Organ Location Map/System Distribution of Pungent Flavor Compounds’ Targets

Curcumin, found in the spice turmeric (a common ingredient in curries), is to be investigated in a Phase I/II trial for the treatment of bowel cancer.

Curcumin (diferuloylmethane) is a polyphenol responsible for the yellow color of the curry spice turmeric. It has been used in a variety of

diseases in traditional medicine. Modern scientific research has demonstrated its anti-inflammatory, anti-oxidant, anti-carcinogenic, antithrombotic,and

cardiovascular protective effects.

Curcumin, as curcuminoids, is an important compound in turmeric. Curcumin is also a natural antioxidant and has shown many pharmacological activities

such as anti-inflammatory, antibacterial, antiviral, antifungal, anti-infective, anti-mutagenic, anti-carcinogenic, anti-coagulant, antiarthrititc,

wound healing potential, diabetes, oxidative stress, obesity, aging, anti-oxidant, antithrombotic, cardiovascular protective effects, hepatoprotective

activity, anti-atherosclerotic, anti-angiogenesis, regulate blood fat.Curcumin have been used to treat diabetes mellitus (DM), Heart disease, neurodegenerative,

cardiovascular diseases, pulmonary, metabolic, autoimmune and neoplastic diseases, rheumatoid arthritisNeurodegenerative diseasesPulmonary disease

diabetic nephropathy , and anti-Alzheimer in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, nephroprotective,

cardioprotective, neuroprotective, hypoglycemic, antirheumatic, and antidiabetic activities and it also suppresses thrombosis and protects against

myocardial infarction.

Curcumin also has the Hepatoprotective activity, Cardioprotective activity, Lung protective activity, Nephroprotective activity, Neuroprotective activity,

neurotoxicity, complementary treatment in heart failure, moderated or reversed Memory impairment, anti-glycation, anti-thrombotic, anti-apoptotic, immune

modulatory activities.

1 Rao M N A. Curcuminoids as potent inhibitors of lipid peroxidationJ.. Journal of Pharmacy and Pharmacology, 1994, 46(12): 1013-1016.

2 Akila G, Rajakrishnan V, Viswanathan P, et al. Effects of curcumin on lipid profile and lipid peroxidation status in experimental hepatic fibrosisJ.. Hepatology research, 1998, 11(3): 147-157.

3 Borra S K, Mahendra J, Gurumurthy P. Effect of curcumin against oxidation of biomolecules by hydroxyl radicalsJ.. Journal of clinical and diagnostic research: JCDR, 2014, 8(10): CC01.

4 Sandur S K, Pandey M K, Sung B, et al. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanismJ.. Carcinogenesis, 2007, 28(8): 1765-1773.

5 Joe B, Lokesh B R. Role of capsaicin, curcumin and dietary n3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophagesJ.. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1994, 1224(2): 255-263.

6 Qadir M I, Naqvi S T, Muhammad S A. Curcumin: a polyphenol with molecular targets for cancer controlJ.. Asian Pac J Cancer Prev, 2016, 17(6): 2735-2739.

7 Wu J, Zhang L, Chen Y, et al. Curcumin pretreatment and post-treatment both improve the antioxidative ability of neurons with oxygen-glucose deprivationJ.. Neural regeneration research, 2015, 10(3): 481.

8 Wang L, Chen X, Du Z, et al. Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase depletion disrupting cellular bioenergeticsJ.. Journal of Experimental & Clinical Cancer Research, 2017, 36(1): 47.

9 C Recio M, Andujar I, L Rios J. Anti-inflammatory agents from plants: progress and potentialJ.. Current medicinal chemistry, 2012, 19(14): 2088-2103.

10 Sugimoto KHanai HTozawa Ket al. Curcumin prevents and ameliorates trinitrobenzene surfonic acid induced colitis in miceJ..Gastroenterology20021231912-1922.

11 C Recio M, Andujar I, L Rios J. Anti-inflammatory agents from plants: progress and potentialJ.. Current medicinal chemistry, 2012, 19(14): 2088-2103.

12 Hussain Z, Thu H E, Amjad M W, et al. Exploring recent developments to improve antioxidant, anti-inflammatory and antimicrobial efficacy of curcumin: A review of new trends and future perspectivesJ.. Materials Science and Engineering: C, 2017, 77: 1316-1326.

13 Rauf A, Imran M, Orhan I E, et al. Health perspectives of a bioactive compound curcumin: a reviewJ.. Trends in Food Science & Technology, 2018.

14 Soetikno V, Suzuki K, Veeraveedu P T, et al. Molecular understanding of curcumin in diabetic nephropathyJ.. Drug discovery today, 2013, 18(15-16): 756-763.

15 AGGARWAL, Bharat B.; HARIKUMAR, Kuzhuvelil B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The international journal of biochemistry & cell biology, 2009, 41.1: 40-59.

16 Wongcharoen, Wanwarang, and Arintaya Phrommintikul. The protective role of curcumin in cardiovascular diseases. International journal of cardiology 133.2 (2009): 145-151.

17 LI, Jian\Mei, et al. Curcumin inhibits hepatic protein\tyrosine phosphatase 1B and prevents hypertriglyceridemia and hepatic steatosis in fructose\fed rats. Hepatology, 2010, 51.5: 1555-1566.

