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The True Nature of Curcumin Polypharmacology

Updated: Oct 16, 2023


Original post: November 12, 2017

The True Nature of Curcumin Polypharmacology

Franco Cavaleri1: William Jia2. 1) Faculty of Medicine; Department of Experimental Medicine; 2) Division of Neurosurgery, Department of Surgery. Center for Brain Health UBC Hospital 2211 Wesbrook Mall Van BC Canada V6T 2B5.

1 Introduction

Curcumin (diferuloylmethane) is a major active constituent of turmeric (Curcuma longa) [1] with an expansive pharmacology including anti-inflammatory [1], anti-carcinogenic [2], wound healing [3] and antibacterial [4] to name just a few features. Its safety is well established by centuries of use in food and traditional medicine [5], [6], [7]. Subcellular signalling proteins such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [8], c-Jun N-terminal kinase (JNK) [9], Protein Kinase C (PKC) [10], AKT and mechanistic (mammalian) target of rapamycin (mTOR) signalling [11], [12], and mitogen-activated protein kinases (MAPKs) [13] have made a sizeable list of curcumin’s pharmacological targets that continues to evolve. Additionally, these targets are central to the pathology of diseases that are prolific in society today such as neurological disease [14], [15], autoimmunity [16], [17], cardiovascular disease [18], [19] and even cancer [20]. This all makes for a rather exciting story for curcumin as a potential medicinal agent. The very fact that the list of targets and mechanisms of activity by curcumin continues to grow is, itself, demonstrative of our incomplete understanding of the fundamental underlying mechanism by which curcumin pharmacology modulates disease pathology. Studies have shown curcumin to inhibit growth factors and growth factor receptors as well as the downstream signals including PI3K and extracellular-signal activated kinase (Erk); and oncogenes such as c-jun and c-myc [21], [22]. The extract is shown to inhibit expression of epidermal growth factor receptor (EGFR) and erythroblastosis oncogene B (ErbB2) [23]; inhibit enzymes such as cyclooxygenase (COX) and lipoxygenase (LOX) [24], [25], [26], [27]; facilitate transcription factors such as nuclear factor erythroid 2-related factor (Nrf2) [28] that can contribute to endogenous antioxidant status and protect cells from oxidation; while it inhibits activator protein – 1 (AP-1) and tumor necrosis factor α (TNFα) [29], [30]. Curcumin is shown to inhibit cytokines such as interleukins 1, 2, 6 and 8 [30], [25], [31], [32]. The extract is also shown to suppress Interleukin (IL)-12 in macrophages [33] while promoting the anti-inflammatory IL-10 [34]. How is all this possible and how can this be harnessed and controlled?

Curcumin comprises a subset of active constituents. The three main naturally occurring curcuminoid analogues found within the curcumin extract are diferuloylmethane (curcumin I), desmethoxycurcumin (curcumin II) and bis-desmethoxycurcumin (curcumin III) [35], [36] as seen in Figure 1. They typically exist naturally in proportions that range between 65-80% curcumin I, 10-25% curcumin II and 0.2-3.0% curcumin III [37].

Curcumin delivers a polypharmacology that exhibits a narrower range of activity than the whole herb [38], [39]. However, the curcumin extract is certainly not maximally selective as it is still delivering multiple active constituents each potentially exhibiting a polypharmacology of their own. There is yet another component of the pharmacology that may be contributing to curcumin’s polypharmacological nature. The sub-constituent curcuminoids readily give rise to auto-oxidative degradation products [40], [41], [42], some of which we know to exhibit pharmacological activity that we may have attributed to the curcuminoids in the past. Despite the conflicting findings on these curcuminoid by-products, they may be playing a monumental role in the pharmacology of this remarkable extract; a role that needs to be viewed with a more focussed lens.

2 Clinical Benefits of Curcumin Since long ago, oral dosing of curcumin with as little as 20 mg three times daily has been shown to improve acute and chronic hepatitis [43]. Curcumin is a potent cholegogue inducing gall-bladder contraction and bile elimination [44] conducive to bladder stone management. However, the more recent understanding of curcumin’s anti-inflammatory pharmacology and what this means in the context of disease management has elevated interest in the extract as a potential treatment for many modern epidemics. Curcumin is also shown clinically to enhance cytotoxicity of various drug-resistant strains of cancer [45]. In clinical trials patients with various cancer-related risks including bladder cancer, cervical cancer, intestinal metaplasia and oral leukoplakia were treated with systematically escalating doses up to 8000 mg daily of curcumin for three months [46]. Results were indicative of a significant anti-cancer effect by the curcumin treatment with relatively little to no toxicity. In murine models curcumin is also shown to ameliorate functional and structural abnormalities associated with cancer drug cisplatin-induced neuropathy [47]. In the treatment of orbital pseudotumors curcumin produces significant positive results. After following these patients for as long as two years at three month intervals, four patients recovered completely among five who stayed in the study to completion. One patient experienced complete regression but with some limited movement as a residual symptom [48]. The treatment of psoriasis by oral curcumin administration is shown to produce an excellent therapeutic outcome in two patients encouraging the need for larger controlled trials [49]. Topical application of curcumin preparation shows curcumin treatment to produce a more profound resolution than calcipotriol or non-treated (control) patients with various degrees of psoriasis [50].

