Intermittent Fasting Attenuates Apoptosis, Modulates Autophagy and Preserve Telocytes in Doxorubicin Induced Cardiotoxicity in Albino Rats: A Histological Study

Abstract

Background: Doxorubicin (DOX) is an effective anticancer drug, however its use is limited due to severe cardiotoxic effects as ventricular dysfunction, cardiomyopathy and heart failure. Intermittent fasting (IF) has a potential preventive and therapeutic effects against variety of diseases including cardiovascular and neurodegenerative disorders. Aim of Work:Investigating the effects of DOX on the histological structure of myocardium and evaluating the possible cardioprotective effects of IF on these changes. Materials and Methods: Forty eight adult male albino rats were divided equally into four groups: control, fasting (16 hours fasting /8 hours eating), DOX (received 3 mg/kg every other day for a total of six intraperitoneal injections) and fasting DOX. Body weight, levels of cardiac biomarkers, Malondialdehyde (MDA) and autophagic indicators (LC3II & p62) were measured. Myocardial specimens were processed for paraffin blocks and stained with H&E, Mallory's trichrome and immunohistochemical stains for p53. Moreover, resin blocks were processed for semithin and ultrathin sections examination. Morphometric and statistical studies were performed. Results: In DOX group, cardiac biomarkers, MDA, LC3II and p62 levels were significantly elevated compared to control group. In addition to, marked histological alterations in myocytes, telocytes and autophagic process. Also, there was significant decrease in cardiomyocytes diameter, significant increase in p53 positive cells and area percent of collagen fibres versus control. On the other hand, IF protected cardiac tissues against the toxic effects of DOX as evidenced by amelioration of histopathological changes and the non significant difference in the levels of cardiac enzymes, MDA, LC3II and p62, cardiomyocytes diameter, p53 positive expressions and area percent of collagen fibres compared to control group. Conclusion: Doxorubicin administration resulted into deleterious effects on the myocardium. Intermittent fasting had cardioprotective effects against Dox-induced cardiotoxicity via restoration of oxidative state, attenuation of apoptosis, regulation of autophagic process and preservation of telocytes.

Beneficial effects of time and energy restriction diets on the development of experimental acute kidney injury in Rat: Bax/Bcl-2 and histopathological evaluation

“…For example, ER has been reported to have a protective effect against kidney damage, the mechanism of which includes exerting anti-apoptotic effects through improving oxidative conditions [ 18 , 41 ]. Similar anti-apoptotic reports exist for TR [ 42 – 44 ] and IF [ 8 , 45 ]. On the contrary, several studies have shown that the HF diet can induce apoptosis in the kidney and cause further damage during AKI [ 46 – 48 ].…”

“…Regarding the effects of diets other than ER, it has been reported that the IF diet has a neuroprotective effect on acute spinal cord injury by reducing the Bax/Bcl-2 ratio [ 45 ]. The TR diet has been shown to have protective effects on the heart by attenuating apoptosis, regulating the autophagy process, and preserving cells [ 42 ]. Another study found that preoperative fasting was protective against renal IRI (ischemic reperfusion injury) by inhibiting apoptosis [ 91 ].…”

Role of mesenchymal stem cells‐derived exosomes on inflammation, apoptosis, fibrosis and telocyte modulation in doxorubicin‐induced cardiotoxicity: A closer look at the structural level

“…Findings of the current work have confirmed the mechanistic insights behind the Dox‐induced cardiotoxicity which could be attributed to the disturbed oxidants (MDA)/antioxidants (SOD, Catalase, GSH, GPX, NRF2, and NO) balance noticed in our study. This disturbance leads to highly toxic free radicals being produced, which in‐turn leads to depletion of the endogenous antioxidants and induction of lipid peroxidation and protein oxidation (Abas & Sabry, 2020; Wenningmann et al, 2019). The efficiency of mitochondrial respiration further declines by Dox's induction of hot spot areas in the mitochondrial DNA, which leads to aberrant replication and upsurge in the concentration of reactive oxygen species (ROS) (Lebrecht et al, 2003).…”

Time-restricted feeding protects against cisplatin-induced acute kidney injury in mice

“…Our findings align with previous research illustrating the anti-apoptotic properties of TRF in diverse animal models. Specifically, TRF has been documented to diminish apoptosis in a mouse model of hepatic IRI [ 31 ] and to mitigate apoptosis through the modulation of autophagy in a doxorubicin-induced cardiotoxicity model of albino rats [ 32 ]. In the context of kidney disease, preoperative TRF administration demonstrated protective effects against renal IRI by inhibiting apoptosis in a mouse model of aortic aneurysm [ 33 ].…”