18 PARK E U N J, Jeon C H, Ko G, et al. Protective effect of curcumin in rat liver injury induced by carbon tetrachlorideJ.. Journal of Pharmacy and Pharmacology, 2000, 52(4): 437-440.

19 Kang H C, Nan J X, Park P H, et al. Curcumin inhibits collagen synthesis and hepatic stellate cell activation in\vivo and in\vitroJ.. Journal of pharmacy and pharmacology, 2002, 54(1): 119-126.

20 Rukkumani R, Balasubashini M S, Vishwanathan P, et al. Comparative effects of curcumin and photo-irradiated curcumin on alcohol-and polyunsaturated fatty acid-induced hyperlipidemiaJ.. Pharmacological research, 2002, 46(3): 257-264.

21 Rukkumani R, Aruna K, Varma P S, et al. Curcumin influences hepatic expression patterns of matrix metalloproteinases in liver toxicityJ.. The Italian journal of biochemistry, 2004, 53(2): 61-66.

22 Shen S Q, Zhang Y, Xiang J J, et al. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymesJ.. World Journal of Gastroenterology: WJG, 2007, 13(13): 1953.

23 Bengmark S. Curcumin, an atoxic antioxidant and natural NFB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseasesJ.. Journal of Parenteral and Enteral Nutrition, 2006, 30(1): 45-51.

24 Maczurek A, Hager K, Kenklies M, et al. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's diseaseJ.. Advanced drug delivery reviews, 2008, 60(13-14): 1463-1470.

25 Menon V P, Sudheer A R. Antioxidant and anti-inflammatory properties of curcuminM.//The molecular targets and therapeutic uses of curcumin in health and disease. Springer, Boston, MA, 2007: 105-125.

26 Hanai H, Sugimoto K. Curcumin has bright prospects for the treatment of inflammatory bowel diseaseJ.. Current pharmaceutical design, 2009, 15(18): 2087-2094.

27 Moriyuki K, Sekiguchi F, Matsubara K, et al. Curcumin inhibits the proteinase-activated receptor-2Ctriggered prostaglandin E2 production by suppressing cyclooxygenase-2 upregulation and Akt-dependent activation of nuclear factor-B in human lung epithelial cellsJ.. Journal of pharmacological sciences, 2010, 114(2): 225-229.

28 Sethi G, Sung B, Aggarwal B B. Nuclear factor-B activation: from bench to bedsideJ.. Experimental Biology and Medicine, 2008, 233(1): 21-31.

29 Buhrmann C, Mobasheri A, Busch F, et al. Curcumin modulates NF-B-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase-Akt pathwayJ.. Journal of Biological Chemistry, 2011: jbc. M111. 256180.

30 Fu X, Yang M, Cao M, et al. Strategy to suppress oxidative damage-induced neurotoxicity in PC12 cells by curcumin: the role of ROS-mediated DNA damage and the MAPK and AKT pathwaysJ.. Molecular neurobiology, 2016, 53(1): 369-378.

31 Anthwal A, Thakur B K, Rawat M S M, et al. Synthesis, characterization and in vitro anticancer activity of C-5 curcumin analogues with potential to inhibit TNF--induced NF-B activationJ.. BioMed research international, 2014, 2014.

32 Gupta S C, Tyagi A K, Deshmukh-Taskar P, et al. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenolsJ.. Archives of Biochemistry and Biophysics, 2014, 559: 91-99.

33 Li B, Hu Y, Zhao Y, et al. Curcumin attenuates titanium particle-induced inflammation by regulating macrophage polarization in vitro and in vivoJ.. Frontiers in immunology, 2017, 8: 55.

34 Ak T, Gl?in ?. Antioxidant and radical scavenging properties of curcuminJ.. Chemico-

35 da Silva A C, de Freitas Santos P D, do Prado Silva J T, et al. Impact of curcumin nanoformulation on its antimicrobial activityJ.. Trends in Food Science & Technology, 2017.

36 Aggarwal B B, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targetsJ.. Trends in pharmacological sciences, 2009, 30(2): 85-94.

37 Kunnumakkara A B, Guha S, Krishnan S, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-BCregulated gene productsJ.. Cancer research, 2007, 67(8): 3853-3861

38 Johnson J J, Mukhtar H. Curcumin for chemoprevention of colon cancerJ.. Cancer letters, 2007, 255(2): 170-181.

39 Holy J M. Curcumin disrupts mitotic spindle structure and induces micronucleation in MCF-7 breast cancer cellsJ.. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2002, 518(1): 71-84.

40 Choudhuri T, Pal S, Agwarwal M L, et al. Curcumin induces apoptosis in human breast cancer cells through p53\dependent Bax inductionJ.. FEBS letters, 2002, 512(1-3): 334-340.

41 Morin D, Barthlmy S, Zini R, et al. Curcumin induces the mitochondrial permeability transition pore mediated by membrane protein thiol oxidationJ.. FEBS letters, 2001, 495(1-2): 131-136.

42 Mishra A, Kumar R, Tyagi A, et al. Curcumin modulates cellular AP-1, NF-kB, and HPV16 E6 proteins in oral cancerJ.. ecancermedicalscience, 2015, 9.

