeostasis of Ca 2+ , through an increase in Ca 2+ levels within the cells [Ca 2+ ]c, is correlated with the pathogenesis of diabetes, cancer, hypertension, and dementia[9,10,12,22-26]. In fact, there is a clear relationship between Ca 2+ signaling, e.g., increased Ca 2+ signals, and inflammatory responses [10, 27] . Corroborating this idea, several studies have highlighted that Ca 2+ channel blockers (CCBs), classic antihypertensive medicines, can improve cognitive function, in addition to decreasing the symptoms of both cancer and diabetes[12,28-31]. A pharmacological tenet for these exciting findings is linked with reestablishing [Ca 2+ ]c, in addition to modulating 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways (Ca 2+ /cAMP signaling)[9,10,24,25]. Due to the experience of our group in this field[9,10,12,24,25,32-36], this article discusses the contributions of Ca 2+ and cAMP signaling in the correlation between cancer, hypertension, diabetes, and dementia. Publications involving dementia, diabetes, hypertension, and cancer were obtained by examining PubMed and EMBASE, using a search strategy with a high sensitivity for studies of etiology, as follows: (1) Searches applied the following strings: Risk (in title or abstract) odds ratio (OR) risk [as a Medical Subject Heading (MeSH) term, not exploded] OR cohort studies (as a MeSH term) OR group (as a text word). Outcomes of these searches were linked with sets conceived with diabetes OR dementia OR cancer OR hypertension OR inflammation; and (2) Bibliographies of the articles obtained were also reviewed for possible data sources.

This article included as a novelty: (1) A timeline of the major events in Ca 2+ /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 CCBs for preventing Ca 2+ signaling disruption due to COVID-19, including the correlation Hypertension: Sympathetic hyperactivity, due to dysregulation of Ca 2+ signaling as in dementia and cancer, has been correlated with hypertension. In fact, studies by Miranda-Ferreira et al [48, 49] validated this principle by demonstrating changes in the kinetics of the release of catecholamines from spontaneously hypertensive rats (SHRs), when compared with normotensive rats. Ca 2+ signaling is argued to be an issue involved in these differences. The authors [48, 49] reinforced that Ca 2+ dyshomeostasis might explain the increased release of catecholamines seen in SHRs, when compared with normotensive rats.

Diabetes: Like dementia, cancer, and hypertension, diabetes is also a serious medical condition. Diabetes is presently categorized according to its origin. For example, in type 1 diabetes if there is a deficiency of insulin released by the pancreas, then it can be categorized as a juvenile diabetes; while in type 2 diabetes if there is resistance to insulin, then it can be categorized as adult-onset diabetes [50] . From a cellular point of view, whereas a physiological increase in the cytoplasmic concentration of Ca 2+ is a significant trigger for releasing insulin, an abnormal elevation of [Ca 2+ ]c could stimulate β-cell apoptosis, then decrease insulin levels, contributing to diabetes[9,12, 25]. Besides Ca 2+ , cAMP modulates the release of various hormones, including insulin released from pancreatic β-cells [51, 52] . Although increasing cAMP levels, e.g., via adrenaline, might stimulate the production of hepatic glucose, increasing levels of cAMP in pancreatic β-cells may stimulate insulin release. The start signal for release of insulin is achieved by elevating [Ca 2+ ]c, and this signal is later amplified via cAMP [53] . Additionally, cAMP is also implicated in other cellular phenomena of β-cells, e.g., inhibiting apoptosis[53].

Nowadays, a clinical link between these discussed diseases (hypertension, cancer, diabetes, and dementia) has been described in several reports[1-12,25,26].

