Mohamed A. Shaheen

Background Acute liver injury, a life-threatening condition, is characterized by oxidative stress, inflammation, and apoptosis with limited effective interventions. This study aimed to investigate the potential use of Sacubitril/valsartan (SAC/VAL) in lipopolysaccharide (LPS) induced acute liver injury. Methods Thirty six adult male albino rats were allocated to 3 groups; control groups received either vehicles or SAC/VAL, LPS group received LPS (10mg/kg, ip) and LPS+SAC/VAL group received LPS and 3 hours later received SAC/VAL (68mg/kg, oral). Rats were sacrificed 6 hours following LPS injection. Results Rats from LPS group had higher serum tumour necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and liver enzymes (ALT and AST), but lower total antioxidant capacity (TAC) than control groups. Histological examination revealed distorted hepatocytes, congested blood vessels, periportal inflammatory cellular infiltration and increased liver injury score in LPS group compared to control group. Ultrastructurally, hepatocytes from LPS group had heterochromatic nuclei with vacuolated cytoplasm, swollen mitochondria and phagosomes. Treatment with SAC/VAL significantly reversed inflammation and oxidative stress and decreased liver injury score in LPS group. Ultrastructurally, hepatocytes from LPS+SAC/VAL group had euchromatic nuclei with intact nucleoplasm. Immunohistochemical evaluation revealed obvious increases in the expression (number of immunopositive cells/field) of Toll-like receptor-4 (TLR-4) and nuclear factor-kappa B (NF-κB) and increased immunoexpression of pyroptotic inflammasome mediators, namely NOD-like receptor protein3 (NLRP3), caspase-1 (Cas-1) and interleukin-1 beta (IL-1β) in LPS group. SAC/VAL treatment, however reduced these increments. Conclusion, SAC/VAL can hinder sepsis-associated acute liver injury by inhibiting inflammation, oxidative stress, mitochondrial distortion, Kupffer cell hyperactivity and cellular pyroptosis.

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca²⁺ in excitation–contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.

Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.

Background and Aim: The use of Doxorubicin (Dox) to treat various tumors is limited by its cardiotoxicity. This study aimed to compare the cardioprotective potential of vitamin E versus liposomal-Dox against cardiotoxic effects on the structure of left ventricle.Materials and Methods: Fifty male albino Wistar rats (180-220g) were divided into control (I), Dox (II), vitamin E with Dox (III) and liposomal-Dox (IV) groups. Groups II, III and IV received Dox and liposomal-Dox (3mg/kg) at days 1, 3, 5, 7, 9 and 11. Group III received Vitamin E (100mg/kg) daily with Dox administration. At day 12, blood was collected and left ventricles were dissected and prepared for LM and EM study.Results: Serum lactate dehydrogenase, creatine phosphokinase and creatine kinase-MB increased by 2.5 folds in Dox-treated rats compared to control rats, but decreased in vitamin E and liposomal-Dox groups compared to Dox group. The maximal decrease was in liposomal-Dox group with values near to control. LM examination of left ventricle from Dox-group showed hemorrhagic areas between widely separated cardiomyocytes containing pyknotic nuclei. Inflammatory cells and adipocytes were seen in the interstitium. EM of Dox group showed variable sized mitochondria with ruptured cristae inbetween fragmented myofibrils. LM and EM examination of ventricles from vitamin E and liposomal-Dox groups showed mild changes with liposomal-Dox group appeared near to control. Left ventricular fiber diameter was decreased in Dox group compared to control group with nearly normal diameter in liposomal-Dox group. Area percent of collagen fibers increased and the optical density of desmin immune-expression was reduced in Dox group compared to control and liposomal-Dox groups which were alike.Conclusion: Dox-induced structural changes of rat ventricle were diminished by concomitant vitamin E intake. Liposomal-Dox administration-only- was more effective in reducing these changes; hence, it can accomplish a successful clinical target to decrease Dox-associated cardiotoxicity.