A twenty-four week double blind placebo-controlled study resulted in an inconclusive position on curcumin’s effects on Alzheimer’s patients [51]. Curcumin use did show signs of β-Amyloid changes in serum indicative of β-Amyloid disaggregation and a tendency towards fewer adverse events for patients using curcumin. However no improvement in cognitive performance in the curcumin group over controls is established. However, since the control group did not shown cognitive decline during the period of the trial, the study design will need to be modified to be able to better evaluate these outcomes; better controls, larger groups and longer trials are expected requirements acknowledged by the authors.

However, researchers have not given up on the extract when it comes to amyloidogenic diseases. In vivo murine studies show that curcumin does cross the blood brain barrier [52], [53]and binds to amyloid plaques when orally fed or directly injected into the carotid artery [54]. When coupled to the known in vitro results associated with Alzheimer’s disease biomarkers these findings are suggestive of efficacy against Alzheimer’s pathology [55]. Other studies show curcumin improves cognitive function in patients with Alzheimer’s disease [53]. More research is required to further define curcumin’s clinical efficacy and mechanisms involved in the framework of Alzheimer’s pathology. Curcumin is shown to deliver anti-depressant like activity similar to that of fluoxetine and imipramine [56] and the mechanism might involve increasing brain derived neurotrophic factor (BDNF) [57]. On the other hand curcumin’s anti-depressant-like activity maybe a function of inhibitory activity on IL-6 and IL-1 [35], [58] since dysregulation of these cytokines and the systemic inflammatory activity that can rise from this may contribute to depression pathology [59], [60].

Curcumin is shown to inhibit p300-HAT to improve cardiac hypertrophy and heart failure in animal models [61] [62]. Curcumin delivers better results than diciofenac sodium in a recent study of patients with active rheumatoid arthritis comparing these therapies [6], [63]. Curcumin appears to correct cystic fibrosis transmembrane conductance(CTFR) defects associated with cystic fibrosis (CF) in murine models [64]. Curcumin administration stimulates muscle regeneration after traumatic injury [65]. Curcumin improves COPD-like airway inflammation [66]. All those in a small group of five ulcerative colitis patients improved using 550 mg curcumin twice daily as treatment for a month followed by a month of three daily 550 mg doses [7].

Curcumin pharmacology looks promising to say the least but these remarkable results are also in conflict with similar studies showing lack of success in clinical and preclinical models with curcumin treatment [67] such as in depression models where curcumin’s effects are found to not be significant [68]; where in other independent studies of CTFR (CF) defects curcumin’s benefits were not repeatable [69]; and in research using high curcumin doses to treat inflammatory conditions such as rheumatoid arthritis patients experienced improvements as much as but not more than those receiving phenylbutazone [7].

3 Curcumin Pharmacokinetics 3.1 Curcumin Bioavailability Despite the abundance of experimental and anecdotal clinical evidence demonstrating the health benefits of orally routed curcumin, limited to no serum curcumin is found in test subjects even at extremely high dosing that exceeds 10,000 mg daily [70] [71]. The reasons for the low tissue or serum availability appear to be due to multiple compounding factors including low bioavailability[72] and expeditious metabolic degradation[73] that causes rapid elimination of the curcuminoids [72]. The naturally occurring curcuminoid analogues are highly hydrophobic [74] [75], a characteristic thought to play a major role in bioavailability [72]. Overcoming the hydrophobic characteristics of the curcuminoids resolves only one of the challenges, however. There are other curcuminoid issues related to pharmacokinetics that are outstanding and are likely far more central to the understanding and efficacy of curcuminoid pharmacology than the bioavailability limitation.

The low bioavailability of curcumin is assumed due to the lack of serum curcuminoids [70] and the common excessive efflux of some curcumin preparations in fecal matter upon oral administration [76]. In comparison with intraperitoneal administration of pure curcumin extract which excludes the tumerone fraction, 75% of orally administered curcumin extract was excreted in feces with more than 10% found in bile [76] in a mouse model. In human patients, Cheng et al report that even with 8000 mg of oral curcumin administered daily, serum concentrations were found to be 1.77 +/- 1.87 microM [46]. In colorectal patients taking up to 3600 mg of curcumin orally daily neither curcumin nor its metabolites were found at quantifiable levels in plasma, blood and urine [77]. In a human Phase I clinical trial, Sharma et al found curcumin and its metabolites in plasma in the 10 nM range after oral dosing as high as 3600 mg daily [70]. In the treatment of pancreatic cancer using orally administered curcumin plasma curcumin levels are found to range between 22-41 ng/ml [71]. Poor curcumin/curcuminoid bioavailability is thought to be caused by the highly hydrophobic property of the phenolic compounds [75]. Many strategies have been applied to overcome the hydrophobicity of curcuminoids in an attempt to improve bioavailability such as interacting them with beta-casein (micellar casein) to improve solubility in aqueous mediums [78]; encapsulation of curcuminoids in hydrophobically modified starch [79], and phosphatidylcholine interactions with curcuminoids to enhance bioavailability and delivery [80],[81]. Administration of complexed curcuminoid-phosphatidylcholine is in fact shown to deliver a higher serum payload of curcumin over curcumin powder alone [82]. However, more detailed studies might be needed to determine if the incremental serum curcuminoids found with this reacted curcuminoid complex is a function of improved solubility and bioavailability. Could the improved survival of serum curcuminoids be a function of recipient-induced alteration in hepatic enzyme activity that may reduce the clearance rate of curcuminoids from blood? In addition, feed type [83], fiber content [84] and many other factors can also play into gastric emptying rate [85] gastrointestinal transition rate and macronutrient digestion and absorption [86]. This all influences drug transition rate and bioavailability as well and are not always fully accounted for in these studies.

