Doxorubicin-induced Rats Research Articles

Antioxidant Activity of Ethanol Extract of Puguntano Herb (Picria fel-terrae Lour.) and Effect on Superoxidase Dismutase and Lactate Dehydrogenase Levels in Doxorubicin-Induced Rats

Antioxidant Activity of Ethanol Extract of Puguntano Herb (Picria fel-terrae Lour.) and Effect on Superoxidase Dismutase and Lactate Dehydrogenase Levels in Doxorubicin-Induced Rats

Cardioprotective Effect of Hydroalcohol Extract of Andaliman (Zanthoxylum acanthopodium DC.) Fruits on Doxorubicin-Induced Rats.

Andaliman (Zanthoxylum acanthopodium DC.) fruit is a spice plant widely used in North Sumatra. The chemical content in the Andaliman plant has a cardioprotective effect, with antioxidant properties that inhibit oxidative stress and free radicals. SOD (superoxide dismutase), BNP (Brain Natriuretic Peptide), and cTnT (troponin T) are measured as markers of heart damage, and histopathology is to see heart damage. Quercetin administration was used as a comparison. The hydroalcoholic extract's phytochemical content and chemical elements were analyzed using LC-HRMS and GC-MS. The findings showed that the hydroalcohol extract of Andaliman fruits affected the blood levels of SOD, BNP, and cTnT in the blood of doxorubicin-induced rats. SOD levels increased, and BNP decreased; the 300 mg/kg BW group was not significantly different from the 50 mg/kg BW quercetin group. cTnT levels also decreased; the 150 mg/kg BW and 300 mg/kg BW groups were not significantly different, and both were better than the 50 mg/kg BW quercetin group. EAF with 150 mg/kg BW and 300 mg/kg BW can also repair damage to rat heart tissue caused by doxorubicin. Andaliman fruit extract has cardioprotective effects and anti-free radical activity due to its content and potential to be developed.

The Effect of Oral Andrographolide on Cardiac Biomarkers in Doxorubicin-induced Rats

The Effect of Oral Andrographolide on Cardiac Biomarkers in Doxorubicin-induced Rats

Moringa oleifera Leaves Extract Ameliorates Doxorubicin-Induced Cardiotoxicity via Its Mitochondrial Biogenesis Modulatory Activity in Rats.

Doxorubicin, an anthracycline class of anticancer, is an effective chemotherapeutic agent with serious adverse effects, mainly cardiotoxicity. Several possible causes of doxorubicin cardiotoxicity are increased oxidative stress, nucleic acid and protein synthesis inhibition, cardiomyocyte apoptosis, and mitochondrial biogenesis disruptions. Moringa oleifera (MO), a naturally derived medicine, is known for its antioxidative properties and activity in alleviating mitochondrial dysfunction. To determine the potency and possible cardioprotective mechanism of MO leaves aqueous extract via the mitochondrial biogenesis pathway in doxorubicin-induced rats. Twenty-four Sprague-Dawley rats were divided into four groups of six. The first group was normal rats; the second group was treated with doxorubicin 4 mg/kg BW intraperitoneally once weekly for four weeks; the third and fourth groups were treated with doxorubicin 4 mg/kg BW intraperitoneally once weekly, and MO leaves extract at 200 mg/kg BW or 400 mg/kg BW orally daily, for four weeks. At the end of the fourth week, blood and cardiac tissues were obtained and analyzed for cardiac biomarkers, mitochondrial DNA copy number, mRNA expressions of peroxisome-activated receptor-gamma coactivator-1 alpha (PGC-1α), the nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), caspase 3, the activity of glutathione peroxidase (GPx), levels of 8-hydroxy-2-deoxyguanosine (8-OH-dG), and malondialdehyde. MO leaves extract was shown to decrease biomarkers of cardiac damage (LDH and CK-MB), malondialdehyde levels, and GPx activity. These changes align with the reduction of mRNA expressions of caspase-3, the increase of mRNA expressions of PGC-1αand Nrf2, and the elevation of mitochondrial DNA copy number.MOleaves extracts did not influence the mRNA expressions of superoxide dismutase 2 (SOD2) or the levels of 8-OH-dG. Moringa oleifera leaves extract ameliorates doxorubicin-induced cardiotoxicity by reducing apoptosis and restoring gene expression of PGC-1α and Nrf2, a key regulator in mitochondrial biogenesis.

