RESUMO
Growing evidence demonstrates the relationship between periodontitis and atherosclerotic cardiovascular diseases. The periodontal pathogen Porphyromonas gingivalis (Pg) has been shown to contribute to the progression of atherosclerosis. Cyclic diadenylate monophosphate (c-di-AMP) has been widely studied as an immune adjuvant for tumor immunotherapy, given its ability to activate the stimulator of interferon genes (STING) and regulate trained immunity. This study sought to elucidate the role of c-di-AMP in Pg-associated atherosclerosis. Periodontitis and atherosclerosis mouse models were established by ligature application around maxillary second molars and feeding ApoE knockout mice with a high-fat diet. We found that periodontitis and atherosclerosis were more severe in mice exposed to Pg than mice that underwent ligature placement only, while prophylactic treatment with c-di-AMP activated trained immunity and elicited significant alleviation of alveolar bone resorption, as well as reduced blood lipid levels and atherosclerotic plaque accumulation. After 3 mo of intervention, c-di-AMP limited the elevation of cytokines interleukin (IL)-6, IL-1ß, tumor necrosis factor α, and interferon ß; extracellular matrix remodeling enzymes MMP-2 and MMP-9; and adhesion molecules ICAM-1 and VCAM-1 gene expression. The mechanism underlying Pg-aggravated atherosclerosis may be attributed to changes in microbiota composition in oral and aortic plaques and excess inflammatory response, whereas c-di-AMP could prevent the effects of Pg infection due to its potential ability to activate trained immunity and regulate microecological balance. Our findings suggest a positive role of c-di-AMP in alleviating Pg-aggravated atherosclerosis by regulating the immune response and influencing the local microenvironment.
Assuntos
Perda do Osso Alveolar , Aterosclerose , Periodontite , Animais , Camundongos , Porphyromonas gingivalis , Interleucina-6 , Monofosfato de AdenosinaRESUMO
Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.
RESUMO
En la década del 60, se asumía que la depresión consistía en una deficiencia de catecolaminas (hipótesis catecolaminérgica) y que los antidepresivos tricíclicos actuaban sobre ellas (principalmente noradrenalina) incrementándolas o potenciándolas a nivel central. Otras teorías sobre las bases biológicas de la depresión y el mecanismo de acción de los antidepresivos fueron planteadas posteriormente a medida que se daban evidencias sobre la participación de otros neurotransmisores. En la actualidad, se asume que el tipo de neurotransmisor implicado no es tan importante como los sistemas intraneuronales de traducción y transcripción de señales activados por la acción de los antidepresivos y que permiten estimular los mecanismos homeostáticos alterados de las neuronas disfuncionales, produciendo adaptaciones terapéuticas que llevan a alteraciones sustanciales y duraderas en la función neurona I y por lo tanto, a un nuevo estado funcional...
In the decade of6Os, were assumed that the depression was consistíng of a deficiency of catecholamines (catecholaminergic hypothesis) and that the trícyclic antidepressants were acting on them (mainly norepinephrine) increasing them at central level. Other theories on the biológical bases of depression and the actíon mechanism of antidepressants were outlined later while were given evidence on the participation of others eurotransmitters. Atpresent, itis assumed that the type of neurotransmitter involved is not so important as the intraneuronal systems ofsigns translation and transcription activated by the action of antidepressants and that permit to stimuíate homeostatic mechanisms alterad of disfunctional neurons, producing therapeutic adjustments that carry to substantial and lasting alterations in the neuronal function and there fore, to a new functíonal state...
Assuntos
Antidepressivos , DepressãoRESUMO
The purpose of this experiment was to study the role of arginine vasopressin (AW) in acute cerebral ischemic edema in mongolian gerbils. The results showed that intracerebroventricular injection (ICV) of AVP exacerbated the ischemic brain edema, while ICV of AW antiserum significantly decreased the ischemic brain edema. Nimodipine couldn't block this role of AW in ischemic brain edema. The cortical Na+ -K+ ATPase activity was significantly decreased, the contents of cAMP in the ischemic cortex and hypothalamus and the contents of cGMP in the hypothalamus were remarkably increased after ICV of AW. These suggest AW was involved in the pathophysiologic process of acute ischemic brain edema. And its mechanism might be the effect of AW on AW receptor mediated by cAMP, cGMP, and that in turn inhibited the Na+ -K+ ATPase activity of brain cell membrane, then exaggerated the formation of ischemic brain edema.