Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway.

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell-cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca2+ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects.

Vitamin D Replacement Mitigates Menopause-Associated Dyslipidaemia and Atherogenic Indices in Ovariectomized Rats; A Biochemical Study.

BACKGROUND & AIM: Dyslipidaemia is highly prevalent among postmenopausal women and its management represents a keystone in the prevention of the worldwide increase in cardiovascular morbidity and mortality. Therapy choices for menopause-associated dyslipidaemia are limited and a matter of debate. So, it becomes prudent to search for natural safe alternatives. Vitamin D (VD) has been acknowledged as an essential factor in cardiovascular health. Thus, we aimed to illustrate the impact of different VD status on dyslipidaemia and atherogenic indices. METHOD: 5 groups of rats were conducted; SHAM group fed control diet, ovariectomized rats fed control diet (OVX), ovariectomized rats fed VD-sufficient-high fat diet (HFD) (1 000 IU/ kg diet), ovariectomized rats fed VD-deficient-HFD (25 IU/ kg diet), and ovariectomized rats fed VD-replete-HFD (10 000 IU/ kg diet) for 16 weeks. RESULTS: Dyslipidaemia with an increased atherogenic index of plasma, atherosclerosis coefficient, cardiac risk ratio, and aortic total cholesterol accumulation in addition to reduced serum 25-hydroxy-VD levels was observed in the OVX and VD-sufficient HFD versus SHAM. These findings were aggravated by VD-deficient-HFD while reversed by VD-replete-HFD. The VD-mediated abundance of aortic ATP-binding cassette transporter A1 (ABCA1) expression, reduced activity of the inflammatory Jun N-terminal kinases (JNK), and downregulation of aortic cluster of differentiation-36 (CD36) receptors expression together with increased serum total antioxidant capacity and reduced serum malondialdehyde were among the supposed mechanisms. CONCLUSIONS: Our study sheds light on alarming levels of VD deficiency among ovariectomized rats. VD repletion improved the menopause-associated dyslipidaemia and atherogenic indices through hypolipidemic, antioxidant, and anti-inflammatory effects.