Effect of andaliman (Zanthoxylum acanthopodium DC.) ethanol extract on doxorubicin-induced toxicity on hematology in male rats

Introduction: Doxorubicin is one of the chemotherapy drugs that have harmful effects on blood hematology. Blood hematological diseases are caused by its adverse effects and anticancer properties. The antioxidant properties of several plants have been reported to be closely related to reduced toxicity in blood hematology. Andaliman (Zanthoxylum acanthopodium) ethanolic extract (AEE) is thought to reduce the toxicity of doxorubicin due to the antioxidant properties of its secondary metabolite content. This study aimed to determine the effect of AEE on doxorubicin-induced rats and its effect on blood cells. Materials and Method: A total of 24 male rats were divided into 6 groups: (1) Normal group; (2) 0.5% Na-CMC group; (3) 50 mg/kg BW quercetin group; (4) AEE 75 mg/kg BW group; (5) AEE 150 mg/kg BW group; and (6) AEE group 300 mg/kg BW administered orally for 9 days. On days 8 and 9, doxorubicin 10 mg/kg BW was administered. Rats were sacrificed for blood collection, and measured at the Integrated Laboratory of the USU Hospital. Results: AEE reduces the toxicity of doxorubicin on blood parameters. Furthermore, it affects Hb, white blood cells, platelet cells, monocytes, lymphocytes, neutrophils, and several related protein metabolisms as well as organ damage. Dose 150 or 300 mg/kg AEE reduce all blood toxins to near-normal levels and decrease the lymphocyte and neutrophil suppressive activity of doxorubicin. Conclusion: Andaliman ethanol extract can improve Hb count, white blood cells, platelet cells, monocytes, lymphocytes, neutrophils, protein metabolism, and organ damage. Furthermore, AEE can be used in combination with doxorubicin to reduce its hematological toxicity.
 Keywords: toxicity, hematology, doxorubicin, andaliman, Zanthoxylum acanthopodium, extract

18F]KS1, a novel ascorbate-based ligand images ROS in tumor models of rodents and nonhuman primates

Over production of reactive oxygen species (ROS) caused by altered redox regulation of signaling pathways is common in many types of cancers. While PET imaging is recognized as the standard tool for cancer imaging, there are no clinically-approved PET radiotracers for ROS-imaging in cancer diagnosis and treatment. An ascorbate-based radio ligand promises to meet this urgent need. Our laboratory recently synthesized [18F] KS1, a fluoroethoxy furanose ring-containing ascorbate derivative, to track ROS in prostate tumor-bearing mice. Here we report cell uptake assays of [18F]KS1 with different ROS-regulating agents, PET imaging in head and neck squamous cell carcinoma (HNSCC) mice, and doxorubicin-induced rats; PET imaging in healthy and irradiated hepatic tumor-bearing rhesus to demonstrate its translational potential. Our preliminary evaluations demonstrated that KS1 do not generate ROS in tumor cells at tracer-level concentrations and tumor-killing properties at pharmacologic doses. [18F]KS1 uptake was low in HNSCC pretreated with ROS blockers, and high with ROS inducers. Tumors in high ROS-expressing SCC-61 took up significantly more [18F]KS1 than rSCC-61 (low-ROS expressing HNSCC); high uptake in doxorubicin-treated rats compared to saline-treated controls. Rodent biodistribution and PET imaging of [18F]KS1 in healthy rhesus monkeys demonstrated its favorable safety, pharmacokinetic properties with excellent washout profile, within 3.0 h of radiotracer administration. High uptake of [18F]KS1 in liver tumor tissues of the irradiated hepatic tumor-bearing monkey showed target selectivity. Our strong data in vitro, in vivo, and ex vivo here supports the high translational utility of [18F]KS1 to image ROS.