43 Mohanty C, Das M, Sahoo S K. Emerging role of nanocarriers to increase the solubility and bioavailability of curcuminJ.. Expert opinion on drug delivery, 2012, 9(11): 1347-1364.

44 Anand P, Sung B, Kunnumakkara A B, et al. RETRACTED: Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: Role of Michael acceptors and Michael donorsJ.. 2011.

45 Ye M X, Zhao Y L, Li Y, et al. Curcumin reverses cis-platin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1 and caspase-3 mechanismsJ.. Phytomedicine, 2012, 19(8-9): 779-787.

46 Kantara C, O'Connell M, Sarkar S, et al. Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNAJ.. Cancer research, 2014.

47 Schaaf C, Shan B, Buchfelder M, et al. Curcumin acts as anti-tumorigenic and hormone-suppressive agent in murine and human pituitary tumour cells in vitro and in vivoJ.. Endocrine-related cancer, 2009, 16(4): 1339-1350.

48 Miller M, Chen S, Woodliff J, et al. Curcumin (diferuloylmethane) inhibits cell proliferation, induces apoptosis, and decreases hormone levels and secretion in pituitary tumor cellsJ.. Endocrinology, 2008, 149(8): 4158-4167.

49 Zanotto-Filho A, Braganhol E, Klafke K, et al. Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomasJ.. Cancer letters, 2015, 358(2): 220-231.

50 Langone P., Debata P. R., Inigo J. D. R., et al. Coupling to a glioblastomadirected antibody potentiates antitumor activity of curcuminJ..International Journal of Cancer,2014,135(3):710C719. doi: 10.1002/ijc.28555.

51 Bisht S, Feldmann G, Soni S, et al. Polymeric nanoparticle-encapsulated curcumin (" nanocurcumin"): a novel strategy for human cancer therapyJ.. Journal of nanobiotechnology, 2007, 5(1): 3.

52 Bangaru M L Y, Chen S, Woodliff J, et al. Curcumin (diferuloylmethane) induces apoptosis and blocks migration of human medulloblastoma cellsJ.. Anticancer research, 2010, 30(2): 499-504.

53 Bachmeier B, Nerlich A, Iancu C, et al. The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient miceJ.. Cellular physiology and biochemistry, 2007, 19(1-4): 137-152.

54 Krejsgaard T, Vetter-Kauczok C S, Woetmann A, et al. Jak3-and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphomaJ.. Leukemia, 2006, 20(10): 1759.

55 Nan B, Lin P, Lumsden A B, et al. Effects of TNF- and curcumin on the expression of thrombomodulin and endothelial protein C receptor in human endothelial cellsJ.. Thrombosis research, 2005, 115(5): 417-426.

56 Mahmmoud Y A. Curcumin modulation of Na, K\ATPase: phosphoenzyme accumulation, decreased K+ occlusion, and inhibition of hydrolytic activityJ.. British journal of pharmacology, 2005, 145(2): 236-245.

57 Yao Q H, Wang D Q, Cui C C, et al. Curcumin ameliorates left ventricular function in rabbits with pressure overload: inhibition of the remodeling of the left ventricular collagen network associated with suppression of myocardial tumor necrosis factor- and matrix metalloproteinase-2 expressionJ.. Biological and Pharmaceutical Bulletin, 2

58 Yallapu M M, Jaggi M, Chauhan S C. Curcumin nanoformulations: a future nanomedicine for cancerJ.. Drug discovery today, 2012, 17(1-2): 71-80.

59 Asai A, Miyazawa T. Dietary curcuminoids prevent high-fat dietCinduced lipid accumulation in rat liver and epididymal adipose tissueJ.. The Journal of nutrition, 2001, 131(11): 2932-2935.

60 Rukkumani R, Balasubashini M S, Vishwanathan P, et al. Comparative effects of curcumin and photo-irradiated curcumin on alcohol-and polyunsaturated fatty acid-induced hyperlipidemiaJ.. Pharmacological research, 2002, 46(3): 257-264.

61 Jiang S, Han J, Li T, et al. Curcumin as a potential protective compound against cardiac diseasesJ.. Pharmacological research, 2017, 119: 373-383.

62 Saeidinia A, Keihanian F, Butler A E, et al. Curcumin in heart failure: a choice for complementary therapy? J.. Pharmacological research, 2018.

63 Shetty D, Kim Y J, Shim H, et al. Eliminating the heart from the curcumin molecule: monocarbonyl curcumin mimics (MACs)J.. Molecules, 2014, 20(1): 249-292.

64 Aydin M S, Caliskan A, Kocarslan A, et al. Intraperitoneal curcumin decreased lung, renal and heart injury in abdominal aorta ischemia/reperfusion model in ratJ.. International Journal of Surgery, 2014, 12(6): 601-605.

65 Katanasaka Y, Sunagawa Y, Hasegawa K, et al. Application of curcumin to heart failure therapy by targeting transcriptional pathway in cardiomyocytesJ.. Biological and Pharmaceutical Bulletin, 2013, 36(1): 13-17.

66 Alwi I, Santoso T, Suyono S, et al. The effect of curcumin on lipid level in patients with acute coronary syndromeJ.. Acta Med Indones, 2008, 40(4): 201-210.

