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Although the two drugs currently available for the treatment of Chagas disease, Benznidazole and Nifurtimox, have proven to be effective in the acute phase of the disease, the 60-90-day treatment leads to high toxicity and unwanted side effects, presenting, in addition, a low efficacy in the chronic phase of the disease. For this reason, new therapies that are more effective are needed. In this regard, we have recently shown that the inhibition of the Epac-Rap1b pathway suppressed the cAMP-mediated host cell invasion by Trypanosoma cruzi. Interestingly, it has been described that vitexin, a natural flavone that protects against ischemia-reperfusion damage, acts by inhibiting the expression of Epac and Rap1 proteins. Vitexin can be found in plants of the genus Crataegus spp., traditionally known as hawthorn, which are of great interest considering their highly documented use as cardio-protectors. Pre-treating cells with an extract of Crataegus oxyacantha produced levels of T. cruzi invasion comparable to the ones observed for the commercially available Epac1-specific inhibitor, ESI-09. In addition, extract-treated cells exhibited a decrease in the activation of Rap1b, suggesting that the effects of the extract would be mediated by the inhibition of the cAMP-Epac-Rap1 signaling pathway. Using HPLC-HRMS2, we could confirm the presence of vitexin, and other flavones that could act as inhibitors of Epac/Rap1b, in the extracts of C. oxyacantha. Most significantly, when cells were treated with the extract of C. oxyacantha in conjunction with Nifurtimox, an increased modulation of invasion was observed.
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BACKGROUND: The hypothesis that a dyshomeostasis of Ca2+ increases the incidence of dementia has been established. Several discoveries have emphasized the concept that a decrease in the excess of Ca2+ could be an interesting pharmacological target to alleviate dementia symptoms. Aging along with a healthy brain can be supported by daily exercise, self-control in caloric ingestion, and participation in intellectually challenging events. These lifestyle factors may alleviate the excess of Ca2+ resulting from a Ca2+ dyshomeostasis. Curiously, epidemiological and clinical studies have also reported a clinical relationship between hypertension, diabetes, and other inflammatory processes, and a higher risk of cognition decline. Considering the cumulative data from the scientific literature, including data of high evidence such as meta-analysis and systematic reviews, we can now link a Ca2+ dyshomeostasis as an upstream factor for hypertension, diabetes and other inflammatory processes, and dementia. Several reports have also indicated that increasing cAMP levels may induce neuroprotective outcomes, thus alleviating dementia symptoms. METHODS: With these concepts in mind, we found that the pharmacological manipulation of Ca2+/cAMP signalling could be a novel plausible target to treat dementia. This article puts together fundamental concepts and current therapies to treat dementia, including novel therapeutics coming from the pharmacological manipulation of Ca2+/cAMP signalling. RESULTS: Then, combined with improvements in the lifestyle issues, these novel therapeutics may allow sustained improvements in the life quality of age-related neurological patients. CONCLUSIONS: In addition, considering coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviewed recent reports about Ca2+ channel blockers' role in restoring Ca2+ signalling disruption due to COVID-19. Finally, this article also presents a timeline of the major events in Ca2+/cAMP signaling.
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Tratamento Farmacológico da COVID-19 , Demência , Diabetes Mellitus , Hipertensão , AMP Cíclico/uso terapêutico , Demência/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , HumanosRESUMO
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.
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COVID-19 , Hipertensão , Neoplasias , COVID-19/complicações , Cálcio/metabolismo , Sinalização do Cálcio , AMP Cíclico/metabolismo , AMP Cíclico/uso terapêutico , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Inflamação , Preparações FarmacêuticasRESUMO
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.
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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.
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Doença de Alzheimer/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , AMP Cíclico/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Fármacos Neuroprotetores/farmacologia , Fatores de RiscoRESUMO
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.
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Antidepressivos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Sinalização do Cálcio/efeitos dos fármacos , Depressão/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Encéfalo/metabolismo , Encéfalo/patologia , Cálcio/metabolismo , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Depressão/complicações , Depressão/genética , Depressão/metabolismo , Regulação da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Doença de Parkinson/complicações , Doença de Parkinson/genética , Doença de Parkinson/metabolismoRESUMO
Limitations on the pharmacotherapy and a high prevalence worldwide are critical issues related to depression and cancer. It has been discussed that a dysregulation of intracellular Ca2+ homeostasis is involved in the pathogenesis of both these diseases. In addition, depression raises the risk of cancer incidence. Consistent data support the concept that depression is an independent risk issue for cancer. However, the cellular mechanisms involved in this link between depression and cancer remain uncertain. Considering our previous reports about Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling), I herein discussed the putative contribution of Ca2+/cAMP signalling in this link between depression and cancer. Moreover, it is important to take depression into account during the process of prevention and treatment of cancer.
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Cálcio/metabolismo , AMP Cíclico/metabolismo , Depressão/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Transdução de SinaisRESUMO
BACKGROUND: Depression and hypertension are medical problems both with clearly restricted pharmacotherapies, along with a high prevalence around the world. In fact, an intensive discussion in the field is that a dysregulation of the intracellular Ca2+ homeostasis (e.g. excess of intracellular Ca2+) contributes to the pathogenesis of both hypertension and depression. Furthermore, depression rises the risk of hypertension incidence. Indeed, several data support the concept that depression is an independent risk issue for hypertension. CONCLUSION: Then, which are the possible cellular mechanisms involved in this link between depression and hypertension? Considering our previous reports about the Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling), in this review I have discussed the virtual involvement of the Ca2+/cAMP signalling in this link (between depression and hypertension). Then, it is important to consider depression into account during the process of prevention, and treatment, of hypertension.
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Pressão Sanguínea , Sinalização do Cálcio , AMP Cíclico/metabolismo , Depressão/metabolismo , Hipertensão/metabolismo , Antidepressivos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Sinalização do Cálcio/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/epidemiologia , Depressão/fisiopatologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Incidência , Fatores de Risco , Transdução de SinaisRESUMO
Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense.
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Diabetes mellitus (DM) is among the top ten causes of death worldwide. It is considered to be one of the major global epidemics of the 21st century, with a significant impact on public health budgets. DM is a metabolic disorder with multiple etiologies. Its pathophysiology is marked by dysfunction of pancreatic ß-cells which compromises the synthesis and secretion of insulin along with resistance to insulin action in peripheral tissues (muscle and adipose). Subjects presenting insulin resistance in DM type 2 often also exhibit increased insulin secretion and hyperinsulinemia. Insulin secretion is controlled by several factors such as nutrients, hormones, and neural factors. Exocytosis of insulin granules has, as its main stimulus, increased intracellular calcium ([Ca+2]i) and it is further amplified by cyclic AMP (cAMP). In the event of this hyperfunction, it is very common for ß-cells to go into exhaustion leading to failure or death. Several animal studies have demonstrated pleiotropic effects of L-type Ca2+ channel blockers (CCBs). In animal models of obesity and diabetes, treatment with CCBs promoted restoration of insulin secretion, glycemic control, and reduction of pancreatic ß-cell apoptosis. In addition, hypertensive individuals treated with CCBs presented a lower incidence of DM when compared with other antihypertensive agents. In this review, we propose that pharmacological manipulation of the Ca2+/cAMP interaction system could lead to important targets for pharmacological improvement of insulin secretion in DM type 2.