Hepatoprotective Effectiveness Test of Salam Leaf Extract in Anthracyclin-Induced Rats

Cancer is the most often diagnosed disease in the world and the top cause of death. Doxorubicin is a widely used systemic therapy, although its efficacy is limited by dose-related toxicity, including haematological suppression, organotoxicity, and hepatotoxicity. Bay leaf is a commonly utilised plant in the community for treating and preventing many diseases because it includes secondary metabolites that are antioxidants such as phenolics, alkaloids, saponins, steroids, triterpenoids, and tannins. The purpose of this work is to characterise EEDS, identify its secondary metabolite content, and test its nephroprotective effect in doxorubicin-induced rats using SGPT and SGOT levels and liver histology. This is a laboratory experimental investigation using rats and comprises of treatment groups receiving 0.5% of CMC-Na, Nature E, or EEDS at doses of 100 mg/kgBW, 300 mg/kgBW, or 500 mg/kgBW, respectively, followed by doxorubicin. The results indicated that EEDS had 21.64 % water soluble material, 1.79 % total ash, 9.98 % water, 45.38 % ethanol soluble extract, and 0.39 % acid insoluble ash. EEDS included alkaloids, flavonoids, tannins, glycosides, saponins, and steroids/triterpenoids, as determined by phytochemical screening. EEDS doses of 100 mg/kgBW, 300 mg/kgBW, and 500 mg/kgBW can significantly lower SGPT by 34%; 52,46%; 59,31% and SGOT levels by 27,05%; 43,96%; 50,07% and can improve the liver histopathology of doxorubicin-induced rats by reducing pyknotic degeneration, inflammatory cell infiltration, bleeding, steatosis and sinusoidal dilatation with an effective dose of 500 mg/kgBW with a significant difference with the doxorubicin group followed by 0.5% CMC Na. The key to bay leaf ethanol extract has hepatoprotective activity.

Antioxidant activity and nephroprotective effect of Lansium parasiticum leaves in doxorubicin-induced rats

Antioxidant activity and nephroprotective effect of Lansium parasiticum leaves in doxorubicin-induced rats

The Effect of Salam Leaf Ethanol Extract on the Histopathology of Doxorubicin-Induced Rats and its Effectiveness in Protecting the Heart Compared with Positive Control (Vitamin E)

This study aims to determine the effect of bay leaf ethanol extract on the histopathological picture of the kidneys of rats induced by doxorubicin. To determine the administration of bay leaf ethanol extract is more effective in protecting the heart than the positive control (Vitamin E). The bay leaves used were obtained from the Harjosari II Medan Amplas area of Medan city. The independent variable in this study was Salam Leaf Ethanol Extract, while the dependent variable was kidney histopathology. This research was conducted at the Pharmacology and Toxicology Laboratory of the Faculty of Pharmacy, University of North Sumatra. The results showed that the administration of vitamin E together with doxorubicin showed a better renal histopathological picture. Vitamin E as a basic antioxidant is able to reduce the damage caused by doxorubicin which is seen in the absence of widening in the Bowman capsule.