The bioavailability limitation of curcumin, however, may be also overstated because studies also show that curcumin can efficiently find its way into serum at concentrations that are rather significant [51]. Thirty-four subjects of a six-month trial using powdered curcumin versus encapsulated curcumin presents a different bioavailability story. This study shows a mean plasma curcumin level of 490 nM amongst both curcumin groups but an interestingly higher (940 nM) level for the curcumin capsule group over the group fed curcumin powder at the daily dose of 1.0 gram daily. A group using 4.0 grams daily was also evaluated but serum curcumin results with this higher dose was not significantly higher. However, it’s interesting to note that while curcumin levels differed, levels of tetrahydrocurcumin, ferulic acid and vanillic acid did not differ between patients using powdered curcumin and those using capsules. The powder form could be performing less effectively due to the need to mix it in aqueous or other solutions that allow the auto-degradation process to start in on curcuminoid degradation long before it even enters the lumen. Interestingly, serum levels of curcumin could only be detected in the presence of glucuronidase inhibitor [51]. Here we have a clear indication that bioavailability of curcumin can be functional and maybe, the serum limitations are more attributable to shortfalls in curcumin formula design and post absorption modification and degradation that play a larger role in serum survival. Figure 3 presents a schematic that highlights multiple sources of curcumin/oid degradation that could affect curcumin “apparent” bioavailability. This degradation starts with the type of curcumin delivery form or formula and carries through to the final reagents and solvents used in analysis.

3.2 Curcumin Metabolism It is well understood that metabolic degradation of curcumin is rapid and efficient. In the preliminary study by Baum et al [51] it was determined that serum curcumin could be increased within 1.5 hours of oral administration with food to 250 nM and to 270 nM by four hours with water only. By twenty-four hours post-administration serum curcumin levels fell to 60 nM. No significant differences were found between the groups taking 1.0 gram curcumin daily versus the group taking 4.0 grams daily. This study proves to be one that highlights the true potential of curcuminoid bioavailability; it can be viable for a properly formulated curcumin treatment. Degradation and metabolic modification, on the other hand, may be the more difficult challenge. In fact, in this same study, at 2.5 hours after oral curcumin administration serum ferulic acid is found to be 110 +/- 20 nM, vanillic acid is 50+/-20 nM, total curcuminoids found to be 1100+/-260 nM, tetrahydrocurcumin is found to be 440+/-100 nM, and no vanillin is found.

Enzymatic metabolism of curcuminoids starts in the intestinal lumen and is quickly followed by hepatic enzyme activity [87], [88]. Although it is not clear whether Phase I metabolic enzymes such as the P450 CYPs are directly involved in curcuminoid metabolism, their influence may be indirect as explained further here. Once in the blood, for example, curcuminoid survival is prolonged or protected by serum albumin [89] which likely forms micellar systems with the systemic curcuminoid. Cationic micelles of curcuminoid [90], for instance, which can be achieved with beta casein are not only said to improve bioavailability but also protect the curcuminoids from premature degradation [78]. Binding of curcuminoids in vitro to bovine serum albumin (BSA), likely in the protein’s hydrophobic pockets, results in a curcumin-BSA complex with improved curcumin stability [91]. In fact, curcumin solubility is increased as much as 10-fold in the presence of BSA [92]. In vivo, curcuminoids are quickly converted to dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, and hexahydrocurcuminol. These metabolites are quickly further subjected to glucuronation and sulfation to form curcumin glucuronide, curcumin sulfate, dihdrocurcumin glucuroside, tetrahydrocurcumin glucuronoside, and hexahydrocurcumin glucuronoside [93], [94], [73], [87]. This likely involves Phase II metabolic enzymes – UDP-glucuronosyltransferases (UGT) and Sulfotransferase enzymes (SULT) [95]. However, the literature is not black and white in this context. To throw another curve in the context of metabolic degradation it must be considered that curcumin metabolic degradation and elimination is shown in some studies to play out differently in the human versus rat model. The human intestinal and hepatic cytosol is more likely to conjugate curcumin and produce the tetrahydrocurcumin metabolite in place of curcumin more abundantly than the rat model does [96]. What this means to total pharmacological potency is unexplored to date but what has been a problem up until now is the direct extrapolation from murine models to human models with lack of scientific support. More work needs to focus on unravelling this mystery.

