Neuroinflammation, diabetes, and COVID-19: Perspectives coming from Ca2+/cAMP signalling

Background: A link between inflammatory diseases, e.g., epilepsy, dementia, diabetes, and COVID-19, has been established. For instance, observational studies with several individuals established that people with epilepsy have shown 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, so an association between these two disorders is also discussed. Intriguingly, some reports have also observed a poor prognosis for 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. Objectives: Therefore, clarifying this clinical relationship among epilepsy, dementia, diabetes, and COVID-19 may outcome in novel hypotheses for identifying the etiology of these disorders.

The interplay among epilepsy, Parkinson´s disease, and inflammation: revisiting the link through Ca2+/cAMPsignalling

Background: Robust evidence has described that Parkinson´s disease (PD) is associated with an increased risk for of developing epileptic seizures. In fact, an interplay between PD and epilepsy has been of interest for many years. An emerging hypothesis is that inflammation could link both diseases. Objective: Considering 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 theis link between PD and epilepsy. Methods: Publications involving Ca2+/cAMPsignalling pathways, PD, and epilepsy (alone or combined) were collected by searching PubMed and EMBASE. Results: The comprehension of the interplay between PD and epilepsy could improve the drug therapy. In addition, a Ca2+signallingsignaling dyshomeostasis due to Coronavirus disease 2019 (COVID-19), an emerging and rapidly evolving situation, has been reported. Conclusion: Thus, this article also discussed debated recent findings about of therapeutics involving Ca2+ channel blockers for preventing Ca2+signallingsignaling dyshomeostasis due to COVID-19, including the correlation among COVID-19, epilepsy, and PD.

Role of membrane lipid rafts in MRP4 (ABCC4)-dependent regulation of the cAMP pathway in blood platelets

Background. Platelet cytosolic cAMP levels are balanced by synthesis, degradation, and efflux. Efflux can occur via MRP4 (multidrug resistant protein-4, ABCC4) present on dense granule and/or plasma membranes. As lipid rafts have been shown to interfere on cAMP homeostasis, we evaluated the relationships between the distribution and activity of MRP4 in lipid rafts and cAMP efflux. Methods. Platelet activation and cAMP homeostasis were analyzed in human and wild-type or MRP4-deleted mouse platelets in the presence of methyl-β-cyclodextrin (MβCD) to disrupt lipid rafts, and of activators of the cAMP signalling pathways. Human platelet MRP4 and effector proteins of the cAMP pathway were analyzed by immunoblots in lipid rafts isolated by differential centrifugation. Results. MβCD dose-dependently inhibited human and mouse platelet aggregation without affecting per se cAMP levels. An additive inhibitory effect existed between the adenylate cyclase (AC) activator forskolin and MβCD that was accompanied by an overincrease of cAMP, and which was significantly enhanced upon MRP4 deletion. Finally, an efflux of cAMP out of resting platelets incubated with PGE1 was observed that was partly dependent on MRP4. Lipid rafts contained a small fraction (≈ 15%) of MRP4 and most of the inhibitory G-protein Gi, whereas Gs protein, AC3, and phosphodiesterases PDE2 and PDE3A were all present as only trace amounts. Conclusion. Our results are in favor of part of MRP4 present at the platelet surface, including in lipid rafts. Lipid raft integrity is necessary for cAMP signalling regulation, although MRP4 and most players of cAMP homeostasis are essentially located outside rafts.

Compartmentalized Signaling in Aging and Neurodegeneration

The cyclic AMP (cAMP) signalling cascade is necessary for cell homeostasis and plays important roles in many processes. This is particularly relevant during ageing and age-related diseases, where drastic changes, generally decreases, in cAMP levels have been associated with the progressive decline in overall cell function and, eventually, the loss of cellular integrity. The functional relevance of reduced cAMP is clearly supported by the finding that increases in cAMP levels can reverse some of the effects of ageing. Nevertheless, despite these observations, the molecular mechanisms underlying the dysregulation of cAMP signalling in ageing are not well understood. Compartmentalization is widely accepted as the modality through which cAMP achieves its functional specificity; therefore, it is important to understand whether and how this mechanism is affected during ageing and to define which is its contribution to this process. Several animal models demonstrate the importance of specific cAMP signalling components in ageing, however, how age-related changes in each of these elements affect the compartmentalization of the cAMP pathway is largely unknown. In this review, we explore the connection of single components of the cAMP signalling cascade to ageing and age-related diseases whilst elaborating the literature in the context of cAMP signalling compartmentalization.

Enhancement of Monascus yellow pigments production by activating the cAMP signalling pathway in Monascus purpureus HJ11

Background : Monascus azaphilone pigments (MonAzPs), which were produced by Monascus species, have been used as important food colorant and food supplements for more than one billion people during their daily life. Moreover, MonAzPs recently have received more attention because of their diverse physiological activities. However, the high microbial production of MonAzPs is still not always guaranteed. Herein, the aim of this study was to develop an efficient biotechnological process for MonAzPs production. Results: In this study, exogenous cyclic adenosine monophosphate (cAMP) treatment not only induced MonAzPs production, but also stimulated the expression of a cAMP phosphodiesterase gene, named as mrPDE , in M. purpureus HJ11. Subsequently, MrPDE was identified as a cAMP phosphodiesterase by in vitro enzymatic reaction with purified enzyme. Further, a gene knockout mutant of mrPDE was constructed to verify the activation of cAMP signalling pathway. Deletion of mrPDE in M. purpureus HJ11 improved cAMP concentration by 378 % and enhanced PKA kinase activity 1.5-fold, indicating that activation of cAMP signalling pathway was achieved. The Δ mrPDE strain produced MonAzPs at 8563 U/g, with a 2.3-fold increase compared with the WT strain. Moreover, the NAPDH/NADP + ratio of the Δ mrPDE strain was obviously higher than that of the wild type strain, which led to a higher proportion of yellow MonAzPs. With fed-batch fermentation of the Δ mrPDE strain, the production and yield of MonAzPs achieved 332.1 U/mL and 8739 U/g. Conclusions: A engineered M. purpureus strain for high MonAzPs production was successfully developed by activating the cAMP signalling pathway. This study not only describes a novel strategy for development of MonAzPs-producing strain, but also provides a roadmap for engineering efforts towards the production of secondary metabolism in other filamentous fungi.