The protective effect of Phyllanthus emblica Linn. extract against doxorubicin-induced hepatotoxicity in rats

Recently many researches have been carried out on Malacca fruit extract and its potential protective effect on in vivo organ toxicity. However, there is still no research on the protective effect of Malacca ( Phyllanthus emblica L.) fruit extract on induced hepatotoxicity of anticancer drugs, especially doxorubicin in rats. The objective of this study is to determine the potential protective effect of ethanol extract of Malacca fruit ( P. emblica L.) against doxorubicin-induced hepatotoxicity in rats. A preliminary phytochemical test was done followed by administration extract into doxorubicin-induced rats. Histological studies were carried out to observe the effect of the extract on liver tissue. Phytochemical test results show that the ethanol extract of Malacca fruit contains flavonoids, phenols, tannins, triterpenoids, terpenoids, and alkaloids. The increasing value of ALT and ALP of doxorubicin-induced liver tissue proved the toxicity in liver tissue caused by doxorubicin. The ethanol extract of P. emblica L . at dosage 200 mg/kg BW and dosage 400 mg/kg BW on doxorubicin-induced rats were successfully played as an antioxidant to decrease the ALT and ALPvalues and improve liver tissue doxorubicin-induced by normal hepatocytes more dominant than lysis and less mark of bleeding and congestion of blood vessels.

Effects of Ethanolic Extract of Curcuma Longa on Cardiac Biomarkers of Doxorubicin-Induced Rats

Cardiotoxicity is a condition where damages caused by toxic chemical exposure are observed in heart and blood vessels. Doxorubicin is the most common chemotherapy agents for various types of cancer therapy. However, doxorubicin is converted into doxorubicinol known to trigger cardiac disfunctions and release of several cardiac biomarkers, such as CK-MB and LDH. Turmeric is known to be an alternative medical treatment that has the effect of neutralizing oxidative stress. This study aimed to evaluate CK-MB and LDH levels in doxorubicin-induced rats (20 mg/kgbw) that received turmeric ethanolic extract from curcuma. This was an experimental study conducted in February 2020 in the Faculty of Pharmacy Universitas Sumatera Utara. The rats were divided into six group and each group consisted of wistar albino male rats. The groups were normal (CMC-Na), positive control (Vitamin E 1% + Dox 20 mg/kgbw), negative control (Dox 20 mg/kgbw), treatment I (EEC 100 mg/kgbw + Dox 20 mg/kgbw), treatment II (EEC 300 mg/kgbw + Dox 20 mg/kgbw), and treatment III (EEC 500 mg/kgbw + Dox 15 mg/kgbw). Doxorubicin was given 5 mg/kg BW once a week for four weeks. Results showed that the groups that received 100 mg/kg BW, 300 mg/kg BW, and 500 mg/kg BW of turmeric ethanol extract demonstrated a reducing effect on the biomarkers of cardiac damage, i.e. CK-MB and LDH. Statistically, serum CK-MB and LDH levels at dose 500 mg/kg BW showed no significant differences (p > 0.05) with the normal and positive treatment group. In conclusion, turmeric has a cardioprotective effect.

Short Communication: Stimulatory effect of Curcuma mangga on immune response against Staphylococcus aureus

Abstract. Yuandani, Nugraha SE, Laila L, Silaban SD, Ramadhani F. 2020. Short Communication: Stimulatory effect of Curcuma mangga on immune response against Staphylococcus aureus. Nusantara Bioscience 12: 109-113. Recently, the ethanol extract of Curcuma mangga Val. rhizomes were found to have immunomodulatory activity by enhancing phagocytic ability. This study was carried out to evaluate the effect of C. mangga rhizomes on antibody titer and delayed-type hypersensitivity response in normal and doxorubicin-induced rats against Staphylococcus aureus. The extract was administered orally at doses of 100, 200, and 400 mg/kg body weight (bw) to rats for 72 hours prior to sensitization of Staphylococcus aureus, then continued for 14 days. Doxorubicin (4.67 mg/kg bw) was administered on days 8 and 11 to suppress the immune system. The antibody titer of normal and immune-suppressed rats after the treatment with C. mangga ethanolic extract was significantly higher than the rats with negative control (P<0.05). Ethanol extract of C. mangga also demonstrated stimulation on delayed-type hypersensitivity response which was indicated by the increase of paw volume. The extract at dose of 400 mg/kg bw showed higher immunostimulatory activity than Levamisole as a positive control. The results indicated that the ethanol extract of C. mangga shows immunostimulatory activity, confirming its potential to be developed as a therapeutic agent.

Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) Modulates TCD4+ and TCD8+ Cell Profile of Doxorubicin-Induced Immuno-Suppressed Rats.

AIM:To evaluate the immunomodulatory effects of ethanolic extract of herb pugun tanoh on TCD4 and TCD8 cells in Doxorubicin-induced rats.METHODS:Fifteen male Sprague Dawley rats were divided into five groups consisting of six rats each as follows: Group 1, DOX-treated rats (4.67 mg/kg BW body weight on day 1 and 4) and were administered normal saline 0.9% orally once daily for 7 consecutive days, Group 2, receiving Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) of dose 150 mg/kg BW orally, Group 3, receiving dose Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) 300 mg/kg BW orally. The rats of group 2-3 were intramuscularly administered with doxorubicin at a dose of 4.67 mg/kg BW at the days 1-4 to suppress immune functions.RESULTS:Treatment of 300 mg/kg BW of Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) succeeded in reducing side effect doxorubicin based on increasing the TCD4+ and TCD8+ blood level.CONCLUSION:Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) could increase the level of TCD4+ and TCD8+ in rats which induced by doxorubicin.

Immunostimulant Effect of Garlic Chives Leaf Ethanolic Extract (Allium tuberosum) by Increasing Level of Antioxidant at Rats Doxorubicin-Induced Rats

Cancer is one of the leading causes of death in the world, approximately 14 million new cases and 8.2 million deaths each year. Doxorubicin is a well-known chemotherapy drug which frequently used in treating various types of cancer. However, doxorubicin posesses several side effects including cardiotoxic, hepatotoxic, nephrotoxic, and immunosuppression. One of the natural product that can be used as an adjuvant of doxorubicin to reduce the toxic effects is garlic chives (Allium tuberosum). The purpose of this study was to determine the effect of Allium tuberosum based on hematological profile, levels of CD4+, CD8+, and MDA serum of male Wistar rats which induced by doxorubicin. The hematological profile was analyzes by blood smear, levels of CD4+ and CD8+ were conducted by flowcytometry and levels of MDA serum were determined by spectrofotometry. The results showed that the etanolic extract of Allium tuberosum (EAT) increased neutrophil and lymphocyte, percentage of CD4+ cells (p<0.01) and CD8+ cells. It also decreased the levels of serum MDA (p<0.01). These results indicated that EAT work as immunostimulant possibly through an antioxidant mechanism (MDA). It can be concluded that EAT can be developed as adjuvant for doxorubicin.Keywords: doxorubicin, Allium tuberosum, immunostimulant, antioxidant, CD4+, CD8+

SMEDDS of Citrus hystrix ethanolic extract improves cardiac and hepar histopathology profile on doxorubicin-induced rats

Citrus hystrix D.C. (kaffir lime) peel contains several flavonoids including rutin, naringenin, hesperidin. C. hystrix peel ethanolic extract (ChEE) has shown its potency as cardioprotector agent in chemotherapy. However, there are limitations to the utilization of ChEE due to its poor water solubility and low oral bioavailability. Accordingly, self-microemulsifying drug delivery system (SMEDDS) formulations were developed to improve the oral absorption of flavonoids. Tween 80, Corn oil, and propylene glicol (5:1:1ml) were combined to form ChEE-SMEDDS. The present study is to evaluated ChEE-SMEDDS for their physicochemical properties and in vivo using combination with doxorubicin to see blood serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitrit oxide (NO) activity and also cardio-hepato-histopathology of female Sprague Dawley rats. The results showed that ChEE-SMEDDS repaired cardio-hepato-histopathology profile of doxorubicin -induced rats, but did not reduce serum activity of NO, ALT and AST. These results indicated that ChEE-SMEDDS has potency to be developed and improved as cardio-hepato-protector agent in chemotherapy.Keywords: Citrus hystrix D.C., SMEDDS, Cardio-hepatoprotector, Histopathology, Chemoterapy

Effects of Shenkangling intervention on the MAPK pathway in rats with doxorubicin-induced nephropathy.