There is no strong evidence to show that curcumin is subject to metabolism by P450. However, the Phase I P450 and the Phase II enzymes tend to aggregate at the membrane and influence each other. P450 (CYP), for instance, interacts intimately with UDP-glucuronosyltransferases (UGT) responsible for glucuronidation to form heteromers at the plasma membrane [97] that result in their competition for substrates and down- and up-regulation of activity [97]. It is possible that any substance or influence that affects P450 activity, such as changes in membrane phospholipid constitution, may indirectly influence curcumin’s metabolism [98]. Phosphatidylcholine in curcumin complexes that has been shown to improve solubility and bioavailability of curcumin [81] may also affect P450’s since membrane phosphatidylcholine is thought to be the anchoring phospholipid for at least some P450 enzymes such as 2B4 [99]. Failure to detect functional levels of curcumin in the plasma after a steady oral loading period or administration by other route may also be attributed to instability and non-enzymatic degradation of the curcuminoids. Various human and rat studies demonstrate a short half-life for the curcuminoids [100], [101]. Researches have shown that curcumin is more stable in solutions at pH < 7.0 while it tends to be less stable in physiological pH of 7.8 or more [102] characteristic of the distal small intestine. The curcumin non-enzymatic degradation products frequently reported are ferulic aldehyde, trans-6-(40-hydroxy-30- methoxyphenyl)-2, 4-dioxo-5-hexenal, feruloyl methane, ferulic acid and vanillin [102]. Ferulic acid and vanillin, are considered very small phenolic molecules with molecular weights of 151.15 g/mole [103] and 66.8 g/mole [104] respectively. They are soluble in aqueous solution and far more stable than the curcuminoids, themselves, in the biological medium [105], [106], [107]. The status of these non-enzymatic auto-oxidative degradation products is also in question and in conflict in the literature as the ones expected to be the major products in the past, vanillin and ferulic acid [42], are said to more recently be preceded by a bicyclopentadione product or other by-products that may not have yet been precisely identified [102], [108], [109], [105]. Too much conflicting data has been presented in this context and although the multiple view-points are great to see for meta-analysis it must be considered that these conflicting positions on the status of the degradation by-products could also be a function of the variable conditions being used to study the curcuminoids. Variable pH, temperature, serum protein and other conditions that, if even mildly varied, result in varying the stability, degradation dynamic and by-product yield. These variables could factor into the equation at multiple levels when it comes to in vitro work; but even with in vivo work the feed types, curcumin specifications and animal condition all play a changeable role in the outcome. Analysis of the blood work extracted including reagents used to treat final yields also influence the stability of the retained target curcuminoids; biochemicals we now know to be extremely vulnerable to degradation. All of these factors as shown in Figure 3 contribute to the variable results and inconsistencies we see in the literature. Somewhere in all this conflict, however, treatment with the right curcumin therapy successfully delivers relief to patients of many diseases. Ultimately, however, we need to pin down the pharmacokinetics and isolated pharmacology of the curcuminoids and their downstream by-products in order to eliminate inconsistencies and produce a reliable curcumin-treatment. 3.3 Curcuminoids or their degradation product? The enzymatic metabolism of curcumin is shown in some studies to reduce curcumin’s pharmacological potency significantly [110], [111]. However, other studies indicate that at least one of these metabolic by-products could be contributing to curcumin’s polypharmacology in tissues [112]. Tetrahydrocurcumin is purported to deliver a significant anti-inflammatory pharmacology [110], [111], [113]. In fact, more recent studies are pointing to this reduced derivative of curcumin having antioxidant activity and antihyperlipidemic effects at least as potent as curcumin [114]. Tetrahydrocurcumin is shown in some studies to perform well as an inhibitor of NF-kappa-B and protector of oxidative damage after ischemic episodes [115]. While it is shown to deliver more anti-inflammatory activity than curcumin in a carrageenan-induced murine inflammatory model [116] it performs not nearly as well as curcumin in other studies [117]. Other studies again, show varied activity with curcumin performing better than tetrahydrocurcumin on targets like COX-2 inhibition [118].

Aside from metabolic degradation as a factor altering curcuminoid pharmacology, the curcuminoids can exist as different tautomers – the enol and keto tautomers, [119], [120] as shown in Figure 2. The keto form predominates in a solution of pH 3-7 while at a pH above 7.8 the enol form predominates in solution [121]. The enol form (>pH 7.8) serves as an electron donor while the keto form (pH 3-7) serves as a hydrogen atom donor; although both forms can serve as antioxidant. Nevertheless, the environment in which the curcuminoid exists influences its electrochemical properties factoring, yet again, as another source of pharmacological variability.

The story with regards to the non-enzymatic auto-degradation products of curcumin is even more colourful and adds even more mystery. Curcuminoids also undergo non-enzymatic auto-oxidative degradation and as we’ve seen this is more likely to occur at pH> 7.0 [102]. It was shown that as much as 90% of curcuminoids are degraded within 30 minutes in a serum-free medium at pH 7 at 37oC [122]. Even in the presence of serum, 50% of curcumin is degraded to its degradation by-products within eight hours [102]. The true nature of this degradation yield is still not conclusively understood.