67 Funk J L, Oyarzo J N, Frye J B, et al. Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritisJ.. Journal of natural products, 2006, 69(3): 351-355.

68 Shakibaei M, John T, Schulze-Tanzil G, et al. Suppression of NF-B activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritisJ.. Biochemical pharmacology, 2007, 73(9): 1434-1445.

69 Maheshwari R K, Singh A K, Gaddipati J, et al. Multiple biological activities of curcumin: a short reviewJ.. Life sciences, 2006, 78(18): 2081-2087.

70 Jain S K, Rains J, Croad J, et al. Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic ratsJ.. Antioxidants & redox signaling, 2009, 11(2): 241-249.

71 Aggarwal B B. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticalsJ.. Annual review of nutrition, 2010, 30: 173-199.

72 Seo K I, Choi M S, Jung U J, et al. Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db miceJ.. Molecular nutrition & food research, 2008, 52(9): 995-1004.

73 Geng S, Wang S, Zhu W, et al. Curcumin attenuates BPA-induced insulin resistance in HepG2 cells through suppression of JNK/p38 pathwaysJ.. Toxicology letters, 2017, 272: 75-83.

74 Balbaa M, El-Zeftawy M, Taha N, et al. Zinc and curcumin lower arylsulfatses and some metabolic parameters in streptozotocin-induced diabetesJ.. Journal of Diabetes & Metabolic Disorders, 2017, 16(1): 11.

75 Chen K, Zhang J, Zhang W, et al. ATP-P2X4 signaling mediates NLRP3 inflammasome activation: a novel pathway of diabetic nephropathyJ.. The international journal of biochemistry & cell biology, 2013, 45(5): 932-943.

76 Gong Z, Zhou J, Li H, et al. Curcumin suppresses NLRP3 inflammasome activation and protects against LPS\induced septic shockJ.. Molecular nutrition & food research, 2015, 59(11): 2132-2142.

77 Lu M, Yin N, Liu W, et al. Curcumin ameliorates diabetic nephropathy by suppressing NLRP3 inflammasome signalingJ.. BioMed research international, 2017, 2017.

78 Smith D G, Cappai R, Barnham K J. The redox chemistry of the Alzheimer's disease amyloid peptideJ.. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2007, 1768(8): 1976-1990

79 Bishnoi M, Chopra K, Kulkarni S K. Protective effect of Curcumin, the active principle of turmeric (Curcuma longa) in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes in rat brainJ.. Pharmacology Biochemistry and Behavior, 2008, 88(4): 511-522.

80 Hafner\Bratkovi? I, Ga?per?i? J, ?mid L M, et al. Curcumin binds to the \helical intermediate and to the amyloid form of prion proteinCa new mechanism for the inhibition of PrPSc accumulationJ.. Journal of neurochemistry, 2008, 104(6): 1553-1564.

81 Parsons P E. Mediators and mechanisms of acute lung injuryJ.. Clinics in chest medicine, 2000, 21(3): 467-476.

82 Literat A, Su F, Norwicki M, et al. Regulation of pro-inflammatory cytokine expression by curcumin in hyaline membrane disease (HMD)J.. Life sciences, 2001, 70(3): 253-267.

83 Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin\induced pulmonary fibrosis in ratsJ.. British journal of pharmacology, 2000, 131(2): 169-172.

84 zdowicz D, Sliwowski Z, Pawlik M W, et al. Curcumin Affords Gastroprotection Against Acute Gastric Lesions Induced by Acid-Independent and Acid-Dependent Ulcerogens. Involvement of Prostaglandins, Sensory Neuropeptides and Vanilloid TRPV-1 ReceptorsJ.. Gastroenterology, 2011, 140(5): S-315.

85 seini A, Hosseinzadeh H. Antidotal or protective effects of Curcuma longa (turmeric) and its active ingredient, curcumin, against natural and chemical toxicities: A reviewJ.. Biomedicine & Pharmacotherapy, 2018, 99: 411-421.

86 Drozdowicz D, Sliwowski Z, Pawlik M W, et al. Curcumin Affords Gastroprotection Against Acute Gastric Lesions Induced by Acid-Independent and Acid-Dependent Ulcerogens. Involvement of Prostaglandins, Sensory Neuropeptides and Vanilloid TRPV-1 Receptors[J]. Gastroenterology, 2011, 140(5): S-315.

87 Hosseini A, Hosseinzadeh H. Antidotal or protective effects of Curcuma longa (turmeric) and its active ingredient, curcumin, against natural and chemical toxicities: A review[J]. Biomedicine & Pharmacotherapy, 2018, 99: 411-421.

88 Y. Shukla, A. Arora, P. Taneja, Antimutagenic potential of curcumin on chromosomal aberrations in Wistar rats, Mutat. Res. Genet. Toxicol. Environ. 515 (1) (2002) 197V202.Mutagen

89 A. Sahebkar, Curcumin: A natural multitarget treatment for pancreatic cancer, Integr. Cancer Ther. 15 (3) (2016) 333V334.

90 Abdel-Wahhab M A, Salman A S, Ibrahim M I M, et al. Curcumin nanoparticles loaded hydrogels protects against aflatoxin B1-induced genotoxicity in rat liver[J]. Food and Chemical Toxicology, 2016, 94: 159-171.

