Magnesium lithospermate B enhances the potential of human-induced pluripotent stem cell-derived cardiomyocytes for myocardial repair.

BACKGROUND: We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model. METHODS: In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups (n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. RESULTS: After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro. CONCLUSIONS: MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.

Non-coding RNAs to regulate cardiomyocyte proliferation: A new trend in therapeutic cardiac regeneration.

Cardiovascular diseases remain the leading cause of death worldwide, particularly ischemic heart disease (IHD). It is also classified as incurable given the irreversible damage it causes to cardiomyocytes. Thus, myocardial tissue rejuvenation following ischemia is one of the global primary research concerns for scientists. Interestingly, the mammalian heart thrives after an injury during the embryonic or neonatal period; however, this ability disappears with increasing age. Previous studies have found that specific non-coding (nc) RNAs play a pivotal role in this process. Hence, the review herein summarizes the research on cardiomyocyte regenerative medicine in recent years and sets forth the biological functions and mechanisms of the micro (mi)RNA, long non-coding (lnc)RNA, and circular (circ)RNA in the posttranscriptional regulation of cardiomyocytes. In addition, this review summarizes the roles of ncRNAs in specific species while enumerating potential therapeutic strategies for myocardial infarction.

Ultrasound-guided Induced Pluripotent Stem Cell-derived Cardiomyocyte Implantation in Myocardial Infarcted Mice.

The key objective of cell therapy after myocardial infarction (MI) is to effectively enhance the cell grafted rate, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising cell source for cardiac repair after ischemic damage. However, a low grafted rate is a significant obstacle for effective cardiac tissue regeneration after transplantation. This protocol shows that multiple hiPSC-CM ultrasound-guided percutaneous injections into an MI area effectively increase cell transplantation rates. The study also describes the entire hiPSC-CM culture process, pretreatment, and ultrasound-guided percutaneous delivery methods. In addition, the use of human mitochondrial DNA help detect the absence of hiPSC-CMs in other mouse organs. Lastly, this paper describes the changes in cardiac function, angiogenesis, cell size, and apoptosis at the infarcted border zone in mice 4 weeks after cell delivery. It can be concluded that echocardiography-guided percutaneous injection of the left ventricular myocardium is a feasible, relatively invasive, satisfactory, repeatable, and effective cellular therapy.

Genetic analysis of potential biomarkers and therapeutic targets in ferroptosis from coronary artery disease.

Ferroptosis plays a key role in the death of cells including cardiomyocytes, and it is related to a variety of cardiac diseases. However, the role of ferroptosis-related genes (FRGs) in coronary artery disease (CAD) is not well characterized. We downloaded CAD-related information and FRGs from the gene expression omnibus (GEO) database and Ferroptosis Database (FerrDb) respectively. A total of 10 CAD-related DE-FRGs were obtained, which were closely linked to autophagy regulation and immune response. Subsequently, CA9, CBS, CEBPG, HSPB1, SLC1A4, STMN1 and TRIB3 among the 10 DE-FRGs were identified as marker genes by LASSO and SVM-RFE algorithms, which had tolerable diagnostic capabilities. Subsequent functional enrichment analysis showed that these marker genes may play a corresponding role in CAD by participating in the regulation of immune response, amino acid metabolism, cell cycle and multiple pathways related to the pathogenesis of CAD. Furthermore, a total of 58 drugs targeting 7 marker genes had been obtained. On the contrary, the ceRNA network revealed a complex regulatory relationship based on the marker genes. Also, CIBERSORT analysis showed that the changes in the immune microenvironment of CAD patients may be related to CBS, HSPB1 and CEBPG. We developed a diagnostic potency and provided an insight for exploring the mechanism for CAD. Before clinical application, further research is needed to test its diagnostic value for CAD.

Cardiac Repair With Echocardiography-Guided Multiple Percutaneous Left Ventricular Intramyocardial Injection of hiPSC-CMs After Myocardial Infarction.

Objective: We investigated the potency of cardiac repair based on echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) after myocardial infarction (MI). Methods: Mice with surgically induced MI were randomly divided into three groups (n = 8 in each group) and subjected to echocardiography-guided percutaneous left ventricular infarcted border injection of hiPSC-CMs (single dose; 10 µl 3 × 105 cells) or repeated injections of hiPSC-CMs at post-MI weeks 1 and 2 (multiple doses). The sham group of animals underwent all surgical procedures necessary for MI induction except for ligation. Then 4 weeks after MI, heart function was measured with transthoracic echocardiography. Engraftment was evaluated through the detection of human-specific cardiac troponin T. Infarct size and collagen volume were calculated with Sirius Red/Fast Green staining. Angiogenesis was evaluated with isolectin B4 staining. Cardiac remodeling was evaluated from the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via TdT-mediated dUTP Nick-End Labeling (TUNEL) staining in cardiomyocytes from the infarcted border zone. Results: No mice died after echocardiography-guided percutaneous left ventricular intramyocardial injection. hiPSC-CMs were about nine-fold higher in the multiple-dose group at week 4 compared to the single-dose group. Multiple-dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis. Conclusion: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive, and effective method of delivering cell therapy. The delivery of hiPSC-CMs indicates a novel therapy for MI.