Research by Martelli et al show that curcumin activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) also known as the vanilliod receptor 1. This receptor is the target of vanillin, a degradation product of curcumin. By this mechanism vanillin and/or curcumin could be inducing symptomatic relief of Dinitrobenzene sulfonic acid (DNBS) -induced colitis in mice [123]. Multiple studies point to NF-kappa-B inhibition by curcumin and this being the root activity that results in subsequent IL-1, IL-6 and IL-8 inhibition [124], [125] [126]. Similarly, vanillin can also inhibit NF-kappa-B and caspase-1 [127]. COX is inhibited by vanillin [127]. In fact, vanillin’s effects are COX-2 specific delivering the beneficial pharmacology associated with nonsteroidal anti-inflammatory drugs. Interestingly, curcumin is shown to inhibit COX as well [128], [129]. Kim et al also show that vanillin protects rat neurons from oxidative stress [130]. Curcumin does the same by inducing expression of antioxidant defensive genes through Nrf2 activation [131], [28].

Ferulic acid, another curcumin degradation product, displays pharmacological activity similar to curcumin’s as well. Studies demonstrate that ferulic acid supplementation can facilitate hypotension through NO-mediated vasodilation [132]; a result also seen with curcumin administration [133]. Ferulic acid is shown to have significant antitumor activity [134] as does curcumin [135]. Ferulic acid is shown to inhibit NF-kappa -B [136]. Curcumin has been shown to destabilize preformed β-amyloid protein including inhibition of soluble oligomer and fibril aggregation to subsequently or also independently reduce associated neurotoxicity by these proteins [137], [138] [54], [139], [140], [141]. Ferulic acid is shown to have similar activities in vitro [142], [130] [139, 143].

Similar pharmacological activities of curcumin and its oxidative degradation products strongly suggests a contribution by curcumin’s auto-oxidative degradation products to curcumin pharmacology in vivo. This may explain the therapeutic results with curcumin administration despite low bioavailability or more accurately low serum levels of the curcuminoid analogues. The fact that we experience efficacious results with oral curcumin administration with or without the identification of significant serum curcuminoid concentrations, supports the notion that vanillin, ferulic acid and/or other degradation products of curcumin may be responsible at least partially for the clinical benefits of curcuminoids.

The variety of experimental models used to investigate curcumin includes in vitro and in vivo studies using various representations of turmeric and the common extract, curcumin. Curcumin’s pleiotropic properties certainly make it a versatile molecule. The question is whether this pleiotropy is a function of one curcuminoid analogue on multiple targets, the naturally inherent three curcuminoid analogues, the degradation products, or all of these factors? A better understanding of the complex nature of this activity can help us decode and identify the active components contributing to the polypharmacology. With this mapping, improved selectivity by curcumin-based drugs can be established and improved indication-specific drug designs with improved reliability and repeatability can be created. As we have it today, too many variables are at play.

4 Conclusion One of the challenges faced today with respect to curcumin acceptance in mainstream medicine is its polypharmacology or lack of clear cellular targeting. Drug target selectivity is central to allopathic drug design for reasons that are valid [144], [145]. However, an emerging drug paradigm that centers on polypharmacology [145] [146] to produce a synergistic therapeutic outcome is gaining some momentum for reasons that may also be valid. In essence, polypharmacology as a treatment model is already established in mainstream allopathic medicine and is in use to treat many complex disorders today including autoimmune disease [147], [148] and especially cancers [146], [149]. Interestingly, curcumin falls into this class of drug perfectly, however, in order to better understand the entire scope of this polypharmacology by curcumin much more work needs to be done. It is evident that curcumin extracts are made up of multiple naturally occurring curcuminoid analogues that must be studied in isolation in order for the distinct pharmacological features for each to be better defined. This may help formulators produce condition-specific products using the curcuminoid analogues with greater precision. In addition, it must be made very clear whether we have an influence in the in vivo model by the auto-oxidative by-products of curcumin or any of the enzymatic degradation products such as tetrahydrocurcumin. The level of contribution not only as constituents to serum bioactives but more accurately the tissue distribution of these potentially active degradation products must be defined.

Serum curcumin levels appear in the literature to not correlate well with efficacy of curcumin-based treatment protocols. Despite low to no serum curcumin upon oral administration in some studies efficacy against various human diseases from cancer to neurological has been well documented [72]. However, as we’ve seen some studies show that serum curcumin levels can be increased significantly with properly designed curcumin therapies. In addition, as serum curcumin/oid levels rise, in just hours the curcumin auto-oxidative degradation by-products can accompany the parent molecules in systemic circulation to contribute synergistic and/or additive pharmacology. This cannot be discounted.

Other challenges seem to compound the curcuminoid mystery including the lack of curcumin extract standardization. Curcumin extracts are notoriously comprised of varying proportions of the naturally inherent curcuminoid analogues. This in itself, produces another layer of inconsistency when testing one curcumin standard against others. Lastly, the reports of the curcuminoid pharmacokinetics in the literature are conflicting and this is expected to be a function of the varying conditions influencing degradation of the variable curcuminoid proportions in multiple additive ways starting with formulation design and delivery form of the curcumin-therapy. This variability continues based on transition time and oxidative status in the lumen to interactions of different biochemicals used in the analysis of blood work as portrayed in Figure 3. Our very attempts to isolate, extract and assay these compounds produces degradation vulnerability that impairs accurate evaluation of curcumin/oid pharmacokinetics.