Cancer and dementia: A link between dementia and cancer can be established through numerous cellular phenomena that are implicated in the etiology of both diseases, e.g., inflammation, oxidative stress, and angiogenesis[1,3,54]. For instance, inflammatory biomarkers linked with a lower cognitive performance have been shown to be increased, including fibrinogen and IL-6[1-3]. In fact, several proteins may be involved in the etiology of this link, e.g., Aβ peptide[1-3]. It is suggested that Aβ peptide overexpression is correlated with cancer as the overexpression of APP has been found in several tumors, and was then linked with cell proliferation, migration, and invasion [1]. In addition, a recognized tumor suppressor protein, the BRCA1 protein, has been linked to AD[2]. Thus, Aβ pathology can partially result from overactivation of BRCA1, and then promote neurodegeneration[2]. Converging with this concept, plasma levels of Aβ peptide have been found to be increased in patients with different cancer types [3] .

In addition, a deficiency in DNA repair mechanisms and/or oxidative stress could lead to DNA damage, an issue which is also important for the etiology of both cancer and dementia [55] . A reduced capacity to repair damaged DNA due to genetic polymorphisms can be correlated to an augmented risk of both cancer and cognitive impairment. Genetic defects in DNA damage repair mechanisms could lead to syndromes such as xeroderma pigmentosum and ataxia telangiectasia, characterized by an augmented risk of cancer and cognitive problems [55] . Thus, understanding the clinical link between cancer and dementia could result in novel therapeutics for both diseases. Therefore, it is essential to determine the etiology of this link, e.g., by analyzing the preclinical phases of both diseases.

A correlation between hypertension and a higher incidence of cancer has been established by epidemiological and clinical reports[4-8]. However, this correlation is not completely elucidated, and has been highly discussed. For example, the Metabolic Syndrome and Cancer Project assessed this issue, and included cohort studies from Norway, Austria, and Sweden[4]. The goal of the Metabolic Syndrome and Cancer Project was to study the association between metabolic issues and the increased incidence of cancer [4, 5] . Patients from cohorts related to the Metabolic Syndrome and Cancer Project were enrolled in health inspections between the 1970's and 2000's[4]. The study observed a strong correlation between hypertension and an enhanced incidence of prostate, oropharynx, rectum, pancreas, bladder, lung, and kidney cancer[4]. Additionally, strong correlations between hypertension and an enhanced incidence of pancreas, breast, corpus uteri cancer and malignant melanoma were observed in women. A positive correlation was also observed for esophagus cancer in men and women[4,5]. Indeed, cancer incidence is augmented linearly by increasing blood pressure levels[4-6]. The augmentation of cancer incidence among men was 1% to 2% points higher in hypertensive patients, compared with normotensive men[4-6].

Finally, in observational reports on renal cell carcinoma, hypertension has been documented as a cancer risk factor[4-8]. A meta-analysis of 18 studies observed a 1.6fold increase in the incidence of renal cell carcinoma in hypertensive patients [7] . Nonetheless, this positive association between hypertension and increased cancer incidence could occur in other disorders, such as obesity [7, 8] . Moreover, CCBs, antihypertensive drugs which decrease the influx of Ca 2+ into the cells, have shown anti-cancer activity[31].

Diabetes is correlated with a higher risk of developing hypertension [56] . Several findings reinforce a clear interaction between diabetes and hypertension [57] . Scientific data suggest that obesity, inflammation, oxidative stress, and insulin resistance could be associated with these diseases [56, 57] . Advances in the knowledge of how to prevent these diseases may provide new insights, and perspectives, for the treatment of both diseases.

In fact, hypertension and diabetes are highlighted as the leading risk factors for atherosclerosis, including heart attacks and strokes [58] . For instance, in the Hong Kong Cardiovascular Risk Factor Prevalence report, just 42% of patients with diabetes had regular blood pressure, and just 56% of patients with hypertension had regular glucose homeostasis [58] . In the United States, patients with type 2 diabetes have a prevalence of hypertension ranging from approximately 50% to 80% [59] . In fact, a prospective cohort report from the United States concluded that hypertensive patients had an increased risk of almost 2.5-fold for developing type 2 diabetes[60]. It is clear that diabetes and hypertension are present in the same individual more often than would occur by causality, suggesting both common genetic and environmental factors in their etiology.

