Therapeutic Effects of Curcumin Derivatives against Obesity and Associated Metabolic Complications: A Review of In Vitro and In Vivo Studies

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

[1]  Csaba Rácz,et al.  Strategies for Improving Bioavailability, Bioactivity, and Physical-Chemical Behavior of Curcumin , 2022, Molecules.

[2]  N. Lipkovska,et al.  Keto-enol tautomerism of curcumin in the preparation of nanobiocomposites with fumed silica. , 2022, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[3]  Takwa Bedhiafi,et al.  Curcumin and Derivatives in Nanoformulations with Therapeutic Potential on Colorectal Cancer , 2022, AAPS PharmSciTech.

[4]  Lei Wu,et al.  In Vitro and In Vivo Cardioprotective Effects of Curcumin against Doxorubicin-Induced Cardiotoxicity: A Systematic Review , 2022, Journal of oncology.

[5]  R. Rusinek,et al.  Curcumin and Weight Loss: Does It Work? , 2022, International journal of molecular sciences.

[6]  Luca Tiano,et al.  Curcumin supplementation improves biomarkers of oxidative stress and inflammation in conditions of obesity, type 2 diabetes and NAFLD: updating the status of clinical evidence. , 2021, Food & function.

[7]  M. Tschöp,et al.  Anti-obesity drug discovery: advances and challenges , 2021, Nature reviews. Drug discovery.

[8]  M. Balbaa,et al.  Ameliorative effect of curcumin and zinc oxide nanoparticles on multiple mechanisms in obese rats with induced type 2 diabetes , 2021, Scientific Reports.

[9]  Huadong Tang,et al.  Curc-mPEG454, a PEGylated curcumin derivative, as a multi-target anti-fibrotic prodrug. , 2021, International immunopharmacology.

[10]  N. Chattipakorn,et al.  Curcumin analogue C66 attenuates obesity-induced myocardial injury by inhibiting JNK-mediated inflammation. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[11]  S. Kim,et al.  Dehydrozingerone inhibits renal lipotoxicity in high‐fat diet–induced obese mice , 2021, Journal of cellular and molecular medicine.

[12]  Bin Yang,et al.  Curcumin analogue C66 attenuates obesity-induced renal injury by inhibiting chronic inflammation. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[13]  Chiadi E. Ndumele,et al.  Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association , 2021, Circulation.

[14]  R. V. van Breemen,et al.  Pharmacokinetics of a Single Dose of Turmeric Curcuminoids Depends on Formulation: Results of a Human Crossover Study , 2021, The Journal of nutrition.

[15]  X. Liao,et al.  Curcumin prevents obesity by targeting TRAF4‐induced ubiquitylation in m6A‐dependent manner , 2021, EMBO reports.

[16]  H. Zimdahl,et al.  Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application , 2021, Molecular metabolism.

[17]  S. Y. Lee,et al.  Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? , 2021, Current Obesity Reports.

[18]  P. Somvanshi,et al.  Reductive metabolites of curcumin and their therapeutic effects , 2020, Heliyon.

[19]  Yan-qiang Liu,et al.  Curcumin anti-diabetic effect mainly correlates with its anti-apoptotic actions and PI3K/Akt signal pathway regulation in the liver. , 2020, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[20]  Elise Adrian Ostrander,et al.  Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications , 2020, Frontiers in Pharmacology.

[21]  P. Matafome,et al.  Curcumin derivatives for Type 2 Diabetes management and prevention of complications , 2020, Archives of Pharmacal Research.

[22]  A. Naiki‐Ito,et al.  Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo , 2020, Molecules.

[23]  C. Ballantyne,et al.  Metabolic Inflammation and Insulin Resistance in Obesity , 2020, Circulation research.

[24]  S. Ray,et al.  Highly Bioavailable Forms of Curcumin and Promising Avenues for Curcumin-Based Research and Application: A Review , 2020, Molecules.

[25]  K. Skalicka‐Woźniak,et al.  Bioactivity of dietary polyphenols: The role of metabolites , 2020, Critical reviews in food science and nutrition.

[26]  Xing Tang,et al.  Pharmaceutical strategies of improving oral systemic bioavailability of curcumin for clinical application. , 2019, Journal of controlled release : official journal of the Controlled Release Society.

[27]  Hong-Min Kim,et al.  Curcumin analog CUR5-8 ameliorates nonalcoholic fatty liver disease in mice with high-fat diet-induced obesity. , 2019, Metabolism: clinical and experimental.

[28]  R. El-Shishtawy,et al.  Curcumin analogues and their hybrid molecules as multifunctional drugs. , 2019, European journal of medicinal chemistry.

[29]  A. Dömling,et al.  Metabolic signature of obesity-associated insulin resistance and type 2 diabetes , 2019, Journal of Translational Medicine.

[30]  R. Ghidoni,et al.  Dietary Curcumin: Correlation between Bioavailability and Health Potential , 2019, Nutrients.

[31]  Bradley S. Fleenor,et al.  Influence of enhanced bioavailable curcumin on obesity-associated cardiovascular disease risk factors and arterial function: A double-blinded, randomized, controlled trial. , 2019, Nutrition.