In fact, we believe the very in vivo pharmacologically active biochemicals have been grossly missed in the past but have not been considered even in tissue distribution analysis – an endeavor that is so easily measured if one accepted the auto-degradation by-products as a plausible source for, at least, part of the curcumin/oid pharmacology. These by-products are relatively stable in aqueous solution where the parent curcuminoids are not. We believe this to more than just plausible; it is cautiously expected to be highly likely. The future requires a completely different outlook; first off by accepting polypharmacology or Network Pharmacology as a viable drug model by which the accepted Systems Biology is addressed with a pharmacological model that fits it like a glove. Secondly, the possibility that the degradation by-products are playing a significant role in one way or another in the expansive curcumin polypharmacology should be seriously investigated. The role that tetrahydrocurcumin might be playing must also be considered. Tissue distribution analysis must be employed with this objective in mind; and with clear consideration of the degradation potential inherent in the analytical process, itself. After this dust settles we’ll get to a starting line and determine what it is we are really studying and with this curcumin may get the credit it deserves even in mainstream medicine.

Authors: Franco Cavaleri1 and William Jia2, 1) Faculty of Medicine; Department of Experimental Medicine, 2) Division of Neurosurgery, Department of Surgery.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents including curcuminoids that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine. FIGURES (as seen in the originally published journal )-

Figure 1: Comparing curcuminoid structure with steroid hormone homology.

Figure 2: Curcumin can exist in different tautomers – the enol and keto tautomers.

Figure 3: Curcuminoids are inherently vulnerable to degradation by various mechanisms including UV light (photo) degradation exposure [150]; in aqueous solution of higher pH [151], exposure to buffers, assay reagents and HPLC solvents and their distinct pH [152]. Everything from formulation, delivery form, intestinal transition rate, diet, serum extraction method and serum storage and analysis can play a role in altering perceived bioavailability and serum stability. These represent multiple sources of variance and conflict from researcher to researcher.