The concept of an association between diabetes and memory dysfunctions has been frequently explored [50, [61] [62] [63] . Type 2 diabetes has been linked with a decrease in both processing and speed of psychomotor functioning, in addition to a memory deficit associated with speech and fluency [61] [62] [63] . Additionally, patients with diabetes have a lengthier walking pace [61] [62] [63] . In fact, mild cognitive impairment was observed in approximately 42% of diabetic patients [64] . The association between diabetes and cognitive imbalance was examined in a report [65] , and the authors concluded that patients with type 2 diabetes had a lower score in the Mini-Mental State Examination [65] . An interesting study [66] assessed if lesions in the brain, associated with both vascular and degenerative disorders, could be the cause of the association between diabetes and cognitive deficit [66] . The authors concluded that memory performance in diabetic patients was significantly reduced [66] .

In addition, these findings were confirmed by reports involving neuroimaging [67] . Brain atrophy was concluded to be highly correlated with type 2 diabetes [67] , which usually progresses up to 3 times faster [68, 69] . Patients suffering from type 2 diabetes have also demonstrated an enhanced incidence of dementia, e.g., AD [70, 71] . In fact, approximately 17.5% of people with type 2 diabetes have shown a modest to a serious deficiency in day-to-day activities [72, 73] , while 11.3% have shown a loss of cognition, and 14.2% have shown symptoms of depression [74] , consequently adversely influencing cognition [75] .

A decrease in brain glucose metabolism manifested before the beginning of a quantifiable cognitive decline in cohorts of patients at risk of AD [76] [77] [78] [79] . Reports from in vitro and animal experiments propose that a decrease in brain glucose metabolism comes first and, therefore, may stimulate the neuropathologic cascade, finally resulting in cognitive decline in AD [76, 77] . Additionally, aging is associated with an augmented risk of worsening glucose homeostasis, which, in turn, may increase the risk of decreasing brain glucose uptake [76, 79] . Thus, pharmacotherapy to decrease the risk of AD could provide the following: (1) Improve insulin sensitivity, and then restore glucose homeostasis; or (2) Reduce the decline in brain glucose metabolism by applying strategies that carefully stimulate a maintainable ketonemia [76, 79] .

A relationship between diabetes and an increased risk of several types of cancer has also been described[9,18,19]. It is now clear that persistent cell proliferation in conditions with abundant inflammatory cells, growth factors, stimulated stroma, and DNA-damage-promoting molecules, increases neoplastic risk [19] . In addition, an inflammatory process is also involved in the etiology of diabetes [17], thus it could be an issue which could link both diseases.

In fact, in laboratory reports, metformin, the most frequently used drug in patients with type 2 diabetes, has been demonstrated to prevent cell proliferation and decrease colony development, causing partial cell cycle arrest in cancer cell phenotypes[9,19]; thus, it is important not to neglect the disruption of glucose homeostasis as a relevant mediator of this link between diabetes and cancer.

Indeed, the brain of patients with hypertension, when compared with normotensive patients, had higher concentrations of β-amyloid plaques, atrophy, and neurofibrillary tangles[12,20]. Thus, hypertension has been recognized as a risk factor for the deposition of cortical fibrillar β-amyloid[12].

Diabetes and COVID-19: COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emerging and rapidly evolving situation [80, 81] . It is accepted that angiotensin-converting enzyme 2, which is a component of the reninangiotensin-aldosterone system, is the key entry receptor for SARS-CoV-2 [80, 81] .

