The role and mechanism of NRG1/ErbB4 in inducing the differentiation of induced pluripotent stem cells into cardiomyocytes.

BACKGROUND: We aimed to investigate the effect and potential mechanism of enhancing Neuregulin1 (NRG1)/v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4) expression on the differentiation of induced pluripotent stem cells (iPSCs) into cardiomyocytes. METHODS: We utilized CRISPR-CAS9 technology to knock in ErbB4 and obtained a single-cell clone IPSN-AAVS1-CMV-ErbB4 (iPSCs-ErbB4). Subsequently, we induced the differentiation of iPSCs into cardiomyocytes and quantified the number of beating embryoid bodies. Furthermore, quantitative real-time PCR assessed the expression of cardiomyocyte markers, including ANP (atrial natriuretic peptide), Nkx2.5 (NK2 transcription factor related locus 5), and GATA4 (GATA binding protein 4). On the 14th day of differentiation, we observed the α-MHC (α-myosin heavy chain)-positive area using immunofluorescent staining and conducted western blotting to detect the expression of cTnT (cardiac troponin) protein and PI3K/Akt signaling pathway-related proteins. Additionally, we intervened the iPSCs-ErbB4 + NRG1 group with the PI3K/Akt inhibitor LY294002 and observed alterations in the expression of cardiomyocyte differentiation-related genes. RESULTS: The number of beating embryoid bodies increased after promoting the expression of NRG1/ErbB4 compared to the iPSCs control group. Cardiomyocyte markers ANP, Nkx2.5, and GATA4 significantly increased on day 14 of differentiation, and the positive area of α-MHC was three times that of the iPSCs control group. Moreover, there was a marked increase in cTnT protein expression. However, there was no significant difference in cardiomyocyte differentiation between the iPSCs-ErbB4 group and the iPSCs control group. Akt phosphorylation was significantly increased in the iPSCs-ErbB4 + NRG1 group. LY294002 significantly reversed the enhancing effect of NRG1/ErbB4 overexpression on Akt phosphorylation as well as the increase in α-MHC and cTnT expression. CONCLUSIONS: In conclusion, promoting the expression of NRG1/ErbB4 induced the differentiation of iPSC into cardiomyocytes, possibly through modulation of the PI3K/Akt signaling pathway.

Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice.

Doxorubicin (DOX) is a popular and potent anticancer drug, but its cardiotoxicity limits its clinical application. Shikonin has a wide range of biological functions, including antioxidant and anti-inflammatory effects. The aim of this study was to investigate the effects of shikonin on DOX-induced cardiac injury and to identify the underlying mechanisms. Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration. Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis. Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In conclusion, shikonin alleviates DOX-induced cardiotoxicity by inhibiting Mst1 and activating Nrf2. Shikonin may be used to treat DOX-induced cardiac injury.

The diagnosis and treatment of pediatric clinical myocarditis in China: a multicenter retrospective study.

This study aims to examine the clinical characteristics and outcomes of clinical myocarditis in pediatric patients in China. This is a multicenter retrospective study. Children diagnosed with clinical myocarditis from 20 hospitals in China and admitted between January 1, 2015, and December 30, 2021, were enrolled. The clinical myocarditis was diagnosed based on the "Diagnostic Recommendation for Myocarditis in Children (Version 2018)". The clinical data were collected from their medical records. A total of 1210 patients were finally enrolled in this study. Among them, 45.6% had a history of respiratory tract infection. An abnormal electrocardiogram was observed in 74.2% of patients. Echocardiography revealed that 32.3% of patients had a left ventricular ejection fraction of less than 50%. Cardiac MRI was performed in 4.9% of children with clinical myocarditis, of which 61% showed localized or diffuse hypersignal on T2-weighted images. Serum levels of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), and N-terminal B-type natriuretic peptide (NT-proBNP) were higher in patients with fulminant myocarditis than in patients with myocarditis, making them potential risk factors for fulminant myocarditis. Following active treatment, 12.1% of patients were cured, and 79.1% were discharged with improvement. CONCLUSION: Clinical myocarditis in children often presents with symptoms outside the cardiovascular system. CK-MB, cTnI, and NT-proBNP are important indicators for assessing clinical myocarditis. The electrocardiogram and echocardiogram findings in children with clinical myocarditis exhibit significant variability but lack specificity. Cardiac MRI can be a useful tool for screening clinical myocarditis. Most children with clinical myocarditis have a favorable prognosis. WHAT IS KNOWN: • Pediatric myocarditis presents complex clinical manifestations and exhibits varying degrees of severity. Children with mild myocarditis generally have a favorable prognosis, while a small number of children with critically ill myocarditis experience sudden onset, hemodynamic disorders, and fatal arrhythmias. Therefore, early diagnosis and timely treatment of myocarditis are imperative. WHAT IS NEW: • To the best of our knowledge, this multicenter retrospective study is the largest ever reported in China, aiming to reveal the clinical characteristics and outcomes of pediatric clinical myocarditis in China. We provided an extensive analysis of the clinical characteristics, diagnosis, treatment, prognosis, and factors impacting disease severity in pediatric clinical myocarditis in China, which provides insights into the epidemiological characteristics of pediatric clinical myocarditis.

Arc and Homer1 are involved in comorbid epilepsy and depression: A microarray data analysis.

