Sacubitril/valsartan alleviates sepsis-induced myocardial injury in rats via dual angiotensin receptor-neprilysin inhibition and modulation of inflammasome/caspase 1/IL1ß pathway.

Sepsis is a life-threatening situation that ultimately affects cardiac function, leading to cardiomyopathy and myocardial injury as a result of uncontrolled response to infection.Till now, there is limited effective treatment to rescue those cases. Thus, novel therapeutic strategies should be identified to achieve better outcomes for septic patients. For the first time, we aimed to evaluate the effect of sacubitril/valsartan (Sac/Val) on sepsis-induced cardiac injury. Wistar male adult albino rats were randomly divided into four groups; Group I received the vehicle; Group II was given the vehicle plus 1 ml saline containing viable Escherichia coli (E. coli) (2.1 × 109 cfu) by intraperitoneal (i.p.) injection on the 1st and 2nd days; Group III received i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) and Nitro- ω-L-arginine (L-NNA) (25 mg/kg/day) for 7 days. Group IV was administered i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) for 7 days. Our data (n = 10) revealed successful induction of sepsis as it showed a significant increase in the measured cardiac enzymes, malondialdehyde (MDA), angiotensin II (Ang II), neprilysin, inflammasome, caspase 1, interleukin (IL)1ß, and caspase 3 with cardiac histopathological changes, but there was a significant decrease in the antioxidants and blood pressure (BP). Co-administration of Sac/Val could obviously improve these changes. Interestingly, L-NNA given group showed a decrease in the cardioprotective effect of Sac/Val. Sac/Val could ameliorate sepsis induced cardiac damage via inhibition of Ang II and neprilysin with anti-inflammatory, anti-oxidant and anti-apoptotic properties.

Sacubitril/valsartan protective effect on induced intestinal ischemia/reperfusion injury via immune modulation of IL6/STAT1 pathway.

OBJECTIVES: Intestinal ischemia reperfusion (IIR) is a critical emergency situation that needs immediate intervention. Small intestine is one of the most sensitive tissues to IR injury and it remains a highly morbid condition, with reported mortality rates ranging from 30% to 90%. Thus, we aimed to evaluate the suspected protective role of sacubitril/valsartan (SAC/VAL) on IIR injury. METHODS: Thirty-two adult male Wistar rats were used in our model and divided into four groups: sham group, SAC/VAL treated group without IIR, IIR group, and SAC/VAL treated group with IIR. SAC/VAL in a dose of 30 mg/kg was administered orally just before induction of IIR. KEY FINDINGS: SAC/VAL significantly ameliorated IIR-induced changes as it decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), angiotensin II (ANG II), interleukin 6 (IL 6), active caspase 3, and signal transducer- and activator-of transcription (STAT1). However, SAC/VAL administration significantly increased antioxidant parameters such as total antioxidant capacity (TAC), superoxide dismutase (SOD), and reduced glutathione (GSH). Moreover, alteration of the histological structure was observed in IIR group that was improved by SAC/VAL. CONCLUSIONS: SAC/VAL prevents IIR-induced damage via modulation of renin angiotensin aldosterone system, antioxidant, anti-apoptotic, anti-inflammatory properties, and regulation of IL6/STAT1 pathway.

Molecular mechanism of empagliflozin cardioprotection in 5-fluorouracil (5-FU)-induced cardiotoxicity via modulation of SGLT2 and TNFα/TLR/NF-κB signaling pathway in rats.

One of the commoly used chemotherapeutic agents is 5-Fluorouracil (5-FU). Unfortunately, the clinical administration of 5-FU is complicated with serious cardiotoxic effects and the safe use becomes an urgent task in cardio-oncology. Till now, there are no studies discussed the role of empagliflozin (EMP) against 5-FU cardiotoxicity. Thus, we investigated this effect and the involved mechanisms in 5-FU induced heart injury. Forty male rats of Wistar albino species were used and divided randomly into four groups. Group I is the control group, group II is EMP given group, group III is 5-FU cardiotoxic group and group IV is 5-FU plus EMP group. 5-FU (150 mg/kg) was administered as a single intraperitoneal (i.p.) dose on 1st day to induce cardiotoxicity with or without EMP (30 mg/kg/d) orally for 5 days. The dose of 5-FU is relevant to the human toxic dose. Our data showed that 5-FU given group caused cardiotoxicity with significant increase of serum cardiac enzymes, toll like receptors, enhancement of nuclear factor kappa B (NF-κB), interleukin1ß (IL1ß), IL6, myeloid-differentiation-factor 88 (MYD88), heart weight, malondialdehyde (MDA), tumor-necrosis-factor-alpha (TNFα), sodium glucose co-transporter 2 (SGLT2), P53 and caspase3 expression with clear histopathological features of cardiotoxicity. Moreover, there is a significant decrease in reduced glutathione (GSH) and total antioxidant capacity (TAC). Interestingly, co-administration of EMP could ameliorate 5-FU induced biochemical and histopathological changes. This effect may be due to modulation of SGLT2, decreasing inflammation, oxidative stress and apoptosis with downregulation of an essential inflammatory cascade that mediates 5-FU cardiotoxicity; TNFα/TLR/NF-κB. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00204-1.

Molecular mechanisms mediate roflumilast protective effect against isoprenaline-induced myocardial injury.

BACKGROUND: Myocardial necrosis is one of the most common cardiac and pathological diseases. Unfortunately, using the available medical treatment is not sufficient to rescue the myocardium. So that, we aimed in our model to study the possible cardioprotective effect of roflumilast (ROF) in an experimental model of induced myocardial injury using a toxic dose of isoprenaline (ISO) and detecting the role of vascular endothelial growth factor/endothelial nitric oxide synthase (VEGF/eNOS) and cyclic guanosine monophosphate/cyclic adenosine monophosphate/ sirtuin1 (cGMP/cAMP/SIRT1) signaling cascade. MATERIALS AND METHODS: Animals were divided into five groups; control, ISO given group (150 mg/kg) i.p. on the 4th and 5th day, 3 ROF co-administered groups in different doses (0.25, 0.5, 1 mg/kg/day) for 5 days. RESULTS: Our data revealed that ISO could induce cardiac toxicity as manifested by significant increases in troponin I, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and cleaved caspase-3 with toxic histopathological changes. Meanwhile, there were significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, eNOS, cGMP, cAMP and SIRT1. However, co-administration of ROF showed significant improvement and normalization of ISO induced cardiac damage. CONCLUSION: We concluded that ROF successfully reduced ISO induced myocardial injury and this could be attributed to modulation of PDE4, VEGF/eNOS and cGMP/cAMP/SIRT1 signaling pathways with antioxidant, anti-inflammatory, and anti-apoptotic properties.