91 Chowdhury R, Nimmanapalli R, Graham T, et al. Curcumin attenuation of lipopolysaccharide induced cardiac hypertrophy in rodents[J]. ISRN inflammation, 2013, 2013.

92 Sandersen C, Bienzle D, Cerri S, et al. Effect of inhaled hydrosoluble curcumin on inflammatory markers in broncho-alveolar lavage fluid of horses with LPS-induced lung neutrophilia[J]. Multidisciplinary respiratory medicine, 2015, 10(1): 16.

93 El-Mahalaway A M. Protective effect of curcumin against experimentally induced aflatoxicosis on the renal cortex of adult male albino rats: a histological and immunohisochemical study[J]. International journal of clinical and experimental pathology, 2015, 8(6): 6019.

94 Ghosh J, Das J, Manna P, et al. Acetaminophen induced renal injury via oxidative stress and TNF-\ production: therapeutic potential of arjunolic acid[J]. Toxicology, 2010, 268(1-2): 8-18.

95 Ismail A F M, Salem A A M. Renoprotective effect of curcumin on acetaminophen-induced nephrotoxicity in rats[J]. J Chem Pharm Res, 2016, 8(2): 773-779.

96 El-Rahman S N A, Al-Jameel S S. Protection of curcumin and curcumin nanoparticles against cisplatin induced nephrotoxicity in male rats[J]. Sch. Acad. J. Biosci, 2014, 2: 214-223.

97 Ugur S, Ulu R, Dogukan A, et al. The renoprotective effect of curcumin in cisplatin-induced nephrotoxicity[J]. Renal failure, 2015, 37(2): 332-336.

98 Tarasub N, Tarasub C, Ayutthaya W D N. Protective role of curcumin on cadmium-induced nephrotoxicity in rats[J]. Journal of environmental chemistry and ecotoxicology, 2011, 3(2): 17-24.

99 He L, Peng X, Zhu J, et al. Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats[J]. Canadian Journal of physiology and Pharmacology, 2015, 93(4): 275-282.

100 El-Zawahry B H, Abu El Kheir E M. The protective effect of curcumin against gentamicin-induced renal dysfunction and oxidative stress in male Albino rats[J]. Egyptian J Hosp Med, 2007, 29: 546-556.

101 Protective effect of curcumin against experimentally induced aflatoxicosis on the renal cortex of adult male albino rats: a histological and immunohisochemical study

102 Nabavi S F, Moghaddam A H, Eslami S, et al. Protective effects of curcumin against sodium fluoride-induced toxicity in rat kidneys[J]. Biological trace element research, 2012, 145(3): 369-374.

103 Azab A E, Fetouh F A, Albasha M O. Nephro-protective effects of curcumin, rosemary and propolis against gentamicin induced toxicity in guinea pigs: Morphological and biochemical study[J]. American Journal of Clinical and Experimental Medicine, 2014, 2(2): 28-35.

104 Kumar P, Padi S S V, Naidu P S, et al. Possible neuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicity[J]. Methods and findings in experimental and clinical pharmacology, 2007, 29(1): 19-26.

105 Banji O J F, Banji D, Ch K. Curcumin and hesperidin improve cognition by suppressing mitochondrial dysfunction and apoptosis induced by D-galactose in rat brain[J]. Food and chemical toxicology, 2014, 74: 51-59.

106 Flora G, Gupta D, Tiwari A. Preventive efficacy of bulk and nanocurcumin against lead-induced oxidative stress in mice[J]. Biological trace element research, 2013, 152(1): 31-40.

107 Tarasub N, Junseecha T, Tarasub C, et al. Protective effects of curcumin, vitamin C, or their combination on cadmium-induced hepatotoxicity[J]. Journal of basic and clinical pharmacy, 2012, 3(2): 273.

108 Yousef M I, El-Demerdash F M, Radwan F M E. Sodium arsenite induced biochemical perturbations in rats: ameliorating effect of curcumin[J]. Food and Chemical Toxicology, 2008, 46(11): 3506-3511.

109 Otuechere C A, Abarikwu S O, Olateju V I, et al. Protective effect of curcumin against the liver toxicity caused by propanil in rats[J]. International scholarly research notices, 2014, 2014.

110 Palipoch S, Punsawad C, Koomhin P, et al. Hepatoprotective effect of curcumin and alpha-tocopherol against cisplatin-induced oxidative stress[J]. BMC complementary and alternative medicine, 2014, 14(1): 111.

111 Salahshoor M, Mohamadian S, Kakabaraei S, et al. Curcumin improves liver damage in male mice exposed to nicotine[J]. Journal of traditional and complementary medicine, 2016, 6(2): 176-183.

112 Liang Z, Wu R, Xie W, et al. Effects of Curcumin on Tobacco Smoke?induced Hepatic MAPK Pathway Activation and EpithelialVMesenchymal Transition In Vivo[J]. Phytotherapy Research, 2017, 31(8): 1230-1239.

113 Garcia-Nino W R, Tapia E, Zazueta C, et al. Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening[J]. Evidence-based complementary and alternative medicine, 2013, 2013.