BACKGROUND: Depression is one of the most common comorbid psychiatric condition associated with epilepsy. It has a negative impact on the patient's quality of life. However, the underlying molecular mechanisms leading to depression are currently unclear. The aim of this study was to determine the hub genes associated with epilepsy and depression. METHODS: Gene expression profiles (GSE47752 and GSE20388) were downloaded from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) for epilepsy and depression groups were separately searched. Subsequently, network analyses methods were employed to establish protein-protein interaction (PPI) networks, and to perform Gene Ontology (GO) terms and pathway enrichment analyses for co-expressed DEGs. RESULTS: A total of 772 genes were upregulated in patients with epilepsy whereas 91 genes were up-regulated in patients with depression. In addition, 1304 genes were down-regulated in epilepsy whereas 141 genes were down-regulated in patients with depression. Among co-expressed DEGs, 5 DEGs were up-regulated and 19 were down-regulated. Further analysis revealed that the co-expressed DEGs were involved in regulation of vasculature development, regulation of angiogenesis, glutamate receptor signaling pathway, cellular response to interleukin-1 and positive regulation of protein kinase B signaling. The Arc and Homer1 genes were identified as the common candidate genes involved in the pathogenesis of epilepsy and depression. CONCLUSIONS: Arc and Homer1 may contribute to the comorbidity of epilepsy and depression.

Neuraminidase 1 deficiency attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory via AMPK-SIRT3 pathway in diabetic cardiomyopathy mice.

Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a lysosomal protein which plays a role in the catabolism of glycosylated proteins. We investigated the role of NEU1 in the myocardium in diabetic heart. Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in mice. Neonatal rat ventricular myocytes (NRVMs) were used to verify the effect of shNEU1 in vitro. NEU1 is up-regulated in cardiomyocytes under diabetic conditions. NEU1 inhibition alleviated oxidative stress, inflammation and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Furthermore, NEU1 inhibition also attenuated the high glucose-induced increased reactive oxygen species generation, inflammation and, cell death in vitro. ShNEU1 activated Sirtuin 3 (SIRT3) signaling pathway, and SIRT3 deficiency blocked shNEU1-mediated cardioprotective effects in vitro. More importantly, we found AMPKα was responsible for the elevation of SIRT3 expression via AMPKα-deficiency studies in vitro and in vivo. Knockdown of LKB1 reversed the effect elicited by shNEU1 in vitro. In conclusion, NEU1 inhibition activates AMPKα via LKB1, and subsequently activates sirt3, thereby regulating fibrosis, inflammation, apoptosis and oxidative stress in diabetic myocardial tissue.

Cardiac Biomarker Abnormalities Are Closely Related to Prognosis in Patients with COVID-19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is erupting and spreading globally. Cardiovascular complications secondary to the infection have caught notice. This study aims to delineate the relationship of cardiac biomarkers and outcomes in severe cases of corona virus disease 2019 (COVID-19). One hundred forty-eight critically ill adult patients with COVID-19 were enrolled. From these patients, the demographic data, symptoms, cardiac biomarkers, treatments, and clinical outcomes were collected. Data were compared between survivors and non-survivors. Four patients in the non-survivor group were selected, and their cardiac biomarkers were collected and analyzed. Among the 148 patients, the incidence of cardiovascular complications was 19 (12.8%). Five of them were survivors (5.2%), and 14 of them were non-survivors (26.9%). Compared with the survivors, the non-survivors had higher levels of high-sensitivity cardiac troponin I, creatine kinase isoenzyme-MB, myoglobin, and N-terminal pro-brain natriuretic peptide (P < 0.05). The occurrence of cardiovascular events began at 11-15 days after the onset of the disease and reached a peak at 14-20 days. COVID-19 not only is a respiratory disease but also causes damage to the cardiovascular system. Cardiac biomarkers have the potential for early warning and prognostic evaluation in patients with COVID-19. It is recommended that cardiac biomarker monitoring in patients with COVID-19 should be initiated at least from the 11th day of the disease course.

The metabolic and immunological characteristics of pregnant women with COVID-19 and their neonates.

Our aim was to investigate whether SARS-CoV-2 infection raised high risks of late pregnancy complications, and posed health problems in fetuses and neonates. We analyzed the data of COVID-19 pregnant women with COVID-19 during late pregnancy and their neonates. Eleven out of 16 (69%) pregnant women with COVID-19 had ++ or +++ of ketone body in urine. The blood uric acid of pregnant patients was 334 µmol/L (IQR, 269-452). D-dimer and FDP in pregnant patients were 3.32 mg/L (IQR, 2.18-4.21) and 9.6 mg/L (IQR, 5.9-12.4). Results of blood samples collected at birth showed that 16 neonates had leukocytes (15.7 × 109/L (IQR, 13.7-17.2)), neutrophils (11.1 × 109/L (IQR, 9.2-13.2)), CK (401 U/L (IQR, 382-647)), and LDH (445 U/L (IQR, 417-559)). Twenty-four hours after birth, a neonate from COVID-19 woman had fever and positive of SARS-CoV-2 gene. Another woman had strongly positive for SARS-CoV-2 gene (+++) for 4 weeks, and delivered one neonate who had SARS-CoV-2 IgM (46 AU/mL) and IgG (140 AU/mL) on day 1 after birth. In the third trimester, COVID-19 infection in pregnant patients raised high risks of ketonuria, hypercoagulable state, and hyperfibrinolysis, which may lead to severe complications. COVID-19 increased the inflammatory responses of placenta, and fetuses and neonates had potential organ dysregulation and coagulation disorders. There was a potential intrauterine transmission while pregnant women had high titer of SARS-CoV-2, but it is necessary to detect SARS-CoV-2 in the blood cord, placenta, and amniotic fluid to further confirm intrauterine infection of fetuses.