References [1] Julie, S. and M. Jurenka, Anti-inflammatory properties of curcumin, a major constituent. Alternative medicine review, 2009. 14(2). [2] Chattopadhyay, I., et al., Turmeric and curcumin: Biological actions and medicinal applications. Current science, 2004. 87(1): p. 44-53. [3] Maheshwari, R.K., et al., Multiple biological activities of curcumin: a short review. Life sciences, 2006. 78(18): p. 2081-2087. [4] Negi, P., et al., Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture. Journal of Agricultural and Food Chemistry, 1999. 47(10): p. 4297-4300. [5] Gota, V.S., et al., Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. Journal of agricultural and food chemistry, 2010. 58(4): p. 2095-2099. [6] Chandran, B. and A. Goel, A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytotherapy research, 2012. 26(11): p. 1719-1725. [7] Hsu, C.-H. and A.-L. Cheng, Clinical studies with curcumin, in The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. 2007, Springer. p. 471-480. [8] Leclercq, I.A., et al., Curcumin inhibits NF-κB activation and reduces the severity of experimental steatohepatitis in mice. Journal of hepatology, 2004. 41(6): p. 926-934. [9] Chen, Y.-R. and T.-H. Tan, Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene, 1998. 17(2): p. 173-178. [10] Woo, M.-S., et al., Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochemical and biophysical research communications, 2005. 335(4): p. 1017-1025. [11] Johnson, S.M., et al., Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer research, 2009. 29(8): p. 3185-3190. [12] Yu, S., et al., Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Molecular cancer therapeutics, 2008. 7(9): p. 2609-2620. [13] Binion, D.G., M.F. Otterson, and P. Rafiee, Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut, 2008. 57(11): p. 1509-1517. [14] Clark, E., et al., Characterization and differential distribution of the three major human protein kinase C isozymes (PKC alpha, PKC beta, and PKC gamma) of the central nervous system in normal and Alzheimer’s disease brains. Laboratory investigation; a journal of technical methods and pathology, 1991. 64(1): p. 35-44. [15] O Neill, C., et al. Dysfunctional intracellular calcium homoeostasis: a central cause of neurodegeneration in Alzheimer’s disease. in Biochemical Society Symposia. 2001. London; Portland on behalf of The Biochemical Society; 1999. [16] Anderson, K., et al., Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases. Autoimmunity, 2006. 39(6): p. 469-478. [17] Manicassamy, S., S. Gupta, and Z. Sun, Selective function of PKC-theta in T cells. Cell Mol Immunol, 2006. 3(4): p. 263-270. [18] Brown, M. and W. Jones, NF-kappaB action in sepsis: the innate immune system and the heart. Frontiers in bioscience: a journal and virtual library, 2004. 9: p. 1201-1217. [19] O’Connor, A.M., et al., Decision aids for people facing health treatment or screening decisions. The Cochrane Library, 2009. [20] Anand, P., et al., Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical research, 2008. 25(9): p. 2097-2116. [21] Lin, J.-K., Molecular targets of curcumin, in The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. 2007, Springer. p. 227-243. [22] Han, S.-S., et al., Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-X L, NF-κB, and p53. Clinical immunology, 1999. 93(2): p. 152-161. [23] Farooqi, A.A., et al., Androgen receptor and gene network: Micromechanics reassemble the signaling machinery of TMPRSS2-ERG positive prostate cancer cells. Cancer cell international, 2014. 14(1): p. 34. [24] Plummer, S.M., et al., Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex. Oncogene, 1999. 18(44). [25] Davis, J.M., et al., Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2007. 292(6): p. R2168-R2173. [26] JANKUN, J., Curcumin inhibits lipoxygenase by binding to its central cavity: theoretical and X-ray evidence. International journal of molecular medicine, 2000. 6: p. 521-526. [27] Huang, M.-T., et al., Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer research, 1991. 51(3): p. 813-819. [28] Yang, C., et al., Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain research, 2009. 1282: p. 133-141. [29] Bierhaus, A., et al., The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B. Thrombosis and haemostasis, 1997. 77(4): p. 772-782. [30] Xu, Y., et al., Curcumin inhibits IL1 alpha and TNF-alpha induction of AP-1 and NF-kB DNA-binding activity in bone marrow stromal cells. Hematopathology and molecular hematology, 1996. 11(1): p. 49-62. [31] Bharti, A.C., N. Donato, and B.B. Aggarwal, Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. The Journal of Immunology, 2003. 171(7): p. 3863-3871. [32] Rafiee, P., et al., Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-κB. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2009. 296(2): p. G388-G398. [33] Cong, Y., et al., Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine‐protective regulatory T cells. European journal of immunology, 2009. 39(11): p. 3134-3146. [34] Larmonier, C.B., et al., Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008. 295(5): p. G1079. [35] Shishodia, S., G. Sethi, and B.B. Aggarwal, Curcumin: getting back to the roots. Annals of the New York Academy of Sciences, 2005. 1056(1): p. 206-217. [36] Yang, K.-Y., et al., Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC–MS/MS. Journal of chromatography B, 2007. 853(1): p. 183-189. [37] Limtrakul, P., S. Anuchapreeda, and D. Buddhasukh, Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC cancer, 2004. 4(1): p. 13. [38] Yue, G.G., et al., The role of turmerones on curcumin transportation and P-glycoprotein activities in intestinal Caco-2 cells. Journal of medicinal food, 2012. 15(3): p. 242-252. [39] Lee, H., Antiplatelet property of Curcuma longa L. rhizome-derived ar-turmerone. Bioresource technology, 2006. 97(12): p. 1372-1376. [40] Tátraaljai, D., et al., Processing stabilisation of PE with a natural antioxidant, curcumin. European Polymer Journal, 2013. 49(6): p. 1196-1203. [41] Metzler, M., et al., Curcumin uptake and metabolism. Biofactors, 2013. 39(1): p. 14-20. [42] Gordon, O.N. and C. Schneider, Vanillin and ferulic acid are not the major degradation products of curcumin. Trends in molecular medicine, 2012. 18(7): p. 361. [43] Rasyid, A. and A. Lelo, The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Alimentary Pharmacology and Therapeutics, 1999. 13(2): p. 245-250. [44] Akram, M., et al., Curcuma longa and curcumin: a review article. Rom J Biol–Plant Biol, 2010. 