Dibenzoylmethane ameliorates lipid-induced inflammation and oxidative injury in diabetic nephropathy

in Journal of Endocrinology
Correspondence should be addressed to C H Chung: cchung@yonsei.ac.kr
Restricted access

48-hour access to this article

USD $30.00

Dibenzoylmethane (DBM) is a beta-diketone analog of curcumin. Numerous studies have shown the beneficial effects of curcumin on diabetes, obesity and diabetic complications including diabetic nephropathy. Recently, we investigated the beneficial metabolic effects of DBM on high-fat diet-induced obesity. However, the effects and mechanisms of action of DBM in the kidney are currently unknown. To investigate the renoprotective effects of DBM in type 2 diabetes, we administered DBM (100 mg/kg) orally for 12 weeks to high-fat diet-induced diabetic model mice. We used mouse renal mesangial (MES13) and macrophage (RAW 264.7) cells to examine the mechanism of action of DBM (20 μM). After DBM treatment, the albumin-to-creatinine ratio was significantly decreased compared to that of the high-fat-diet group. Moreover, damaged renal ultra-structures and functions including increased glomerular volume, glomerular basement membrane thickness and inflammatory signals were ameliorated after DBM treatment. Stimulation of MES13 and RAW264.7 cells by palmitate or high-dose glucose with lipopolysaccharides increased inflammatory signals and macrophage migration. However, these changes were reversed by DBM treatment. In addition, DBM inhibited NADPH oxidase 2 and 4 expression and oxidative DNA damage. Collectively, these data suggested that DBM prevented diabetes-induced renal injury through its anti-inflammatory and antioxidant effects.


An official journal of

Society for Endocrinology



  • View in gallery

    Chemical structures of curcumin and dibenzoylmethane (DBM).

  • View in gallery

    Changes in number of high-fat diet (HFD)-induced crown-like structures in white adipose tissue and levels of renal triglycerides caused by dibenzoylmethane (DBM) administration. (A) H&E staining of white adipose tissue. (B) Measurement of adipocyte sizes. (C) Renal TG levels were measured by converting TG to glycerol. (D) Renal p-AMPK and p-ACC levels were analyzed using western blotting. Arrow, crown-like structures; DBM, HFD plus dibenzoylmethane; H&E, hematoxylin and eosin; HFD, high-fat diet group; ND, normal diet group; TG, triglycerides; WAT, white adipose tissue. aP < 0.05 compared with the ND group; bP < 0.05 compared with HFD group. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

  • View in gallery

    Effects of dibenzoylmethane (DBM) on high-fat diet (HFD)-induced diabetic nephropathy (DN). (A) Albumin-to-creatinine ratio (ACR) was measured in urine over a 24-h collection period. (B) Glomerular expansion was analyzed using H&E staining of renal glomeruli and renal ultrastructure was analyzed using transmission electron microscopy (TEM). Changes in glomerular volumes (C), slit pore numbers (D and E) and GBM thickness (D and F) were determined. ACR, albumin/creatinine ratio; DBM, HFD plus dibenzoylmethane; GBM, glomerular basement membrane; HFD, high-fat diet group; ND, normal diet group. aP < 0.05 compared with the ND group; bP < 0.05 compared with HFD group. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

  • View in gallery

    Effects of dibenzoylmethane (DBM) on macrophage infiltration and inflammatory signals in the kidney. Renal nephrin, CD68, and arginase 2 levels were analyzed using western blotting and quantified (A). Renal MCP1 mRNA level was quantified using qPCR (B). Immunohistochemical staining of the MCP1 (C), F4/80 and CD11c (D). p-AMPK and inflammatory signals, including p-p38 and p-IKKβ, were detected by western blotting in the kidney and quantified (E). AMPK, AMP-activated protein kinase; DBM, HFD plus dibenzoylmethane; HFD, high-fat diet group; ND, normal diet group; qPCR, quantitative polymerase chain reaction. aP < 0.05 compared with the ND group; bP < 0.05 compared with HFD group. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

