alamandine and Inflammation

Doxorubicin (DOX) is an anthracycline antibiotic. Despite its unwanted side effects, it has been successfully used in tumor therapy. Given that oxidative stress and inflammatory factors are essential to cardiotoxicity caused by DOX, we assumed that alamandine, which enhances endogenous antioxidants and has anti-inflammatory effects, may prevent DOX-induced cardiotoxicity. Rats received DOX (3.75 mg/kg) i.p on days 14, 21, 28, and 35 (total cumulative dose = 15 mg/kg) and alamandine (50 μg/kg/day) via mini-osmotic pumps for 42 days. At the end of the 42-day period, we evaluated hemodynamic parameters, electrocardiogram, cardiac troponin I (cTnI), superoxidase dismutase (SOD), total antioxidant capacity (TAC), malondialdehyde (MDA), inflammatory cytokines (tumor necrosis factor-α (TNF-α), IL-1β, NF-κB), apoptosis markers (caspase 3), and histopathology of haemotoxylin- and eosin-stained cardiac muscle fibers were evaluated. DOX significantly increased QT, corrected QT (QTc), and RR intervals. Alamandine co-therapy prevented ECG changes. Alamandine administration restored DOX-induced disruptions in the cardiac muscle architecture and vascular congestion. Alamandine co-therapy also alleviated other effects of DOX, including cardiac contractility, decreased systolic and diastolic blood pressure, and increased left ventricular end-diastolic pressure. Moreover, alamandine co-therapy substantially decreased the elevation of oxidative stress markers, inflammatory cytokines, and caspase 3 in DOX-treated rats. The results suggest that alamandine reduced DOX-induced cardiotoxicity via antioxidant, anti-inflammatory, and anti-apoptotic activities.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Biomarkers; Cytokines; Doxorubicin; Gene Expression Regulation; Heart Diseases; Inflammation; Male; Oligopeptides; Random Allocation; Rats; Rats, Sprague-Dawley

This study was to determine whether alamandine (Ala) could reduce ischaemia and reperfusion (I/R) injury of kidney in rats.. Renal I/R was induced by an occlusion of bilateral renal arteries for 70 min and a 24-h reperfusion in vivo, and rat kidney proximal tubular epithelial cells NRK52E were exposed to 24 h of hypoxia and followed by 3-h reoxygenation (H/R) in vitro.. The elevated serum creatinine (Cr), blood cystatin C (CysC) and blood urea nitrogen (BUN) levels in I/R rats were inhibited by Ala treatment. Tumour necrosis factor alpha (TNF)-α, IL-1β, IL-6, cleaved caspase-3, cleaved caspase-8 and Bax were increased, and Bcl2 was reduced in the kidney of I/R rats, which were reversed by Ala administration. Ala reversed the increase of TNF-α, IL-1β, IL-6, cleaved caspase-3, cleaved caspase-8 and Bax and the decrease of Bcl2 in the H/R NRK52E cells. Ala could also inhibit the increase of oxidative stress levels in the kidney of I/R rats. NADPH oxidase 1 (Nox1) overexpression reversed the improving effects of Ala on renal function, inflammation and apoptosis of I/R rats.. These results indicated that Ala could improve renal function, attenuate inflammation and apoptosis in the kidney of I/R rats via inhibiting oxidative stress.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 8; Cell Line; Disease Models, Animal; Inflammation; Interleukin-1beta; Interleukin-6; Ischemia; Kidney; Kidney Tubules, Proximal; Male; NADPH Oxidase 1; Oligopeptides; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Sepsis is a frequent cause of kidney injury. The present study investigated whether Alamandine (Ala) could alleviate sepsis-associated renal injury by reducing inflammation and apoptosis. In addition, we investigated downstream signaling pathways modulated by Ala. Studies were performed in mice treated with lipopolysaccharide (LPS) and in the human proximal tubular epithelial cell line HK-2. The increase in serum creatinine, blood urea nitrogen, cystatin C and Fg, and neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in the kidneys of mice treated with LPS were reduced after administration of Ala. Exposure to LPS increased interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) in mice and HK-2 cells, but were reduced after Ala treatment. Furthermore, increased levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9, cleaved poly (ADP-ribose) polymerase (PARP) and Bax and reduced levels of Bcl2 in LPS-treated mice and HK-2 cells were reversed after Ala administration. In addition, LPS increased the levels of p-PI3K/PI3K, p-Akt/Akt, p-ERK/ERK, p-JNK/JNK, p-p38/p38 and p-FoxO1 in HK-2 cells, and all were reversed after Ala administration. These results indicate that Ala could improve renal function and inhibit inflammation and apoptosis in LPS induced sepsis mouse models. We demonstrated that Ala attenuated LPS induced sepsis by inhibiting the PI3K/Akt and MAPK signaling pathways.

Topics: Angiotensin I; Animals; Apoptosis; Cell Line; Dose-Response Relationship, Drug; Humans; Inflammation; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Oligopeptides; Peptide Fragments; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sepsis; Signal Transduction