Intriguingly, some reports have observed increased severity of COVID-19 in patients with diabetes. To assess this issue, a meta-analysis [80] was performed by conducting a literature review of Scopus, PubMed, Science Direct, and Web of Science. Observational studies, case-reports, and case-series reports that analyzed diabetes in COVID-19 patients were included in the meta-analysis [80] . It was concluded that diabetes is a risk factor, and plays a role in disease severity and the mortality of individuals with COVID-19. This study also provided suggestions, and guidelines, June 15, 2021

Volume 12 Issue 6 which could be helpful for the prevention and treatment of diabetic patients suffering from COVID-19 [80] . As already discussed in the present article, hyperglycemia may modulate both immune and inflammatory processes, thus prejudicing patients and resulting in severe COVID-19, and possible fatal consequences. In addition, a retrospective clinical report involving hospitalized patients with COVID-19 and hypertension, concluded that therapy with the CCB amlodipine besylate was correlated with decreased mortality [82] . In fact, CCBs were described to possess antiviral activity against several evolving viruses, including bunyaviruses, arenaviruses, and flaviviruses [82] . Furthermore, CCBs were described to possess antiinflammatory ability to control patients' intracellular Ca 2+ levels, including decreasing the death rate in septic animal models with severe inflammatory outcomes [83, 84] . Severe inflammatory outcomes are described to be linked to a critical COVID-19 result [85] . Thus, it is plausible that CCBs may operate in a synergistic way by combining their antiviral efficacy with alleviation of inflammatory responses [85] .

Complementing the present discussion, and in addition to Ca 2+ signaling, the participation of cAMP signaling (Ca 2+ /cAMP signaling) in the correlation between cancer, hypertension, diabetes, and dementia is considered.

Our reports on Ca 2+ /cAMP signaling have recognized the participation of these cellular processes in regulating the release of both neurotransmitters and hormones, as well as the death of neurons and tumor growth[9,10,12,24,25,32-36, 86, 87] . Our studies proved that by decreasing the influx of Ca 2+ via voltage activated Ca 2+ channels (VACCs), adenylyl cyclases (ACs) are stimulated (thus increasing the levels of cAMP, and the Ca 2+ /cAMP signaling interaction, Figure 1) . Considering this working model, CCBs-responses can be significantly increased through their pharmaceutical association with cAMP-enhancer agents [such as phosphodiesterase inhibitors]. The working model through which the release of both transmitter and hormone can be significantly augmented by regulating Ca 2+ /cAMP signaling is related to (1) elevating the concentrations of transmitters and hormones in the secretory apparatus; and (2) enhancing the release of transmitters and hormones [10, 12] . Actually, Ca 2+ signaling is essential for supporting the release process: Via rising cAMP levels, this can augment the release of Ca 2+ from endoplasmic reticulum (ER), thus increasing the release of transmitters and hormones. The timeline of the major events in Ca 2+ /cAMP signaling can be found below (Table 1) .

Additionally, a higher [Ca 2+ ]c from critical dysregulations of Ca 2+ signaling, such as an enhanced Ca 2+ influx, has been linked to dementia, diabetes, hypertension, and cancer[9,10,12,24,25]. For instance, it was observed that L-type Ca 2+ channels are significantly up-regulated in different types of cancer cells, contributing to abnormal cell proliferation[9,40-44]. The pharmaceutical modulation of these channels could then improve the therapeutics for antitumor purposes.

As well as cancer, dysregulations related to aging have also been detected in Ca 2+ signaling pathways, stimulating the death of neurons, e.g., an increase in intracellular Ca 2+ levels, an augmented Ca 2+ influx via the VACC and abnormalities in Ca 2+ regulation in ryanodine and IP 3 -sensitive Ca 2+ stores[10,12,24].