  • View in gallery

    AMP-activated protein kinase (AMPK) activation by dibenzoylmethane (DBM) and curcumin. (A) Comparison of effects of curcumin and DBM on AMPK activation in NRK-52E cells. (B) DBM dose-dependently activated p-AMPK. (C) Changes in p-AMPK expression induced by high-glucose (HG), compound C, or both in the presence or absence of DBM. (D) PA-induced inflammatory signals (IkB and p-NFkB p65) in MES-13 cells caused by DBM treatment. (E) LPS-induced macrophage migration was affected by DBM treatment. (F) p-IKK, IkB, and p-NFkB p65 levels were changed by CM and changes were reversed by DBM treatment. CM, Raw 264.7 cultured medium with LPS; DBM, dibenzoylmethane; HG, high-glucose, 30 mM glucose in DMEM; LG, low-glucose, 5.5 mM glucose in DMEM; LPS, lipopolysaccharide; PA, palmitate. aP < 0.05 compared with LG; bP < 0.05 compared with HG. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

  • View in gallery

    Antioxidant effects of dibenzoylmethane (DBM). (A) Oxidative DNA damage marker, 8-OHdG, showed staining in glomeruli. (B) Changes in Nrf2/HO-1 expression by DBM in HG and LPS-stimulated MES-13 cells. (C and D) NOX2 and NOX4 protein and mRNA expressions change by DBM treatment in HG with LPS-stimulated MES-13. 8-OHdG, 8-hydroxy-2′-deoxyguanosine; DBM, dibenzoylmethane; HG, high-glucose, 30 mM glucose in DMEM; LG, low-glucose, 5.5 mM glucose in DMEM; LPS, lipopolysaccharide. aP < 0.05 compared with LG; bP < 0.05 compared with HG. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

  • View in gallery

    Schematic presentation of effects of dibenzoylmethane (DBM) on diabetic nephropathy (DN) in mouse model of high-fat diet (HFD)-induced diabetes. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.


AnandPKunnumakkaraABNewmanRAAggarwalBB 2007 Bioavailability of curcumin: problems and promises. Molecular Pharmaceutics 4 807818. (https://doi.org/10.1021/mp700113r)

AnandPSungBKunnumakkaraABRajasekharanKNAggarwalBB 2011 Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analoguesdibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: role of Michael acceptors and Michael donors. Biochemical Pharmacology 82 19011909. (https://doi.org/10.1016/j.bcp.2011.09.001)

DeshmaneSLKremlevSAminiSSawayaBE 2009 Monocyte chemoattractant protein-1 (MCP-1): an overview. Journal of Interferon and Cytokine Research 29 313326. (https://doi.org/10.1089/jir.2008.0027)

EardleyKSZehnderDQuinklerMLepeniesJBatesRLSavageCOHowieAJAduDCockwellP 2006 The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney International 69 11891197. (https://doi.org/10.1038/sj.ki.5000212)

Eun LeeJKimJELeeMHSongHKGheeJYKangYSMinHSKimHWChaJJHanJYet al. 2016 DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury. Laboratory Investigation 96 547560. (https://doi.org/10.1038/labinvest.2016.34)

HallowsKRMountPFPastor-SolerNMPowerDA 2010 Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. American Journal of Physiology-Renal Physiology 298 F1067F1077. (https://doi.org/10.1152/ajprenal.00005.2010)

HeHJWangGYGaoYLingWHYuZWJinTR 2012 Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World Journal of Diabetes 3 94104. (https://doi.org/10.4239/wjd.v3.i5.94)

HoCHsuYCLeiCCMauSCShihYHLinCL 2016 Curcumin rescues diabetic renal fibrosis by targeting superoxide-mediated wnt signaling pathways. American Journal of the Medical Sciences 351 286295. (https://doi.org/10.1016/j.amjms.2015.12.017)

JacksonKMDeLeonMVerretCRHarrisWB 2002 Dibenzoylmethane induces cell cycle deregulation in human prostate cancer cells. Cancer Letters 178 161165. (https://doi.org/10.1016/S0304-3835(01)00844-8)

JeongHWHsuKCLeeJWHamMHuhJYShinHJKimWSKimJB 2009 Berberine suppresses proinflammatory responses through AMPK activation in macrophages. American Journal of Physiology-Endocrinology and Metabolism 296 E955E964. (https://doi.org/10.1152/ajpendo.90599.2008)

KeaneyJFJrLarsonMGVasanRSWilsonPWLipinskaICoreyDMassaroJMSutherlandPVitaJABenjaminEJet al. 2003 Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arteriosclerosis Thrombosis and Vascular Biology 23 434439. (https://doi.org/10.1161/01.ATV.0000058402.34138.11)