[32]  Kok-Gan Chan,et al.  Curcumin Nanoformulations for Colorectal Cancer: A Review , 2019, Front. Pharmacol..

[33]  C. Mantzoros,et al.  Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. , 2019, Metabolism: clinical and experimental.

[34]  A. Stefanović,et al.  Obesity and dyslipidemia. , 2019, Metabolism: clinical and experimental.

[35]  S. Nabavi,et al.  Mechanistic insights of hepatoprotective effects of curcumin: Therapeutic updates and future prospects. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[36]  K. Davis,et al.  Early and late complications of bariatric operation , 2018, Trauma Surgery & Acute Care Open.

[37]  Amirhossein Sahebkar,et al.  Therapeutic potential of curcumin in diabetic complications , 2018, Pharmacological research.

[38]  Yong Chen,et al.  The pharmacokinetics and tissue distribution of curcumin and its metabolites in mice. , 2018, Biomedical chromatography : BMC.

[39]  F. Ursini,et al.  Phytosome complex of curcumin as complementary therapy of advanced pancreatic cancer improves safety and efficacy of gemcitabine: Results of a prospective phase II trial , 2018, Pharmacological research.

[40]  A. Sahebkar,et al.  Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review , 2018, Phytotherapy research : PTR.

[41]  Huadong Tang,et al.  Curc-mPEG454, a PEGylated Curcumin Derivative, Improves Anti-inflammatory and Antioxidant Activities: a Comparative Study , 2017, Inflammation.

[42]  G. Frühbeck,et al.  Obesity and Type 2 Diabetes: Two Diseases with a Need for Combined Treatment Strategies - EASO Can Lead the Way , 2017, Obesity Facts.

[43]  D. Kalman,et al.  Curcumin: A Review of Its’ Effects on Human Health , 2017, Foods.

[44]  Qin Shen,et al.  Transport of curcumin derivatives in Caco‐2 cell monolayers , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[45]  Muheeb Beg,et al.  Curcumin-3,4-Dichloro Phenyl Pyrazole (CDPP) overcomes curcumin's low bioavailability, inhibits adipogenesis and ameliorates dyslipidemia by activating reverse cholesterol transport. , 2017, Metabolism: clinical and experimental.

[46]  Huadong Tang,et al.  PEGylated Curcumin Derivative Attenuates Hepatic Steatosis via CREB/PPAR-γ/CD36 Pathway , 2017, BioMed research international.

[47]  Dongwei Zhang,et al.  Recent Advances of Curcumin in the Prevention and Treatment of Renal Fibrosis , 2017, BioMed research international.

[48]  X. Liu,et al.  Diarylpentadienone derivatives (curcumin analogues): Synthesis and anti-inflammatory activity. , 2017, Bioorganic & medicinal chemistry letters.

[49]  Jayme L. Dahlin,et al.  The Essential Medicinal Chemistry of Curcumin , 2017, Journal of medicinal chemistry.

[50]  T. Efferth,et al.  Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines. , 2016, Toxicology and applied pharmacology.

[51]  M. Sridhar,et al.  Preventive effect of curcumin on inflammation, oxidative stress and insulin resistance in high-fat fed obese rats , 2016, Journal of complementary & integrative medicine.

[52]  Gretchen A. Stevens,et al.  Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants , 2016, The Lancet.

[53]  Chen Li,et al.  Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer , 2016, Scientific Reports.

[54]  S. Rivera-Mancía,et al.  Experimental evidence for curcumin and its analogs for management of diabetes mellitus and its associated complications. , 2015, European journal of pharmacology.

[55]  Xiaokun Li,et al.  A Newly Designed Curcumin Analog Y20 Mitigates Cardiac Injury via Anti-Inflammatory and Anti-Oxidant Actions in Obese Rats , 2015, PloS one.

[56]  J. O. Lee,et al.  Dehydrozingerone exerts beneficial metabolic effects in high-fat diet-induced obese mice viaAMPK activation in skeletal muscle , 2015, Journal of cellular and molecular medicine.

[57]  B. Aggarwal,et al.  Curcumin Differs from Tetrahydrocurcumin for Molecular Targets, Signaling Pathways and Cellular Responses , 2014, Molecules.

[58]  K. Priyadarsini The Chemistry of Curcumin: From Extraction to Therapeutic Agent , 2014, Molecules.

[59]  Alan D. Lopez,et al.  Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2014, The Lancet.

[60]  Jun Ren,et al.  Novel Curcumin Derivative CNB-001 Mitigates Obesity-Associated Insulin Resistance , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[61]  L. Rao,et al.  Structure-function activity of dehydrozingerone and its derivatives as antioxidant and antimicrobial compounds , 2014, Journal of Food Science and Technology.

[62]  Zhe Wang,et al.  Inhibition of MAPK-mediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy , 2013, Journal of cellular and molecular medicine.

[63]  S. Esmaeili,et al.  Obesity as an Important Risk Factor for Certain Types of Cancer , 2013, Iranian journal of cancer prevention.

