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The effects of meldonium on the acute ischemia/reperfusion liver injury in rats.

ABSTRACT: Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, we investigated the effects of a 4-week meldonium pre-treatment (300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that meldonium ameliorates I/R-induced liver inflammation and injury, as confirmed by liver histology, and by attenuation of serum alanine- and aspartate aminotransferase activity, serum and liver high mobility group box 1 protein expression, and liver expression of Bax/Bcl2, haptoglobin, and the phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells. Through the increased hepatic activation of the nuclear factor erythroid 2-related factor 2, meldonium improves the antioxidative defence in the liver of animals subjected to I/R, as proved by an increase in serum and liver ascorbic/dehydroascorbic acid ratio, hepatic haem oxygenase 1 expression, glutathione and free thiol groups content, and hepatic copper-zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Based on our results, it can be concluded that meldonium represent a protective agent against I/R-induced liver injury, with a clinical significance in surgical procedures.

SUBMITTER: ?urasevic S

PROVIDER: S-EPMC7809046 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The effects of meldonium on the acute ischemia/reperfusion liver injury in rats.

Đurašević Siniša S Stojković Maja M Sopta Jelena J Pavlović Slađan S Borković-Mitić Slavica S Ivanović Anđelija A Jasnić Nebojša N Tosti Tomislav T Đurović Saša S Đorđević Jelena J Todorović Zoran Z

Scientific reports 20210114 1

Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, we investigated the effects of a 4-week meldonium pre-treatment (300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that meldonium ameliorates I/R-induced liver inflammation and injury, as confirmed by liver histology, and by a ...[more]

PMID: 33446709

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Project description:Introduction: Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this study was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Methods: Left renal ischemia was induced in rats by clamping renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n=8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (Saline) intraperitoneally. Animals were sacrificed at 3h, 24h or 120h post- IR and blood, urine and kidney were collected. Results: Serum creatinine (mg/dL) at 24 h IR in VPA (2.7±1.8) and Dex (2.3±1.2) was reduced (P<0.05) compared to Vehicle (3.8±0.5). At 3h post-IR, urine albumin (mg/ml) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to uninjured/untreated control (0.14±0.26) group. At 24h post-IR urine Lipocalin-2 (µg/ml) was significantly higher (P<0.05) in VPA, Dex and Vehicle groups (9.61-11.36) compared to uninjured/untreated control (0.67±o.29); also, Kidney Injury Molecule-1 (KIM-1; ng/ml) was significantly higher in VPA, Dex and Vehicle groups (13.7-18.7) compared uninjured/untreated control (1.7±1.9). KIM-1 levels were significantly (P<0.05) higher in all groups compared to uninjured/untreated control levels. Histopathology at 3h post IR demonstrated (P<0.05) reduction in ischemic injury in the renal cortex in VPA (Grade 1.6± 1.5) compared to Vehicle (Grade 2.9±1.1) group. Inflammatory cytokines IL1β and IL6 were down-regulated in VPA and Dex groups. BCL2 was higher in VPA group. DNA microarray analysis demonstrated reduced stress response and injury, and improved recovery related gene expression in the kidneys of VPA treated animals. Conclusions: VPA administration reduced kidney IR injury and improved regeneration. KIM-1 and Lipocalin-2 appear to be promising early urine biomarkers of acute ischemic kidney injury. We had three experimental groups. Group A, VPA treatment; Group B, Dexamethasone treatment; and Group C, No treatment (vehicle saline control). Treatments were administered prior to the induction of left renal ischemia. Animals underwent 45 minutes of left renal ischemia, followed by reperfusion, and right nephrectomy as described above. Following reperfusion, animals were sacrificed at 3, 24 or 120 hours (n=8/group). In the 3 hour group, rats were maintained under anesthesia after surgery until sacrifice. In the 24 and 120 hour groups, the rats were recovered and returned to the cages for normal housing. Analgesic buprenorphine (0.05mg/kg) was administered every 12 h for three days post-operatively. After animal sacrifice, urine, blood, and kidney were collected for kidney functional biomarker assays, histology and / or molecular analyses. Urine was obtained via cystocentesis and blood was obtained via the left renal vein. Tissue and urine samples collected from normal (naïve) animals (n=5) were used for baseline measurements. A subset of 46 animals (n = 4-5 per group) were selected for microarray analysis.

Project description:BACKGROUND:Ischemic stroke is a deadly disease that poses a serious threat to human life. Superoxide dismutase 3 (SOD3, ECSOD) is the main antioxidant enzyme that removes superoxide anions from cells. This study aimed to investigate the effect of SOD3 overexpression on cerebral ischemia-reperfusion injury in rats. METHODS:GV230-EGFP-ECSOD, the recombinant SOD3-overexpressed vector, was constructed by genetic engineering technology, and mesenchymal stem cells (MSCs) were infected with lentiviral packaging. In animal experiment, cerebral ischemia-reperfusion injury model rats were successfully established. ECSOD-MSCs are the MSCs that successfully transfected with SOD3 overexpression vector. The animals were injected with ECSOD-MSCs (ECSOD-MSC group), normal MSCs (MSCs group), PBS (PBS group), and not do any processing (Model group) via the tail vein. Then MRI was used to detect the infarct volume of rats, modified Neurological Severity Scores (mNSS), and immunohistochemistry were used to evaluate the expression of neurological function and apoptosis-related genes in rats. RESULTS:Western blot analysis revealed that the SOD3 was highly expressed in MSCs. Animal experiments showed that the transplantation of ECSOD-MSCs significantly reduced the infarct volume of ischemic stroke rats (p < 0.05), significantly improved neurological function in rats (p < 0.05), and found proapoptotic gene, Bax, expression was significantly decreased (p < 0.05), the expression of anti-apoptotic gene, Bcl-2, was significantly increased (p < 0.05). The highly expressed SOD3 has no correction with brain infarct volume, and the highly expressed SOD3 has a positive correlation with cell apoptosis. It is speculated that overexpression of SOD3 affects the expression of Bax and Bcl-2, and improves apoptosis to alleviate ischemic stroke. CONCLUSION:Our results indicated that MSCs transfected with SOD3 can effectively alleviate cerebral ischemia-reperfusion injury in rats.

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The effects of meldonium on the acute ischemia/reperfusion liver injury in rats.

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The effects of meldonium on the acute ischemia/reperfusion liver injury in rats.

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