KhorTOYuSBarveAHaoXHongJLLinWFosterBHuangMTNewmarkHLKongAN 2009 Dietary feeding of dibenzoylmethane inhibits prostate cancer in transgenic adenocarcinoma of the mouse prostate model. Cancer Research 69 70967102. (https://doi.org/10.1158/0008-5472.CAN-09-0597)

KimJKwakHJChaJYJeongYSRheeSDKimKRCheonHG 2014 Metformin suppresseslipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. Journal of Biological Chemistry 289 2324623255. (https://doi.org/10.1074/jbc.M114.577908)

KimNKimHMLeeESLeeJOLeeHJLeeSKMoonJWKimJHKimJKKimSJet al. 2015 Dibenzoylmethane exerts metabolic activity through regulation of AMP-activated protein kinase (AMPK)-mediated glucose uptake and adipogenesis pathways. PLoS ONE 10 e0120104. (https://doi.org/10.1371/journal.pone.0120104)

KimBHLeeESChoiRNawabootJLeeMYLeeEYKimHSChungCH 2016 Protective effects of curcumin on renal oxidative stress and lipid metabolism in a rat model of type 2diabetic nephropathy. Yonsei Medical Journal 57 664673. (https://doi.org/10.3349/ymj.2016.57.3.664)

KoderaRShikataKTakatsukaTOdaKMiyamotoSKajitaniNHirotaDOnoTUsuiHKMakinoH 2014 Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes. Biochemical and Biophysical Research Communications 443 828833. (https://doi.org/10.1016/j.bbrc.2013.12.049)

LuMYinNLiuWCuiXChenSWangE 2017 Curcumin ameliorates diabetic nephropathy by suppressing NLRP3 inflammasome signaling. BioMed Research International 2017 1516985. (https://doi.org/10.1155/2017/1516985)

MaithilikarpagaselviNSridharMGSwaminathanRPSripradhaR 2016 Preventive effect of curcumin on inflammation, oxidative stress and insulin resistance in high-fat fed obese rats. Journal of Complementary and Integrative Medicine 13 137143. (https://doi.org/10.1515/jcim-2015-0070)

McArdleMAFinucaneOMConnaughtonRMMcMorrowAMRocheHM 2013 Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. Frontiers in Endocrinology 4 52. (https://doi.org/10.3389/fendo.2013.00052)

MezzanoSArosCDroguettABurgosMEArdilesLFloresCSchneiderHRuiz-OrtegaMEgidoJ 2004 NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrology Dialysis Transplantation 19 25052512. (https://doi.org/10.1093/ndt/gfh207)

MillerEJLiJLengLMcDonaldCAtsumiTBucalaRYoungLH 2008 Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451 578582. (https://doi.org/10.1038/nature06504)

NguyenDPingFMuWHillPAtkinsRCChadbanSJ 2006 Macrophage accumulation in human progressive diabetic nephropathy. Nephrology 11 226231. (https://doi.org/10.1111/j.1440-1797.2006.00576.x)

NistalaRHabibiJLastraGManriqueCAroorARHaydenMRGarroMMeuthAJohnsonMWhaley-ConnellAet al. 2014 Prevention of obesity-induced renal injury in male mice by DPP4 inhibition. Endocrinology 155 22662276. (https://doi.org/10.1210/en.2013-1920)

PanYZhangXWangYCaiLRenLTangLWangJZhaoYLiuQet al. 2013a Targeting JNK by a new curcumin analog to inhibit NF-kB-mediated expression of cell adhesion molecules attenuates renal macrophage infiltration and injury in diabetic mice. PLoS ONE 8 e79084. (https://doi.org/10.1371/journal.pone.0079084)

PanYZhuGWangYCaiLCaiYHuJLiYYanYWangZLiXet al. 2013b Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart. Journal of Nutritional Biochemistry 24 146155. (https://doi.org/10.1016/j.jnutbio.2012.03.012)

QatananiMLazarMA 2007 Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes and Development 21 14431455. (https://doi.org/10.1101/gad.1550907)

Sassy-PrigentCHeudesDMandetCBelairMFMichelOPerdereauBBarietyJBrunevalP 2000 Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes 49 466475. (https://doi.org/10.2337/diabetes.49.3.466)

SedeekMCalleraGMontezanoAGutsolAHeitzFSzyndralewiezCPagePKennedyCRBurnsKDTouyzRMet al. 2010 Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. American Journal of Physiology-Renal Physiology 299 F1348F1358. (https://doi.org/10.1152/ajprenal.00028.2010)