114 Wan X H, Li Y W, Luo X P. Curcumin attenuated the lipid peroxidation and apoptotic liver injury in copper-overloaded rats[J]. Zhonghua er ke za zhi= Chinese journal of pediatrics, 2007, 45(8): 604-608.

115 Messarah M, Amamra W, Boumendjel A, et al. Ameliorating effects of curcumin and vitamin E on diazinon-induced oxidative damage in rat liver and erythrocytes[J]. Toxicology and industrial health, 2013, 29(1): 77-88.

116 Abo?Salem O M, Harisa G I, Ali T M, et al. Curcumin Ameliorates Streptozotocin?Induced Heart Injury in Rats[J]. Journal of biochemical and molecular toxicology, 2014, 28(6): 263-270.

117 Imbaby S, Ewais M, Essawy S, et al. Cardioprotective effects of curcumin and nebivolol against doxorubicin-induced cardiac toxicity in rats[J]. Human & experimental toxicology, 2014, 33(8): 800-813.

118 Sagiroglu T, Kanter M, Yagci M A, et al. Protective effect of curcumin on cyclosporin A-induced endothelial dysfunction, antioxidant capacity, and oxidative damage[J]. Toxicology and industrial health, 2014, 30(4): 316-327.

119 Kukongviriyapan U, Pannangpetch P, Kukongviriyapan V, et al. Curcumin protects against cadmium-induced vascular dysfunction, hypertension and tissue cadmium accumulation in mice[J]. Nutrients, 2014, 6(3): 1194-1208.

120 Nemmar A, Subramaniyan D, Ali B H. Protective effect of curcumin on pulmonary and cardiovascular effects induced by repeated exposure to diesel exhaust particles in mice[J]. PLoS One, 2012, 7(6): e39554.

121 Kalpana C, Rajasekharan K N, Menon V P. Modulatory effects of curcumin and curcumin analog on circulatory lipid profiles during nicotine-induced toxicity in Wistar rats[J]. Journal of medicinal food, 2005, 8(2): 246-250.

122 Chakraborty M, Bhattacharjee A, Kamath J V. Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity[J]. Indian journal of pharmacology, 2017, 49(1): 65.

123 Al Moundhri M S, Al-Salam S, Al Mahrouqee A, et al. The effect of curcumin on oxaliplatin and cisplatin neurotoxicity in rats: some behavioral, biochemical, and histopathological studies[J]. Journal of Medical Toxicology, 2013, 9(1): 25-33.

124 Bishnoi M, Chopra K, Kulkarni S K. Protective effect of Curcumin, the active principle of turmeric (Curcuma longa) in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes in rat brain[J]. Pharmacology Biochemistry and Behavior, 2008, 88(4): 511-522.

125 Khalil R M, Khedr N F. Curcumin protects against monosodium glutamate neurotoxicity and decreasing NMDA2B and mGluR5 expression in rat hippocampus[J]. Neurosignals, 2016, 24(1): 81-87.

126 Kumar A, Dogra S, Prakash A. Protective effect of curcumin (Curcuma longa), against aluminium toxicity: Possible behavioral and biochemical alterations in rats[J]. Behavioural brain research, 2009, 205(2): 384-390.

127 Sethi P, Jyoti A, Hussain E, et al. Curcumin attenuates aluminium-induced functional neurotoxicity in rats[J]. Pharmacology Biochemistry and Behavior, 2009, 93(1): 31-39.

128 Abu-Taweel G M, Ajarem J S, Ahmad M. Protective effect of curcumin on anxiety, learning behavior, neuromuscular activities, brain neurotransmitters and oxidative stress enzymes in cadmium intoxicated mice[J]. Journal of Behavioral and Brain Science, 2013, 3(01): 74.

129 Sharma C, Suhalka P, Sukhwal P, et al. Curcumin attenuates neurotoxicity induced by fluoride: an in vivo evidence[J]. Pharmacognosy magazine, 2014, 10(37): 61.

130 Ciftci G, Aksoy A, Cenesiz S, et al. Therapeutic role of curcumin in oxidative DNA damage caused by formaldehyde[J]. Microscopy research and technique, 2015, 78(5): 391-395.

131 Cui Q, Li X, Zhu H. Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway[J]. Molecular medicine reports, 2016, 13(2): 1381-1388.

132 Greeshma N, Prasanth K G, Balaji B. Tetrahydrocurcumin exerts protective effect on vincristine induced neuropathy: behavioral, biochemical, neurophysiological and histological evidence[J]. Chemico-biological interactions, 2015, 238: 118-128.

133 Jayaraj R L, Elangovan N, Manigandan K, et al. CNB-001 a novel curcumin derivative, guards dopamine neurons in MPTP model of Parkinsons disease[J]. BioMed research international, 2014, 2014.

134 Kaur H, Bal A, Sandhir R. Curcumin supplementation improves mitochondrial and behavioral deficits in experimental model of chronic epilepsy[J]. Pharmacology Biochemistry and Behavior, 2014, 125: 55-64.

135 Ji M H, Qiu L L, Yang J J, et al. Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice[J]. Neurotoxicology, 2015, 46: 155-164.

