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Magnolia bioactive constituent 4-O-methylhonokiol prevents the impairment of cardiac insulin signaling and the cardiac pathogenesis in high-fat diet-induced obese mice.

Zhang Z, Chen J, Zhou S, Wang S, Cai X, Conklin DJ, Kim KS, Kim KH, Tan Y, Zheng Y, Kim YH, Cai L - Int. J. Biol. Sci. (2015)

Bottom Line: Mechanistically, MH treatment significantly reduced HFD-induced impairment of cardiac insulin signaling by preferentially augmenting Akt2 signaling.The increased Nrf2 signaling was associated with decreased oxidative stress and damage, as reflected by lowered malondialdehyde and 3-nitrotyrosine levels.Furthermore, MH reduced HFD-induced cardiac lipid accumulation along with lowering expression of cardiac fatty acid translocase/CD36 protein.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Cardiology at the First Hospital of Jilin University, Changchun, 130021, China ; 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.

ABSTRACT
In obesity, cardiac insulin resistance is a putative cause of cardiac hypertrophy and dysfunction. In our previous study, we observed that Magnolia extract BL153 attenuated high-fat-diet (HFD)-induced cardiac pathogenic changes. In this study, we further investigated the protective effects of the BL153 bioactive constituent, 4-O-methylhonokiol (MH), against HFD-induced cardiac pathogenesis and its possible mechanisms. C57BL/6J mice were fed a normal diet or a HFD with gavage administration of vehicle, BL153, or MH (low or high dose) daily for 24 weeks. Treatment with MH attenuated HFD-induced obesity, as evidenced by body weight gain, and cardiac pathogenesis, as assessed by the heart weight and echocardiography. Mechanistically, MH treatment significantly reduced HFD-induced impairment of cardiac insulin signaling by preferentially augmenting Akt2 signaling. MH also inhibited cardiac expression of the inflammatory factors tumor necrosis factor-α and plasminogen activator inhibitor-1 and increased the phosphorylation of nuclear factor erythroid-derived 2-like 2 (Nrf2) as well as the expression of a Nrf2 downstream target gene heme oxygenase-1. The increased Nrf2 signaling was associated with decreased oxidative stress and damage, as reflected by lowered malondialdehyde and 3-nitrotyrosine levels. Furthermore, MH reduced HFD-induced cardiac lipid accumulation along with lowering expression of cardiac fatty acid translocase/CD36 protein. These results suggest that MH, a bioactive constituent of Magnolia, prevents HFD-induced cardiac pathogenesis by attenuating the impairment of cardiac insulin signaling, perhaps via activation of Nrf2 and Akt2 signaling to attenuate CD36-mediated lipid accumulation and lipotoxicity.

No MeSH data available.


Related in: MedlinePlus

Effects of MH on HFD-induced oxidative stress and damage in heart tissue. (A) Lipid peroxidation in heart tissue was measured by a thiobarbituric acid reactive substances (TBARS) assay (TBARS was equivalent to MDA). (B, C) The levels of reactive nitrogen stress were measured by 3-nitrotyosine (3-NT) in ND-fed mice (B) and HFD-fed mice (C) with western blotting. (D, E) The levels of phosphorylated p-Nrf2 were measured in ND-fed mice (D) and HFD-fed mice (E) by western blotting. (F) mRNA expression of HO-1, as the target gene of p-Nrf2, was measured by real-time RT-PCR. Data are presented as means ± SD (n=5). a, p<0.05 vs. ND; b, p< 0.05 vs. HFD
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Figure 4: Effects of MH on HFD-induced oxidative stress and damage in heart tissue. (A) Lipid peroxidation in heart tissue was measured by a thiobarbituric acid reactive substances (TBARS) assay (TBARS was equivalent to MDA). (B, C) The levels of reactive nitrogen stress were measured by 3-nitrotyosine (3-NT) in ND-fed mice (B) and HFD-fed mice (C) with western blotting. (D, E) The levels of phosphorylated p-Nrf2 were measured in ND-fed mice (D) and HFD-fed mice (E) by western blotting. (F) mRNA expression of HO-1, as the target gene of p-Nrf2, was measured by real-time RT-PCR. Data are presented as means ± SD (n=5). a, p<0.05 vs. ND; b, p< 0.05 vs. HFD

Mentions: Animal studies have shown that HFD-induced obesity increases oxidative stress 15. Here we found that HFD feeding significantly increased oxidative stress in the heart tissue as demonstrated by increased levels of MDA (TBARS assay, Fig. 4A) and 3-NT (Fig. 4C). Both MH and BL153 significantly reduced the endogenous (basal) and HFD-induced levels of MDA (Fig. 4A) and 3-NT (Fig. 4B,C).