Opposing Ca 2+ signaling, stimulation of cAMP/protein kinase/cAMP-response element binding protein pathways can reduce both neuronal death and abnormal cell proliferation, thus resulting in anti-cancer and anti-dementia effects [88] [89] [90] [91] . Thus, both the death of neurons and abnormal cell proliferation may also be a consequence of reduced activity of signaling pathways controlled by cAMP, as well as an increase in [ Ca 2+ ]c, resulting from disruption of Ca 2+ /cAMP signaling interactions. Indeed, there is a clear relationship between Ca 2+ signaling, e.g., increased Ca 2+ signals, and inflammatory responses [92] . cAMP also modulates inflammatory responses: medicines which increase intracellular levels of cAMP can diminish the generation of pro-inflammatory factors, and enhance the generation of anti-inflammatory molecules [93] . Furthermore, whereas a physiological increase in the cytoplasmic concentration of Ca 2+ is a significant trigger to release insulin, an abnormal elevation in [Ca 2+ ]c could stimulate β-cell apoptosis, then decrease insulin levels, contributing to diabetes [9, 12, 25] . Together with Ca 2+ , cAMP modulates the release of various hormones, as well as insulin from the pancreatic β-cells[51,52]. Although increasing cAMP levels, e.g., via adrenaline, might stimulate the biosynthesis of hepatic glucose, increasing cAMP levels within pancreatic β-cells can stimulate insulin release. A start signal for the release of insulin is achieved through an increase in Ca 2+ concentration, and after this signal is amplified via cAMP[53]. Besides the cellular effect of increasing the biosynthesis of insulin, cAMP is implicated in other cellular processes of β-cell, e.g., stimulating both proliferation and differentiation of the cell, and by rescuing the cells from death[53]. These effects are summarized in Figure 2 . Table 2 .

Undeniably, an increase in the release of neurotransmitters, and a reduction in the death of neurons in the CNS (e.g., limbic brain sites), could cause as a consequence a decrease in symptoms related to dementia, a working model that can be controlled by Ca 2+ and cAMP signaling pathways[10,12,25,33]. Analogous to dementia[10,12,33], Figure 1 Pharmaceutical modulation of Ca 2+ /3'-5'-cyclic adenosine monophosphate signaling. Decreasing Ca 2+ influx through L-type Ca 2+ channels, e.g., endorsed by Ca 2+ channel blockers (CCBs), enhances adenylyl cyclase activity (and consequently increases 3'-5'-cyclic adenosine monophosphate (cAMP) levels; identified as a Ca 2+ /cAMP signaling interaction), and these effects of CCBs could be increased by cAMP-enhancer compounds (such as phosphodiesterase inhibitors). CCBs: Ca 2+ channel blockers; cAMP: 3'-5'-cyclic adenosine monophosphate; AC: Adenylyl cyclase; PDEs: Phosphodiesterases. discoveries have shown that CCBs can also mitigate the symptoms of both cancer and diabetes[9,12,94-96]. Reestablishing the dyshomeostasis associated with Ca 2+ signaling is a working model for these CCBs-mentioned responses, reached due to intervening in the Ca 2+ /cAMP signaling interactions. In fact, CCBs stimulate the activity of ACs, following an increase in [cAMP] c , promoting Ca 2+ release from the ER, ultimately inducing the release of both neurotransmitters and hormones, and decreasing the death of neurons and attenuating tumor growth. Considering that the link between diseases (cancer, diabetes, hypertension, and dementia) could be a consequence of persistent dysregulations of [Ca 2+ ] c , the persistent increase in [Ca 2+ ] c might also disturb Ca 2+ /cAMP signaling interactions.

Both Ca 2+ and cAMP signaling pathways regulate the release of neurotransmitters and hormones, including those involved in neurodegeneration and tumor growth.

Furthermore, there is a clear relationship between Ca 2+ signaling, e.g., increased Ca 2+ signals and inflammatory responses. cAMP also regulates pro-and anti-inflammatory responses. It is concluded that both signaling pathways play an important role in the link between diabetes and inflammatory diseases, thus impacting therapeutics including CCBs and medicines which increase the levels of cAMP. Finally, as COVID-19 is an emerging and rapidly evolving situation, it is also concluded that Ca 2+ channel blockers could be useful for preventing Ca 2+ signaling disruption due to COVID-19.

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Dr. Leandro Bergantin would like to thank the reviewers and editors for their suggestions to improve this manuscript.