Tricarboxylic acid cycle metabolites: new players in macrophage.

Metabolic remodeling is a key feature of macrophage activation and polarization. Recent studies have demonstrated the role of tricarboxylic acid (TCA) cycle metabolites in the innate immune system. In the current review, we summarize recent advances in the metabolic reprogramming of the TCA cycle during macrophage activation and polarization and address the effects of these metabolites in modulating macrophage function. Deciphering the crosstalk between the TCA cycle and the immune response might provide novel potential targets for the intervention of immune reactions and favor the development of new strategies for the treatment of infection, inflammation, and cancer.

XRCC2 reduced the sensitivity of NSCLC to radio-chemotherapy by arresting the cell cycle.

OBJECTIVE: This study aimed to reveal the role and mechanism of X-ray repair cross complementing 2 (XRCC2) and bevacizumab combined with radiotherapy in the treatment of non-small cell lung cancer (NSCLC). METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) database and Starbase database were used to predict the expression level of XRCC2 in NSCLC tissues and the survival time of patients diagnosed with NSCLC, respectively. Besides, qRT-PCR (quantitative real time polymerase chain reaction) and immunoblotting were conducted to confirm the expression of XRCC2 NSCLC tissues and cells. Moreover, cell viability and colony formation were measured by CCK-8 (cell counting kit-8) assay. Cell migration and invasion capabilities were determined by transwell assay. Flow cytometry analysis was employed to detect cell cycle. RESULTS: XRCC2 was highly expressed in NSCLC tissues and cells. Additionally, bevacizumab combined with radiotherapy significantly inhibited NSCLC cell proliferation, migration and invasion. Knockdown of XRCC2 further aggravated the role of bevacizumab and radiotherapy in NSCLC, while XRCC2 overexpression reversed these effects efficiently. Furthermore, XRCC2 silence exacerbated the arrest of cell cycle induced by bevacizumab combined with radiotherapy in NSCLC cells, whereas overexpression of XRCC2 alleviated the arrest remarkably. CONCLUSION: Collectively, our research revealed that XRCC2 inhibited the sensitivity of NSCLC to bevacizumab combined with radiotherapy by decreasing cell cycle arrest.

Antiarrhythmic efficacy of CPUY102122, a multiple ion channel blocker, on rabbits with ischemia/reperfusion injury.

BACKGROUND: The antiarrhythmic potential of a novel multichannel blocker CPUY102122 (CY22) was investigated in the present study. METHODS: The effect of CY22 on rapid delayed rectifier potassium channel current (IKr) was studied using whole-cell patch clamp techniques in Chinese Hamster Ovary cells stably expressing human Ether-à-go-go-Related Gene. We further evaluated the antioxidant effects of CY22 and demonstrated the reversal of connexin down-regulation in the development of cardiac ventricular arrhythmias, which was produced using coronary ligation/reperfusion in rabbits. CY22 and Amiodarone were administered 30min prior to the procedure. Next, electrocardiograms were recorded, protein expression of left ventricular Connexin43 (Cx43), non-phosphorylation-Cx43 (np-Cx43), Rac-1 and gp-91[phox] were assayed using Western blot analysis, microstructural changes in the myocardium were observed and redox system activity was assayed. RESULTS: CY22 inhibited IKr in a concentration-dependent manner with IC50 value of 2.8±0.8µmol/L. CY22 treatment significantly decreased T-wave amplitude and QTc arrhythmic scores and ameliorated the shape of the infarcted myocardium compared to the model group. CY22 decreased the serum levels of creatine kinase, lactate dehydrogenase, and myocardial levels of malondialdehyde, as well as increased superoxide dismutase activity. Cx43 expression in the left ventricle was significantly increased by CY22 treatment, which significantly decreased np-43 expression, Rac-1 activity and gp-91[phox] protein expression. CONCLUSIONS: These results indicated that CY22 has both antiarrhythmic and cardiovascular protective effects partly by blocking IKr, the production of antioxidants and protection of Cx43.

Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I).

Kv1.5 potassium channel is an efficacious and safe therapeutic target for the treatment of atrial fibrillation (AF), the most common arrhythmia that threatens human. Herein, by modifying the hit compound 7k from an in-house database, 48 derivatives were synthesized for the assay of their Kv1.5 inhibitory effects by whole cell patch clamp technique. Six compounds which showed better potency than the positive compound dronedarone were selected for the next evaluation of their drug-like properties. Compound 8 exhibited balanced solubility and permeability. It also showed acceptable pharmacodynamics profile with very low acute toxicity. Taking all these data into account, compound 8 can serve as a promising lead for the development of novel therapeutic agent for the treatment of AF.