Magnolia bioactive constituent 4-O-methylhonokiol prevents the impairment of cardiac insulin signaling and the cardiac pathogenesis in high-fat diet-induced obese mice.

Zhang Z, Chen J, Zhou S, Wang S, Cai X, Conklin DJ, Kim KS, Kim KH, Tan Y, Zheng Y, Kim YH, Cai L - Int. J. Biol. Sci. (2015)

Effects of MH on HFD-induced oxidative stress and damage in heart tissue. (A) Lipid peroxidation in heart tissue was measured by a thiobarbituric acid reactive substances (TBARS) assay (TBARS was equivalent to MDA). (B, C) The levels of reactive nitrogen stress were measured by 3-nitrotyosine (3-NT) in ND-fed mice (B) and HFD-fed mice (C) with western blotting. (D, E) The levels of phosphorylated p-Nrf2 were measured in ND-fed mice (D) and HFD-fed mice (E) by western blotting. (F) mRNA expression of HO-1, as the target gene of p-Nrf2, was measured by real-time RT-PCR. Data are presented as means ± SD (n=5). a, p<0.05 vs. ND; b, p< 0.05 vs. HFD
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495406&req=5

Figure 4: Effects of MH on HFD-induced oxidative stress and damage in heart tissue. (A) Lipid peroxidation in heart tissue was measured by a thiobarbituric acid reactive substances (TBARS) assay (TBARS was equivalent to MDA). (B, C) The levels of reactive nitrogen stress were measured by 3-nitrotyosine (3-NT) in ND-fed mice (B) and HFD-fed mice (C) with western blotting. (D, E) The levels of phosphorylated p-Nrf2 were measured in ND-fed mice (D) and HFD-fed mice (E) by western blotting. (F) mRNA expression of HO-1, as the target gene of p-Nrf2, was measured by real-time RT-PCR. Data are presented as means ± SD (n=5). a, p<0.05 vs. ND; b, p< 0.05 vs. HFD
Mentions: Animal studies have shown that HFD-induced obesity increases oxidative stress 15. Here we found that HFD feeding significantly increased oxidative stress in the heart tissue as demonstrated by increased levels of MDA (TBARS assay, Fig. 4A) and 3-NT (Fig. 4C). Both MH and BL153 significantly reduced the endogenous (basal) and HFD-induced levels of MDA (Fig. 4A) and 3-NT (Fig. 4B,C).

Bottom Line: Mechanistically, MH treatment significantly reduced HFD-induced impairment of cardiac insulin signaling by preferentially augmenting Akt2 signaling.The increased Nrf2 signaling was associated with decreased oxidative stress and damage, as reflected by lowered malondialdehyde and 3-nitrotyrosine levels.Furthermore, MH reduced HFD-induced cardiac lipid accumulation along with lowering expression of cardiac fatty acid translocase/CD36 protein.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Cardiology at the First Hospital of Jilin University, Changchun, 130021, China ; 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.

ABSTRACT
In obesity, cardiac insulin resistance is a putative cause of cardiac hypertrophy and dysfunction. In our previous study, we observed that Magnolia extract BL153 attenuated high-fat-diet (HFD)-induced cardiac pathogenic changes. In this study, we further investigated the protective effects of the BL153 bioactive constituent, 4-O-methylhonokiol (MH), against HFD-induced cardiac pathogenesis and its possible mechanisms. C57BL/6J mice were fed a normal diet or a HFD with gavage administration of vehicle, BL153, or MH (low or high dose) daily for 24 weeks. Treatment with MH attenuated HFD-induced obesity, as evidenced by body weight gain, and cardiac pathogenesis, as assessed by the heart weight and echocardiography. Mechanistically, MH treatment significantly reduced HFD-induced impairment of cardiac insulin signaling by preferentially augmenting Akt2 signaling. MH also inhibited cardiac expression of the inflammatory factors tumor necrosis factor-α and plasminogen activator inhibitor-1 and increased the phosphorylation of nuclear factor erythroid-derived 2-like 2 (Nrf2) as well as the expression of a Nrf2 downstream target gene heme oxygenase-1. The increased Nrf2 signaling was associated with decreased oxidative stress and damage, as reflected by lowered malondialdehyde and 3-nitrotyrosine levels. Furthermore, MH reduced HFD-induced cardiac lipid accumulation along with lowering expression of cardiac fatty acid translocase/CD36 protein. These results suggest that MH, a bioactive constituent of Magnolia, prevents HFD-induced cardiac pathogenesis by attenuating the impairment of cardiac insulin signaling, perhaps via activation of Nrf2 and Akt2 signaling to attenuate CD36-mediated lipid accumulation and lipotoxicity.

No MeSH data available.


Related in: MedlinePlus