关键词： Calmodulin kinase II   Atrial fibrillation   Supraventricular tachycardia   Atrioventricular node conduction   Ventricular rate control   Ca21 transient   Sarcomere  

摘要： BACKGROUND Ca21/calmodulin-dependent protein kinase II (CaMKII) inhibition decelerates atrioventricular node (AVN) conduction, providing a potential treatment of tachycardia. However, the effectiveness of CaMKII inhibition on tachycardia and its underlying mechanism remains unclear. OBJECTIVE We aimed to assess the effectiveness of CaMKII inhibition in reducing ventricular rates during atrial fibrillation and to elucidate the underlying mechanism in affecting AVN electrophysiology. METHODS Cardiac CaMKII inhibition (AC3-I) mice were used. Transesophageal atrial pacing was performed to evaluate AVN conduction function and to induce atrial fibrillation. Patch-clamp techniques were employed to record action potentials and ionic currents in AVN cells. Intracellular Ca21 transients and sarcomere length measurements were obtained with the IonOptix system. Masson trichrome stain was used to evaluate fibrosis in the AVN region. Western blotting and immunofluorescence techniques were employed to detect connexin expression and localization. RESULTS CaMKII inhibition decreased the ventricular rate during atrial fibrillation and isoproterenol-induced tachycardia. Esophageal electrocardiogram results from AC3-I mice showed longer AVN conduction than in wild-type mice. AN-and Ntype AVN cells from AC3-I mice exhibited slower action potential frequencies and diastolic depolarization rates than those of wild-type mice. The study revealed that CaMKII inhibition reduced AVN cell sarcoplasmic reticulum (SR) Ca21 content, Ca21 release rate from the SR during diastole, Ca21 transient amplitude, and SR Ca21 uptake rate. In addition, CaMKII inhibition prolonged the sarcomere diastole duration and enhanced the sensitivity of sarcomeres to Ca21. CONCLUSION CaMKII inhibition effectively decreases the ventricular rate during atrial fibrillation and tachycardia by slowing down AVN conduction through suppressing Ca21 overload in AVN cells.

关键词： Alfalfa   MsCML70   Salt stress tolerance  

摘要： Calmodulin-like proteins (CMLs), which are widely involved in various abiotic stress responses, are important calcium ion sensors in plants. However, systematic identification and functional analysis of these proteins have not been performed in alfalfa. Here, a total of 211 MsCMLs were identified in the alfalfa genome. Conserved domain analysis revealed that most MsCMLs contained three EF-hand domains. A total of 17 tandem duplication events and 292 segmental duplication events were identified, indicating that segmental duplications were the major factor in the expansion of MsCMLs. There were 28, 36 and 18 MsCMLs that responded to drought, salt and cold stress, respectively, in alfalfa. In addition, MsCML70 overexpression significantly increased salt tolerance in Arabidopsis. MsCML70 participates in the plant salt stress response through various biological pathways, including transcriptional regulation, protein modification, plant hormone metabolism and secondary metabolism. Moreover, MsCML70 significantly increased the expression of HKT1 (high-affinity K+transporter 1), DREB19 (dehydration responsive element binding protein 19), PRX32 (peroxidase 32), JAL10 (jacalin-associated lectins 10), HB17 (homeobox 17), and NPF2.3 (nitrate transporter 2.3) under salt stress to promote tolerance to salt stress in Arabidopsis. The results of this study help elucidate the function of alfalfa CML genes and provide a new gene resource for the breeding of stress-resistant alfalfa.

关键词： Fc fragment of IgG binding protein   Colorectal cancer   Wild type P53   Ubiquitination   MDM2  

摘要： The Fc fragment of IgG binding protein (FCGBP) exhibits differential expression across various tumor types. but its role in cancer progression remains underexplored. This research discovered that FCGBP is downregulated in colorectal cancer (CRC) cells and is negatively associated with poor prognosis. Overexpression of FCGBP inhibited the growth of P53 wild-type CRC cells both in vitro and in vivo. Mechanistically, immunoprecipitation experiments revealed that FCGBP competitively binds to MDM2, thereby attenuating the formation of the P53/MDM2 complex. This, in turn, reduces P53 ubiquitination and stabilizes the protein. Our findings reveal a novel mechanism through which FCGBP significantly inhibits CRC cell growth and propose a new targeted therapeutic strategy for CRC treatment.