Mitochondrial ROS-Mediated Metabolic and Cytotoxic Effects of Isoproterenol on Cardiomyocytes Are p53-Dependent and Reversed by Curcumin.

Acute ß-adrenergic stimulation contributes to heart failure. Here, we investigated the role of p53 in isoproterenol (ISO)-mediated metabolic and oxidative stress effects on cardiomyocytes and explored the direct protective effects offered by the antioxidant nutraceutical curcumin. Differentiated H9C2 rat cardiomyocytes treated with ISO were assayed for glucose uptake, lactate release, and mitochondrial reactive oxygen species (ROS) generation. Survival was assessed by sulforhodamine B assays. Cardiomyocytes showed significantly decreased glucose uptake and lactate release, as well as increased cellular toxicity by ISO treatment. This was accompanied by marked dose-dependent increases of mitochondria-derived ROS. Scavenging with N-acetyl-L-cysteine (NAC) effectively lowered ROS levels, which completely recovered glycolytic metabolism and survival suppressed by ISO. Mechanistically, ISO reduced extracellular-signal-regulated kinase (ERK) activation, whereas it upregulated p53 expression in an ROS-dependent manner. Silencing of p53 with siRNA blocked the ability of ISO to stimulate mitochondrial ROS and suppress glucose uptake, and partially recovered cell survival. Finally, curcumin completely reversed the metabolic and ROS-stimulating effects of ISO. Furthermore, curcumin improved survival of cardiomyocytes exposed to ISO. Thus, ISO suppresses cardiomyocyte glycolytic metabolism and survival by stimulating mitochondrial ROS in a p53-dependent manner. Furthermore, curcumin can efficiently rescue cardiomyocytes from these adverse effects.

Injectable glycol chitosan thermogel formulation for efficient inner ear drug delivery.

We prepared a new injectable thermogel to enhance the efficiency of inner ear delivery of dexamethasone (DEX). Hexanoyl glycol chitosan (HGC) was synthesized and evaluated as an amphiphilic thermogel (Tgel ~ 32 °C) for use as a solubilizing agent as well as an injectable carrier for intratympanic delivery of the hydrophilic and hydrophobic forms of DEX. Various thermogel formulations with different drug types and concentrations were prepared, and their physicochemical and thermogelling properties were characterized by 1H NMR, ATR-FTIR, and rheometer. They exhibited versatile release kinetics from several hours to more than 2 weeks, depending on drug type and concentration. Our formulations further showed good residual stability for more than 21 days without any cytotoxicity or inflammation in the middle and inner ear and could deliver a considerably high drug concentration into the inner ear. Therefore, HGC thermogel has great potential as an effective and safe formulation for inner ear drug delivery.

Deep Learning for Human Disease Detection, Subtype Classification, and Treatment Response Prediction Using Epigenomic Data.

Deep learning (DL) is a distinct class of machine learning that has achieved first-class performance in many fields of study. For epigenomics, the application of DL to assist physicians and scientists in human disease-relevant prediction tasks has been relatively unexplored until very recently. In this article, we critically review published studies that employed DL models to predict disease detection, subtype classification, and treatment responses, using epigenomic data. A comprehensive search on PubMed, Scopus, Web of Science, Google Scholar, and arXiv.org was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among 1140 initially identified publications, we included 22 articles in our review. DNA methylation and RNA-sequencing data are most frequently used to train the predictive models. The reviewed models achieved a high accuracy ranged from 88.3% to 100.0% for disease detection tasks, from 69.5% to 97.8% for subtype classification tasks, and from 80.0% to 93.0% for treatment response prediction tasks. We generated a workflow to develop a predictive model that encompasses all steps from first defining human disease-related tasks to finally evaluating model performance. DL holds promise for transforming epigenomic big data into valuable knowledge that will enhance the development of translational epigenomics.

Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study.

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.

Infectious Respiratory Diseases Decreased during the COVID-19 Pandemic in South Korea.

Infectious respiratory diseases are highly contagious and very common, and thus can be considered as one of the leading causes of morbidity and mortality worldwide. We followed up the incidence rates (IRs) of eight infectious respiratory diseases, including chickenpox, measles, pertussis, mumps, invasive pneumococcal disease, scarlet fever, rubella, and meningococcal disease, after COVID-19 mitigation measures were implemented in South Korea, and then compared those with the IRs in the corresponding periods in the previous 3 years. Overall, the IRs of these diseases before and after age- or sex-standardization significantly decreased in the intervention period compared with the pre-intervention periods (p < 0.05 for all eight diseases). However, the difference in the IRs of all eight diseases between the IRs before and after age-standardization was significant (p < 0.05 for all periods), while it was not significant with regard to sex-standardization. The incidence rate ratios for eight diseases in the pre-intervention period compared with the intervention period ranged from 3.1 to 4.1. These results showed the positive effects of the mitigation measures on preventing the development of respiratory infectious diseases, regardless of age or sex, but we need to consider the age-structure of the population to calculate the effect size. In the future, some of these measures could be applied nationwide to prevent the occurrence or to reduce the transmission during outbreaks of these infections. This study provides evidence for strengthening the infectious disease management policies in South Korea.

Targeted therapy of triple negative MDA-MB-468 breast cancer with curcumin delivered by epidermal growth factor-conjugated phospholipid nanoparticles.

Triple-negative breast cancer (TNBC) is associated with poor survival as chemotherapy is currently limited to conventional cytotoxic agents. Curcumin has promising anticancer actions against TNBC, but its application is hindered by poor bioavailability and rapid degradation in vivo. In the present study, curcumin-loaded phospholipid nanoparticles (Cur-NPs) conjugated with epidermal growth factor (EGF) were prepared for specific targeting of EGF receptors overexpressed in TNBC. NP formulation was performed by reacting EGF peptide with N-hydroxysuccinimide-Polyethylene Glycol-1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine (NHS-PEG10000-DSPE), followed by efficient curcumin loading through lipid film hydration. EGF conjugation did not significantly affect NP size, zeta potential or morphology. Specific targeting was confirmed by EGF receptor activation and blocking of 125I-labeled NP binding by excess EGF. EGF-Cur-NP dose-dependently suppressed MDA-MB-468 TNBC cell survival (IC50, 620 nM), and completely abolished their capacity to form colonies. The cytotoxic effects were more potent compared with those of free curcumin or Cur-NP. In mice bearing MDA-MB-468 tumors, injections of 10 mg/kg EGF-Cur-NP caused a 59.1% retardation of tumor growth at 3 weeks compared with empty NP, whereas the antitumor effect of Cur-NP was weak. These results indicate that EGF-conjugated NHS-PEG10000-DSPE phospholipid NPs loaded with curcumin may be useful for treating TNBCs that overexpress the EGF receptor.