Delayed Therapy of Descending Aortic Coarctation Results in Anterior Cerebral Rupture: A Case Report.

Background: Coarctation of the aorta (CoA) is the congenital constriction or narrowing of the aortic lumen. These constrictions are primarily located in the descending aorta causing significant discrepancies in systolic blood pressures of the upper and lower extremities. Thus, a delay in diagnosis and treatment may lead to severe and adverse consequences. Case presentation: Herein, we present a 13-year-old boy with anterior cerebral rupture following a delayed diagnosis for descending CoA. Percutaneous transluminal balloon dilatation and endovascular stent implantation were urgently and successfully performed alongside cerebral clipping of the vascular aneurysm. Conclusion: An early diagnosis is crucial for CoA's successful treatment and management to prevent complications, including anterior cerebral rupture.

A large congenital atrial septal defect in an adult with delayed therapy.

Patients with a large congenital atrial septal defect (ASD) traditionally have the ASD repaired at the preschool age. Unfortunately, insufficient education of patients regarding medical science and clinical recommendations can lead to delayed therapy, resulting in complications during adulthood. We report a rare case of a large congenital ASD in a 20-year-old man. Echocardiography showed a 67-mm ostium secundum defect and moderate mitral and tricuspid regurgitation. The patient underwent transthoracic ASD repair along with mitral and tricuspid valvuloplasty. This report emphasizes the importance of educating patients about congenital malformations and potential interventions in developing countries, particularly in rural communities.

Comparison of transcatheter arterial chemoembolization with raltitrexed plus liposomal doxorubicin vs. tegafur plus pirarubicin for unresectable hepatocellular carcinoma.

BACKGROUND: There is still no general consensus on the optimal chemotherapeutic agent selection for transcatheter arterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). The present study aimed to compare the efficacy and safety of TACE with raltitrexed plus liposomal doxorubicin (R + PGLD) vs. tegafur plus pirarubicin (T + P) in patients with unresectable HCC. METHODS: A total of 148 patients with unresectable HCC treated with TACE between January 2012 and December 2016 were retrospectively analyzed. Of them, 74 patients were in the R + PGLD group and 74 patients were in the T + P group (1:1). The treatment response of the tumor, overall survival (OS) time, and adverse effects were compared between the two groups. RESULTS: There were no significant differences in patient characteristics or embolization effect (lipiodol deposition) between the two groups (P>0.05). R + PGLD treatment had a better clinical efficacy than T + P treatment (OR: 64.9% vs. 45.9%, P=0.031; DC: 89.2% vs. 74.3%, P=0.032). Portal vein invasion, hepatic vein invasion, tumor size and BCLC stage were associated with OR or DC after TACE using R + PGLD treatment. Survival analysis revealed that patients who received TACE with R + PGLD had a better prognosis than those treated with T + P. Moreover, some complications in the R + PGLD group, including vomiting, myelosuppression and cardiotoxicity, were significantly lower than those in the T + P group (P<0.05). CONCLUSIONS: TACE with raltitrexed and liposomal doxorubicin could reduce the incidence of adverse reactions and significantly improve the OS of patients with unresectable HCC.

Platelet count on preoperative day 1 predicts the long-term responses to laparoscopic splenectomy for Chinese patients with medically refractory idiopathic thrombocytopenic purpura.

BACKGROUND: Laparoscopic splenectomy (LS) is regarded as a second-line treatment for medically refractory idiopathic thrombocytopenic purpura (ITP), but the predictive factors for the long-term postoperative responses to ITP are still a matter of debate. We aimed to investigate the factors that can predict the long-term response after LS for Chinese patients with medically refractory ITP. METHODS: From January 2011 to September 2016, 78 Chinese patients with ITP who underwent LS were retrospectively analyzed. Twelve parameters were analyzed by univariate and multivariate methods. RESULTS: Univariate analysis revealed that platelet count on preoperative day (PRD) 1 (P < 0.001) and operative time (P = 0.011) were significantly associated with long-term response of ITP after LS. Multivariate analysis revealed that platelet count on PRD 1 was a predictive factor of long-term response (P < 0.001). Furthermore, a long-term, stable response of platelet count on PRD 1 of > 30.0 × 109/L was easier to achieve than a platelet count on PRD 1 ≤ 30.0 × 109/L after LS for ITP. CONCLUSIONS: LS is a valuable and effective option in the treatment of medically refractory ITP. Platelet count on PRD 1 is an independent predicting factor for long-term response after LS for Chinese patients with ITP.