Life sciences · 2023
LCZ696 attenuates sepsis-induced liver dysfunction in rats; the role of oxidative stress, apoptosis, and JNK1/2-P38 signaling pathways.
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Mohyeldin Reham H, Alaaeldin Rania, Sharata Ehab E, Attya Mina Ezzat, Elhamadany Eyad Y, Fathy Moustafa
Аннотация
AIM: Sepsis is a serious inflammatory response to infection with an annual incidence rate of >48 million cases and 11 million fatalities worldwide. Furthermore, sepsis remains the world's fifth-greatest cause of death. For the first time, the current study aims to evaluate the possible hepatoprotective benefits of LCZ696, a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor prodrug (sacubitril), on cecal ligation and puncture (CLP)-induced sepsis in rats.
MAIN METHODS: CLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined.
KEY FINDINGS: CLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1β, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone.
SIGNIFICANCE: LCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis.
MAIN METHODS: CLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined.
KEY FINDINGS: CLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1β, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone.
SIGNIFICANCE: LCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis.