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The spleen, an important tissue for the immune system, acts as a filter for blood within the immune system. Accumulating evidence suggests that the spleen affects a number of brain functions in health and diseases via immune modulation. Systemic inflammation or chronic social defeat stress (CSDS) can cause splenomegaly in rodents. Interestingly, the new antidepressant arketamine could normalize splenomegaly and depression-like behaviors in CSDS-susceptible mice. A recent study strongly supports the direct connection pathway between the brain and spleen, whereby the spleen can regulate the humoral immune defense by the two brain regions, such as corticotropin-related neurons in the paraventricular nucleus (PVN) and the central nucleus of the amygdala (CeA). Furthermore, afferent and efferent vagus nerve signaling may contribute to brain and spleen communication. In this article, we review recent findings of the brain-spleen axis in health and diseases.

Myeloid differential protein-2 (MD2) has been shown to play a critical role in the progression of diabetic cardiomyopathy (DCM). This study aims to explore the non-inflammatory mechanisms mediated by MD2 in DCM and to test the therapeutic effects of MD2 inhibitor C30 on DCM. Streptozotocin (STZ) was used to construct DCM model in wild-type and MD2 knockout mice. The collected heart samples were subjected to RNA-sequencing assay. Gene set enrichment analysis of the RNA-seq data indicated that MD2 knockout was associated with energy metabolism pathways in diabetic mouse heart. Further data showed that AMPK pathway was impaired under high glucose condition, which was mediated by p38MAPK activation. MD2 knockout or pharmacological inhibitor C30 completely rescued AMPK signaling through p38MAPK inhibition. Importantly, C30 treatment significantly prevented myocardial damage and dysfunction in T1DM mice evidenced by improved cardiac function and reduced cardiomyocyte apoptosis and cardiac fibrosis. Furthermore, the therapeutic effect of C30 on DCM was correlated to p38MAPK inhibition and AMPK pathway activation in vivo and in vitro. In conclusion, MD2 inhibition exhibits therapeutic effects on DCM through p38MAPK inhibition and AMPK activation, which enables MD2 a promising target for DCM treatment by suppressing metaflammation and improving cardiac metabolism.

Acehytisine, a multi-ion channel blocker, can markedly inhibit INa, ICa, IKur, If at various concentrations and effectively terminate and prevent atrial fibrillation (AF) in patients and animal models, but the molecular mechanism underlying its blockage remains elusive. In this study, we investigated the effects of acehytisine on action potentials and sodium channels of atrial and ventricular myocytes isolated from rabbit, using whole-cell recording system. We found that acehytisine exerted stronger blocking effects on sodium channels in atria than in ventricles, especially at depolarization (IC50: 48.48 ± 7.75 μmol/L in atria vs. 560.17 ± 63.98 μmol/L in ventricles). It also significantly shifted steady state inactivation curves toward negative potentials in atrial myocytes, without affecting the recovery kinetics from inactivation of sodium channels in the same cells. In addition, acehytisine inhibited INa in a use-dependent manner and regulated slow inactivation kinetics by different gating configurations. These findings indicate that acehytisine selectively blocks atrial sodium channels and possesses affinity to sodium channel in certain states, which provides additional evidence for the anti-AF of acehytisine.

Ethnopharmacological relevance The root of Aconitum coreanum (Levl.) Raipaics has been extensively used to treat various kinds of disorders including cardiovascular disease in China for a long time. According to recent studies, its antiarrhythmic actions are attributable to the active component, acehytisine. However, the underlying mechanism remains poorly understood. Aim of the study The effects of acehytisine on the spontaneous activity in sinoatrial nodes and the electropharmacological action of this drug on If in pacemaker cells and hHCN4 channels in oocytes were to be investigated. Materials and methods Sinoatrial nodes were cut from rabbit heart, and transmembrane potentials were recorded by standard microelectrode technique. A whole-cell patch clamp technique was employed to record If isolated enzymatically from rabbit sinoatrial node pacemaker cells. Human HCN4 channels were heterologously expressed in Xenopus oocytes and studied using the two-electrode voltage clamp technique. Results Acehytisine decreased the pacemaker rate of firing and slope of diastolic depolarization, modified the action potential configurations and blocked If in rabbit sinoatrial node cells and hHCN4 channels expressed in Xenopus oocytes in a concentration-dependent, voltage-independent and non-use-dependent manner. Its electropharmacological properties were consistent with those of a close-state blocker. Conclusion Our findings are likely to shed light on the clinical application of acehytisine in the treatment of cardiovascular disorders.

Much evidence indicates that increased persistent sodium current (I(Na.P)) is associated with cellular calcium overload and I(Na.P) is considered to be a potential target for therapeutic intervention in ischaemia and heart failure. By inhibiting type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate (cAMP), with a positive inotropic effect. However, the effect of milrinone on increased I(Na.P) under pathological conditions remains unknown. Accordingly, we investigated the effect of milrinone on increased I(Na.P) induced by hypoxia or hydrogen dioxide in guinea pig ventricular myocytes. While milrinone (0.01 mM or 0.1mM) or cAMP (0.1 mM) decreased I(Na.P) respectively in control condition, application of 1 microM H-89, a selective cAMP-dependant protein kinase inhibitor, prevented the effect of 0.1mM milrinone in control condition. Milrinone (0.1 mM) reduced the increased I(Na.P) induced by hypoxia. Furthermore, 0.01 mM or 0.1mM milrinone reduced the enhanced I(Na.P) induced by 0.3 mM hydrogen peroxide. In addition, 0.01 mM or 0.1 mM milrinone shortened action potential duration at 90% repolarization (APD(90)). Bath application of 0.3 mM hydrogen dioxide markedly prolonged APD(90), while 2 microM tetrodotoxin (TTX) reversed the prolonged APD(90). In the other two groups, 0.01 mM or 0.1 mM milrinone shortened the prolonged APD(90) induced by 0.3 mM hydrogen peroxide, ultimately 2 microM TTX causing a further decurtation of APD(90). These findings demonstrate that milrinone inhibited I(Na.P) under normal condition, hypoxia or hydrogen dioxide-induced I(Na.P), and the APD(90) prolonged by hydrogen dioxide-induced I(Na.P) in ventricular myocytes, which is associated with the mechanism of milrinone increasing intracellular cAMP.

Previous data have showed that application of ivabradine, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, leaded to divergent trends regarding proarrhythmic and antiarrhythmic effects in atrial fibrillation (AF). The aim of this study was to investigate the