136 Prasad S N. Neuroprotective effect of geraniol and curcumin in an acrylamide model of neurotoxicity in Drosophila melanogaster: relevance to neuropathy[J]. Journal of insect physiology, 2014, 60: 7-16.

137 Samy D M, Ismail C A, Nassra R A, et al. Downstream modulation of extrinsic apoptotic pathway in streptozotocin-induced Alzheimer's dementia in rats: Erythropoietin versus curcumin[J]. European journal of pharmacology, 2016, 770: 52-60.

138 Prakash C, Soni M, Kumar V. Mitochondrial oxidative stress and dysfunction in arsenic neurotoxicity: a review[J]. Journal of Applied Toxicology, 2016, 36(2): 179-188.

139 Sankar P, Telang A G, Kalaivanan R, et al. Oral nanoparticulate curcumin combating arsenic-induced oxidative damage in kidney and brain of rats[J]. Toxicology and industrial health, 2016, 32(3): 410-421.

140 Waseem M, Parvez S. Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin[J]. Protoplasma, 2016, 253(2): 417-430.

141 Hassani S, Sepand M R, Jafari A, et al. Protective effects of curcumin and vitamin E against chlorpyrifos-induced lung oxidative damage[J]. Human & experimental toxicology, 2015, 34(6): 668-676.

142 Venkatesan N. Pulmonary protective effects of curcumin against paraquat toxicity[J]. Life sciences, 1999, 66(2): PL21-PL28.

143 Devi K R, Mosheraju M, Reddy K D. Curcumin prevents chromium induced sperm characteristics in mice[J]. IOSR J Pharm, 2012, 2: 312-316.

144 Dev K R, Yadamma K, Reddy K D. Protective effects of curcumin in cyclophosmphamide induced sperm head abnormalities in male mice[J]. Int J Pharm Biol Sci, 2013, 4(1): 1131-1137.

145 Corona-Rivera A, Urbina-Cano P, Bobadilla-Morales L, et al. Protectivein vivo effect of curcumin on copper genotoxicity evaluated by comet and micronucleus assays[J]. Journal of applied genetics, 2007, 48(4): 389-396.

146 Saeidinia A, Keihanian F, Butler A E, et al. Curcumin in heart failure: A choice for complementary therapy?[J]. Pharmacological research, 2018.

147 Sanei M, Demneh A S. Effect of curcumin on memory impairment: A systematic review[J]. Phytomedicine, 2018.

148 Ganjali S, Blesso C N, Banach M, et al. Effects of curcumin on HDL functionality[J]. Pharmacological research, 2017, 119: 208-218.

149 Parsamanesh N, Moossavi M, Bahrami A, et al. Therapeutic potential of curcumin in diabetic complications[J]. Pharmacological research, 2018.

150 Bahrami A, Atkin S L, Majeed M, et al. Effects of curcumin on hypoxia-inducible factor as a new therapeutic target[J]. Pharmacological research, 2018.

151 Egan M E, Pearson M, Weiner S A, et al. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects[J]. Science, 2004, 304(5670): 600-602.

152 Chen J, He Z M, Wang F L, et al. Curcumin and its promise as an anticancer drug: an analysis of its anticancer and antifungal effects in cancer and associated complications from invasive fungal infections[J]. European journal of pharmacology, 2016, 772: 33-42.

153 Sun J, Chen F, Braun C, et al. Role of curcumin in the management of pathological pain[J]. Phytomedicine, 2018.

154 da Silva A C, de Freitas Santos P D, do Prado Silva J T, et al. Impact of curcumin nanoformulation on its antimicrobial activity[J]. Trends in Food Science & Technology, 2017.

155 Arablou T, Kolahdouz-Mohammadi R. Curcumin and endometriosis: Review on potential roles and molecular mechanisms[J]. Biomedicine & Pharmacotherapy, 2018, 97: 91-97.

156 Mohanty C, Sahoo S K. Curcumin and its topical formulations for wound healing applications[J]. Drug discovery today, 2017.

157 Sunagawa Y, Katanasaka Y, Hasegawa K, et al. Clinical applications of curcumin[J]. PharmaNutrition, 2015, 3(4): 131-135.

158 Gupta S C, Patchva S, Aggarwal B B. Therapeutic roles of curcumin: lessons learned from clinical trials[J]. The AAPS journal, 2013, 15(1): 195-218.

159 Dhillon N, Aggarwal B B, Newman R A, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer[J]. Clinical Cancer Research, 2008, 14(14): 4491-4499.

160 Miyamoto S, Kawamura T, Morimoto T, et al. Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo[J]. Circulation, 2006, 113(5): 679-690.

161 Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, et al. Curcumin extract for prevention of type 2 diabetes[J]. Diabetes care, 2012: DC_120116.

162 Madhu K, Chanda K, Saji M J. Safety and efficacy of Curcuma longa extract in the treatment of painful knee osteoarthritis: a randomized placebo-controlled trial[J]. Inflammopharmacology, 2013, 21(2): 129-136.

163 Yao Y, Wang W, Li M, et al. Curcumin Exerts its Anti-hypertensive Effect by Down-regulating the AT 1 Receptor in Vascular Smooth Muscle Cells[J]. Scientific reports, 2016, 6: 25579.