Shenkangling plays a role of Yishenhuoxue effect for the treatment of children with nephrotic syndrome. The aim of this study was to investigate the effects of Shenkangling intervention on the mitogen-activated protein kinase (MAPK) pathway in rats with Adriamycin-induced nephropathy (AN) and its underlying mechanism of action. Nephrosis was induced in healthy Sprague-Dawley rats by doxorubicin and the rats were untreated or treated with prednisone, simvastatin, Shenkangling, or a combination thereof. Using real-time PCR, the mRNA expression levels of Chemokine (C-X-C motif) ligand 16 (CXCL16), A Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and ADAM17 in the renal tissues of these rats were found to be decreased by the various treatments compared to those in the untreated doxorubicin-induced nephrosis rats. To quantify the activation of the MAPK pathway, western blotting was used to detect the phosphorylation levels of MAPK pathway-associated proteins (p38, ERK1/2, SAPK/JNK) and nuclear factor (NF)-κB p65, which were reduced by the various treatments compared to those in the untreated doxorubicin-induced rats. Serum levels of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, quantified by ELISA, were decreased by the various treatments compared to the levels in the untreated doxorubicin-induced nephrosis rats. The rats treated with prednisone, simvastatin, and Shenkangling showed the best outcome. The Chinese medicine Shenkangling that is known for nourishing the kidney and promoting blood circulation reduced urinary protein levels, increased serum albumin levels, and reduced cholesterol levels by reducing the release of CXCL16, ADAM10, ADAM17, TGF-β1, TNF-α, IL-1β, IL- 6, and other inflammatory mediators and inhibiting the activation of the MAPK signaling pathway, thereby effectively improving the state of nephropathy in AN rats. These results indicate that Shenkangling can be used clinically to treat nephropathy.

Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity.

The clinical application of doxorubicin is limited by its cardiotoxicity. The present study investigated the effect of valsartan on doxorubicin-induced cardiotoxicity in rats. Rats were divided into 6 groups: control, control + valsartan (10 mg/kg, for 14 days, orally), doxorubicin-treated (2.5 mg/kg, 3 times/week for 2 weeks, intraperitoneally), valsartan then doxorubicin, valsartan + doxorubicin, and doxorubicin then valsartan. ECG, isolated heart, lipid peroxidation (thiobaribituric acid reactive substances (TBARS)), total antioxidant capacity (TAC), and Bax, Bcl-2, and senescence marker protein 30 (SMP30) gene expression were measured in cardiac tissue. Blood samples were collected to measure lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB). Doxorubicin significantly increased LDH, CK-MB, TBARS, heart rate (HR), Bax gene expression, and -dP/dtmax and decreased TAC, Bcl-2 and SMP30 gene expression, left ventricular developed pressure (LVDP), and +dP/dtmax. Also, doxorubicin lengthened ST, QT, and QTc intervals. Concurrent or post- but not pre-treatment of doxorubicin-treated rats with valsartan reduced LDH, CK-MB, TBARS, HR, Bax gene expression, -dP/dtmax, and ST, QT, and QTc intervals and increased TAC, Bcl-2 and SMP30 gene expression, LVDP, and +dP/dtmax. Therefore, we conclude that concurrent or post- but not pre-treatment of doxorubicin-induced rats with valsartan attenuated doxorubicin-induced cardiotoxicity through inhibiting oxidative stress, apoptosis, and senescence.

Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation

Context: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed.Objective: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation.Materials and methods: Male Sprague–Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-α), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels.Results: Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-α by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p < 0.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p > 0.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters.Discussion and conclusion: MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis.