Dr. Youngil Lee

Doxorubicin (DOX) is an efficient antineoplastic chemotherapeutic drug utilized in the treatment of many different types of cancer. Unfortunately, DOX treatment is a double-edged sword, leading to heart failure in up to 9% of cases. Cardiotoxicity caused by DOX treatment can be defined as acute, subacute, or chronic. DOX-induced cardiotoxicity (DIC) is multifaceted, with evidence suggesting that DOX leads to an increase in oxidative stress, loss of mitochondria, altered autophagy, and premature senescence. DOX-induced heart is dose-dependent, leading to a decrease in the lifetime dose prescribed to cancer patients. The need for a co-treatment to reduce DIC is paramount in ensuring cancer patients receive the therapeutic dose of DOX. A candidate for co-treatment would need to be safe, well-tolerated, and provide no interference with DOX treatment. It is theorized that endurance exercise would be the optimal pre-treatment, as the relationship with cardio-protection is well understood. However, in patients who are not capable of performing exercise prior to DOX treatment, pharmacologic intervention is required. AICAR is a widely studied exercise mimetic used in in-vitro experiments. Evidence showing the potentially harmful effects of AICAR treatment necessitated alternative considerations. Metformin (MET) was a great candidate as literature showed the potential cardioprotective effects and safety of the drug. In this study, metformin pretreatment was administered to rat cardiomyocytes (H9C2 cell line) for two hours, followed by doxorubicin treatment for 24 hours. Increased apoptosis and oxidative stress were observed in cells treated with doxorubicin; however, no cardiac protection was observed in cells pretreated with metformin.

Metabolic distress caused by an excess High-fat diet (HFD) is linked to various types of heart diseases. Inerestingly, recent studies have reported that HFD per se may directly damage
cardiac cells independent of vascular diseases. Although mechanisms remain to be determined, dysregulation of autophagy (self-eating), metabolic signaling, and cellular senescence (aging) are possible factors involved in HFD-induced cardiac degeneration. Given that regular endurance exercise confers various cardioprotective benefits against metabolic diseases by promoting
autophagy, improving antioxidant capacity, and attenuating aging processes in the heart, we hypothesized that exercise-induced cardiac benefits would directly come from the cardiac cells
aside from the vascular origin. Our study, using a cell culture model of HDF, investigated whether a pharmacological exercise memetic
(5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside:AICAR) rescued cardiac cells against HFD-induced cellular injuries via promoting autophagy, metabolic paradigm shifts, and anti-aging reprogramming. Rat ventricular cells were cultured in three different conditions: 1) normal culture media (CON, n=4), 2) high fat diet, treated with 0.5 mM sodium palmitate (Pal, n=4), and 3) high fat diet+ AICAR, treated with 0.5 mM sodium palmitate and 1 mM AICAR (Pal + AICAR). Our study showed that AICAR treatment mitigated mitochondrial morphological disfiguration but neither rescued HFD-induced autophagy disruption nor improved mitochondrial biogenesis nor enhanced glucose metabolic signaling compared to the HFD-treated group. Instead, AICAR rescued llpolysis and improved antioxidant capacity, which was downregulated by an HFD. Our data suggest that improved lipolysis in conjunction with antioxidant capacity by AICAR rather than autophagy modulation seems to provide cardiac protection against HFD-induced cell impairment as reflected in morphology data.

Metabolic distress caused by excess caloric intake (e.g., high-fat and high-carbohydrate diet) contributes to non-alcoholic fatty liver disease (NAFLD), one of the most common diseases in the United States, affecting almost 25% of the U.S. population. While there is no cure for NAFLD, growing evidence has emerged that endurance exercise protects the liver against NAFLD through the restoration of liver function. However, mechanisms of exercise-induced hepatic protection remain an unresolved topic. The present study investigated if endurance exercise (EXE)-mediated alterations of lipid and carbohydrate metabolism (e.g., lipogenesis, lipolysis, mitochondria biosymhesis, and insulin signaling) and cell turnover (e.g., senescence and apoptosis) were associated with protection against NAFLD. To generate a mouse model ofNAFLD, female mice were randomly divided into three groups: normal diet group (CON, n = l 1); high.fat dict/high·fructose group (HFDHF, n= l l); and HFD/HF with EXE group (HFD/HF + EXE, n = l I). The mice assigned to HFD/HF and HFD/HF + EXE groups were fed with HFD/HF for 12 weeks, after which the mice assigned to the EXE group began treadmill running exercise for 13 weeks (60 min a day, five days a week), with HFD/HF diet continued. Our study showed that EXE attenuated hepatic steatosis, reduced de novo lipogcnesis (e.g., reduction in ACLY and DGATI) and enhanced mitochondrial biogenesis and fatty.acid activation and transport proteins to the mitochondria (e.g., OXPHOS, ACSLI, and CPT-IA). Also, EXE improved hepatic glucose regulation (e.g., upregulation of glycogenic signaling; p-lRP, p-AKT, p-GSK3P, and GLUT2; and downregulation of gluconeogenic protein: GAPDH) and prevented hepatic senescence (e.g., suppression of senescence-related proteins p53, p22, and pl6 and pro-inflammatory cytokines TNF-u and IL-IP and oxidative stress markers NOX2). Finally, EXE improved cell turnover via apoptosis (e.g., activation of CASPASE 3 and PARPI cleavage). This study suggests that EXE·mediated metabolic reprogramming (inhibition of tipogenesis and enhancement of lipid oxidation) may be a crucial protective mechanism against NAFLD by preventing hepatic