164 Zhu Q, Sun Y, Yun X, et al. Antinociceptive effects of curcumin in a rat model of postoperative pain[J]. Scientific reports, 2014, 4: 4932.

165 Ali A, Banerjea A C. Curcumin inhibits HIV-1 by promoting Tat protein degradation[J]. Scientific Reports, 2016, 6: 27539.

166 Hu A, Huang J J, Li R L, et al. Curcumin as therapeutics for the treatment of head and neck squamous cell carcinoma by activating SIRT1[J]. Scientific reports, 2015, 5: 13429.

167 Rodwell C. Curcumin curries favour?[J]. Nature Reviews Cancer, 2012, 12(6): 376.

168 Frey N, Olson E N. Cardiac hypertrophy: the good, the bad, and the ugly[J]. Annual review of physiology, 2003, 65(1): 45-79.

169 Heineke J, Molkentin J D. Regulation of cardiac hypertrophy by intracellular signalling pathways[J]. Nature reviews Molecular cell biology, 2006, 7(8): 589.

170 Kolodziejczyk S M, Wang L, Balazsi K, et al. MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium[J]. Current biology, 1999, 9(20): 1203-1206.

171 Backs J, Olson E N. Control of cardiac growth by histone acetylation/deacetylation[J]. Circulation research, 2006, 98(1): 15-24.

172 Lill N L, Grossman S R, Ginsberg D, et al. Binding and modulation of p53 by p300/CBP coactivators[J]. Nature, 1997, 387(6635): 823.

173 Yao T P, Oh S P, Fuchs M, et al. Gene dosageVdependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300[J]. Cell, 1998, 93(3): 361-372.

174 Hancock W W, Buelow R, Sayegh M H, et al. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes[J]. Nature medicine, 1998, 4(12): 1392.

175 Ishikawa K, Sugawara D, Wang X, et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL-receptor knockout mice[J]. Circulation research, 2001, 88(5): 506-512.

176 Motterlini R, Foresti R, Bassi R, et al. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress[J]. Free Radical Biology and Medicine, 2000, 28(8): 1303-1312.

177 Duvoix A, Blasius R, Delhalle S, et al. Chemopreventive and therapeutic effects of curcumin[J]. Cancer letters, 2005, 223(2): 181-190.

178 Jan T R, Yeh S F. Inhibitory effect of curcumin, an inflammatory agent, on vascular smooth muscle proliferation[J]. Eur J Pharmacol, 1992, 221: 381.

179 Wongcharoen W, Phrommintikul A. The protective role of curcumin in cardiovascular diseases[J]. International journal of cardiology, 2009, 133(2): 145-151.

180 Virani S S, Polsani V R, Nambi V. Novel markers of inflammation in atherosclerosis[J]. Current atherosclerosis reports, 2008, 10(2): 164-170.

181 Schoonderwoerd B A, Smit M D, Pen L, et al. New risk factors for atrial fibrillation: causes of not-so-lone atrial fibrillation[J]. Europace, 2008, 10(6): 668-673.

182 Jiang S, Han J, Li T, et al. Curcumin as a potential protective compound against cardiac diseases[J]. Pharmacological research, 2017, 119: 373-383.

183 Soetikno V, Suzuki K, Veeraveedu P T, et al. Molecular understanding of curcumin in diabetic nephropathy[J]. Drug discovery today, 2013, 18(15-16): 756-763.

184 Lelli D, Pedone C, Sahebkar A. Curcumin and treatment of melanoma: The potential role of microRNAs[J]. Biomedicine & Pharmacotherapy, 2017, 88: 832-834.

185 Mohajeri M, Sahebkar A. Protective effects of curcumin against doxorubicin-induced toxicity and resistance: A review[J]. Critical Reviews in Oncology/Hematology, 2018, 122: 30-51.

186 Lelli D, Sahebkar A, Johnston T P, et al. Curcumin use in pulmonary diseases: State of the art and future perspectives[J]. Pharmacological research, 2017, 115: 133-148.

187 Serafini M M, Catanzaro M, Rosini M, et al. Curcumin in Alzheimers disease: Can we think to new strategies and perspectives for this molecule?[J]. Pharmacological research, 2017, 124: 146-155.

188 Kaufmann F N, Gazal M, Bastos C R, et al. Curcumin in depressive disorders: an overview of potential mechanisms, preclinical and clinical findings[J]. European journal of pharmacology, 2016, 784: 192-198.

189 Srivastava R M, Singh S, Dubey S K, et al. Immunomodulatory and therapeutic activity of curcumin[J]. International immunopharmacology, 2011, 11(3): 331-341.

190 Agrawal R, Mishra B, Tyagi E, et al. Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat[J]. Pharmacological research, 2010, 61(3): 247-252.

191 Lu T, Pan Y, Kao S Y, et al. Gene regulation and DNA damage in the ageing human brain[J]. Nature, 2004, 429(6994): 883.

192 Cruz-Correa M, Hylind L M, Marrero J H, et al. Efficacy and Safety of Curcumin in Treatment of Intestinal Adenomas in Patients with Familial Adenomatous Polyposis[J]. Gastroenterology, 2018.

193 Aggarwal B B, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets[J]. Trends in pharmacological sciences, 2009, 30(2): 85-94.