SeokSJLeeESKimGTHyunMLeeJHChenSChoiRKimHMLeeEYChungCH 2013 Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrology Dialysis Transplantation 28 17001710. (https://doi.org/10.1093/ndt/gfs555)

Serrano RiosM 1998 Relationship between obesity and the increased risk of major complications in non-insulin-dependent diabetes mellitus. European Journal of Clinical Investigation 28 (Supplement 2) 1417 discussion 17–18. (https://doi.org/10.1046/j.1365-2362.1998.0280s2014.x)

ShishuSinglaAKKaurIP 2003 Inhibitory effect of dibenzoylmethane on mutagenicity of food-derived heterocyclic amine mutagens. Phytomedicine 10 575582. (https://doi.org/10.1078/094471103322331575)

SoetiknoVSariFRVeeraveeduPTThandavarayanRAHarimaMSukumaranVLakshmananAPSuzukiKKawachiHWatanabeK 2011 Curcumin ameliorates macrophage infiltration by inhibiting NF-kappaB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy. Nutrition and Metabolism 8 35. (https://doi.org/10.1186/1743-7075-8-35)

SoetiknoVSariFRSukumaranVLakshmananAPHarimaMSuzukiKKawachiHWatanabeK 2013 Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats. Journal of Nutritional Biochemistry 24 796802. (https://doi.org/10.1016/j.jnutbio.2012.04.013)

SunKKusminskiCMSchererPE 2011 Adipose tissue remodeling and obesity. Journal of Clinical Investigation 121 20942101. (https://doi.org/10.1172/JCI45887)

TakanoKKitaoYTabataYMiuraHSatoKTakumaKYamadaKHibinoSChoshiTIinumaMet al. 2007 A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress. American Journal of Physiology-Cell Physiology 293 C1884C1894. (https://doi.org/10.1152/ajpcell.00305.2007)

TrevisanRDodesiniARLeporeG 2006 Lipids and renal disease. Journal of the American Society of Nephrology 17 S145S147. (https://doi.org/10.1681/ASN.2005121320)

TrujilloJChirinoYIMolina-JijonEAnderica-RomeroACTapiaEPedraza-ChaverriJ 2013 Renoprotective effect of the antioxidant curcumin: recent findings. Redox Biology 1 448456. (https://doi.org/10.1016/j.redox.2013.09.003)

WangYChangJYaoBNiuAKellyEBreeggemannMCAbboud WernerSLHarrisRCZhangMZ 2015 Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury. Kidney International 88 12741282. (https://doi.org/10.1038/ki.2015.295)

WuHKongLTanYEpsteinPNZengJGuJLiangGKongMChenXMiaoLet al. 2016 C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21. Diabetologia 59 15581568. (https://doi.org/10.1007/s00125-016-3958-8)

XiongZEDongWGWangBYTongQYLiZY 2015 Curcumin attenuates chronic ethanol-induced liver injury by inhibition of oxidative stress via mitogen-activated protein kinase/nuclear factor E2-related factor 2 pathway in mice. Pharmacognosy Magazine 11 707715. (https://doi.org/10.4103/0973-1296.165556)

YaoFZhangMChenL 2016 5′-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications. Acta Pharmaceutica Sinica B 6 2025. (https://doi.org/10.1016/j.apsb.2015.07.009)

YouYHOkadaSLySJandeleit-DahmKBaritDNamikoshiTSharmaK 2013 Role of Nox2 in diabetic kidney disease. American Journal of Physiology-Renal Physiology 304 F840F848. (https://doi.org/10.1152/ajprenal.00511.2012)

ZhangXChenMZouPKanchanaKWengQChenWZhongPJiJZhouHHeLet al. 2015 Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells. BMC Cancer 15 866. (https://doi.org/10.1186/s12885-015-1851-3)

ZhaoNJLiaoMJWuJJChuKX 2018 Curcumin suppresses Notch1 signaling: improvements in fatty liver and insulin resistance in rats. Molecular Medicine Reports 17 819826. (https://doi.org/10.3892/mmr.2017.798)

Index Card


Google Scholar

Related Articles



All Time Past Year Past 30 Days
Abstract Views 336 336 205
Full Text Views 538 538 67
PDF Downloads 59 59 13