[64]  Xiaokun Li,et al.  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 , 2013, PloS one.

[65]  Jin‐Ming Lin,et al.  Analysis of keto-enol tautomers of curcumin by liquid chromatography/mass spectrometry , 2013 .

[66]  H. Ishihara Current status and prospects of polyethyleneglycol-modified medicines. , 2013, Biological & pharmaceutical bulletin.

[67]  S. Rössner,et al.  Obesity management: what brings success? , 2013, Therapeutic advances in gastroenterology.

[68]  A. Al-Malki,et al.  Effect of novel water soluble curcumin derivative on experimental type- 1 diabetes mellitus (short term study) , 2012, Diabetology & Metabolic Syndrome.

[69]  Xiaokun Li,et al.  Inhibition of high glucose‐induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats , 2012, British journal of pharmacology.

[70]  Salma Khan,et al.  Curcumin molecular targets in obesity and obesity-related cancers. , 2012, Future oncology.

[71]  K. Tomita-Yokotani,et al.  Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism , 2011, Proceedings of the National Academy of Sciences.

[72]  J. Mckim,et al.  CeeTox™ Analysis of CNB-001 a Novel Curcumin-Based Neurotrophic/Neuroprotective Lead Compound to Treat Stroke: Comparison with NXY-059 and Radicut , 2011, Translational Stroke Research.

[73]  T. Kálai,et al.  Cellular uptake, retention and bioabsorption of HO-3867, a fluorinated curcumin analog with potential antitumor properties , 2010, Cancer biology & therapy.

[74]  B. Zhang,et al.  Amphiphilic curcumin conjugate-forming nanoparticles as anticancer prodrug and drug carriers: in vitro and in vivo effects. , 2010, Nanomedicine.

[75]  S. Vareed,et al.  Pharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human Subjects , 2008, Cancer Epidemiology Biomarkers & Prevention.

[76]  P. Maher,et al.  A broadly neuroprotective derivative of curcumin , 2008, Journal of neurochemistry.

[77]  T. Tsai,et al.  Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[78]  P. Mukherjee,et al.  Curcumin-phospholipid complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats. , 2007, International journal of pharmaceutics.

[79]  Daniel Normolle,et al.  Dose escalation of a curcuminoid formulation , 2006, BMC complementary and alternative medicine.

[80]  W. Shin,et al.  Synthesis of novel curcumin mimics with asymmetrical units and their anti-angiogenic activity. , 2005, Bioorganic & medicinal chemistry letters.

[81]  V. Menon,et al.  Comparative effects of curcumin and its analog on alcohol- and polyunsaturated fatty acid-induced alterations in circulatory lipid profiles. , 2005, Journal of medicinal food.

[82]  S. Jachak,et al.  Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents. , 2005, Bioorganic & medicinal chemistry letters.

[83]  V. Menon,et al.  Protective Role of a Novel Curcuminoid on Alcohol and PUFA-Induced Hyperlipidemia , 2005, Toxicology mechanisms and methods.

[84]  Thorsteinn Loftsson,et al.  Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. , 2002, International journal of pharmaceutics.

[85]  D. Scholz,et al.  Ferula asa-foetida and Curcuma longa in traditional medical treatment and diet in Nepal. , 1999, Journal of ethnopharmacology.

[86]  Jen-kun Lin,et al.  Biotransformation of curcumin through reduction and glucuronidation in mice. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[87]  M. Majeed,et al.  Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. , 1998, Planta medica.

[88]  K. N. Rajasekharan,et al.  Antimutagenic and anticarcinogenic activity of natural and synthetic curcuminoids. , 1996, Mutation research.

[89]  K. N. Rajasekharan,et al.  SIMPLIFIED CONDITION FOR SYNTHESIS OF CURCUMIN I AND OTHER CURCUMINOIDS , 1994 .

[90]  V. Lampe,et al.  Studien über Curcumin , 1913 .

[91]  Ayman El-Meghawry El-Kenawy,et al.  Tumeric or Curcuma longa Linn. , 2019, Nonvitamin and Nonmineral Nutritional Supplements.

[92]  Adrian L. Lopresti The Problem of Curcumin and Its Bioavailability: Could Its Gastrointestinal Influence Contribute to Its Overall Health-Enhancing Effects? , 2018, Advances in nutrition.

[93]  Havva Sezer,et al.  Insulin Resistance, Obesity and Lipotoxicity. , 2017, Advances in experimental medicine and biology.

[94]  K. Kathiresan,et al.  Curcumin–Piperine/Curcumin–Quercetin/Curcumin–Silibinin dual drug-loaded nanoparticulate combination therapy: A novel approach to target and treat multidrug-resistant cancers , 2013 .

[95]  V. Menon,et al.  Antioxidant and anti-inflammatory properties of curcumin. , 2007, Advances in experimental medicine and biology.

[96]  Donald J L Jones,et al.  Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[97]  J. Miłobȩdzka,et al.  Zur Kenntnis des Curcumins , 1897 .