55(2): p. 65-70. [45] Bharti, A.C., et al., Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood, 2003. 101(3): p. 1053-1062. [46] Cheng, A.-L., et al., Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer research, 2000. 21(4B): p. 2895-2900. [47] Agthong, S., A. Kaewsema, and T. Charoensub, Curcumin Ameliorates Functional and Structural Abnormalities in Cisplatin-induced Neuropathy. Experimental Neurobiology, 2015. 24. [48] Lal, B., et al., Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytotherapy Research, 2000. 14(6): p. 443-447. [49] Kurd, S.K., et al., Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective clinical trial. Journal of the American Academy of Dermatology, 2008. 58(4): p. 625-631. [50] Thangapazham, R.L., A. Sharma, and R.K. Maheshwari, Beneficial role of curcumin in skin diseases, in The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. 2007, Springer. p. 343-357. [51] Baum, L., et al., Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. Journal of clinical psychopharmacology, 2008. 28(1): p. 110-113. [52] Garcia‐Alloza, M., et al., Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. Journal of neurochemistry, 2007. 102(4): p. 1095-1104. [53] Mishra, S. and K. Palanivelu, The effect of curcumin (turmeric) on Alzheimer’s disease: An overview. Annals of Indian Academy of Neurology, 2008. 11(1): p. 13. [54] Yang, F., et al., Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. Journal of Biological Chemistry, 2005. 280(7): p. 5892-5901. [55] Ringman, J.M., et al., A potential role of the curry spice curcumin in Alzheimer’s disease. Current Alzheimer Research, 2005. 2(2): p. 131. [56] Sanmukhani, J., A. Anovadiya, and C.B. Tripathi, Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study. Acta Pol Pharm, 2011. 68(5): p. 769-75. [57] Hurley, L.L., et al., Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behavioural brain research, 2013. 239: p. 27-30. [58] Cho, J.-W., K.-S. Lee, and C.-W. Kim, Curcumin attenuates the expression of IL-1β, IL-6, and TNF-α as well as cyclin E in TNF-α-treated HaCaT cells; NF-κB and MAPKs as potential upstream targets. International journal of molecular medicine, 2007. 19(3): p. 469-474. [59] Maes, M., et al., Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine, 1997. 9(11): p. 853-858. [60] Frommberger, U.H., et al., Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission. European archives of psychiatry and clinical neuroscience, 1997. 247(4): p. 228-233. [61] Wongcharoen, W. and A. Phrommintikul, The protective role of curcumin in cardiovascular diseases. International journal of cardiology, 2009. 133(2): p. 145-151. [62] Morimoto, T., et al., The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. The Journal of clinical investigation, 2008. 118(3): p. 868. [63] Gharate, M., Rheumatoid arthritis & Complementary and Alternative Medicine. Pharmainfo. net, 2007. 5. [64] Egan, M.E., et al., Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science, 2004. 304(5670): p. 600-602. [65] Allam, G., Immunomodulatory effects of curcumin treatment on murine schistosomiasis mansoni. Immunobiology, 2009. 214(8): p. 712-727. [66] Moghaddam, S.J., et al., Curcumin inhibits COPD-like airway inflammation and lung cancer progression in mice. Carcinogenesis, 2009. 30(11): p. 1949-1956. [67] Belkacemi, A., et al., Challenges associated with curcumin therapy in Alzheimer disease. Expert reviews in molecular medicine, 2011. 13: p. e34. [68] Seo, H.-J., et al., Curcumin as a putative antidepressant. Expert review of neurotherapeutics, 2015. 15(3): p. 269-280. [69] Mall, M. and K. Kunzelmann, Correction of the CF defect by curcumin: hypes and disappointments. Bioessays, 2005. 27(1): p. 9-13. [70] Sharma, R.A., et al., Phase I clinical trial of oral curcumin biomarkers of systemic activity and compliance. Clinical Cancer Research, 2004. 10(20): p. 6847-6854. [71] Dhillon, N., et al., Phase II trial of curcumin in patients with advanced pancreatic cancer. Clinical Cancer Research, 2008. 14(14): p. 4491-4499. [72] Anand, P., et al., Bioavailability of curcumin: problems and promises. Molecular pharmaceutics, 2007. 4(6): p. 807-818. [73] Pan, M.-H., T.-M. Huang, and J.-K. Lin, Biotransformation of curcumin through reduction and glucuronidation in mice. Drug metabolism and disposition, 1999. 27(4): p. 486-494. [74] Altunbas, A., et al., Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. Biomaterials, 2011. 32(25): p. 5906-5914. [75] Tsai, Y.-M., et al., Optimised nano-formulation on the bioavailability of hydrophobic polyphenol, curcumin, in freely-moving rats. Food chemistry, 2011. 127(3): p. 918-925. [76] Holder, G.M., J.L. Plummer, and A.J. Ryan, The metabolism and excretion of curcumin (1, 7-bis-(4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-dione) in the rat. Xenobiotica, 1978. 8(12): p. 761-768. [77] Garcea, G., et al., Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. British journal of cancer, 2004. 90(5): p. 1011-1015. [78] Esmaili, M., et al., Beta casein-micelle as a nano vehicle for solubility enhancement of curcumin; food industry application. LWT-food science and technology, 2011. 44(10): p. 2166-2172. [79] Yu, H. and Q. Huang, Enhanced in vitro anti-cancer activity of curcumin encapsulated in hydrophobically modified starch. Food Chemistry, 2010. 119(2): p. 669-674. [80] Kumar, A., et al., Conundrum and therapeutic potential of curcumin in drug delivery. Critical Reviews™ in Therapeutic Drug Carrier Systems, 2010. 27(4). [81] Belcaro, G., et al., Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev, 2010. 15(4): p. 337-44. [82] Khan, J., et al., Recent advances and future prospects of phyto-phospholipid complexation technique for improving pharmacokinetic profile of plant actives. Journal of Controlled Release, 2013. 168(1): p. 50-60. [83] Kim, H.J. and P.J. White, In vitro digestion rate and estimated glycemic index of oat flours from typical and high β-glucan oat lines. Journal of agricultural and food chemistry, 2012. 60(20): p. 5237-5242. [84] Durback, L.F., G.P. Wedin, and D.E. Seidler, Management of lead foreign body ingestion. Clinical Toxicology, 1989. 27(3): p. 173-182. [85] Benini, L., et al., Gastric emptying of a solid meal is accelerated by the removal of dietary fibre naturally present in food. Gut, 1995. 36(6): p. 825-830. [86] Zhang, G., Z. Ao, and B.R. Hamaker, Slow digestion property of native cereal starches. Biomacromolecules, 2006. 7(11): p. 3252-3258. [87] Ireson, C.R., et al., Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiology Biomarkers & Prevention, 2002. 11(1): p. 105-111. [88] Aggarwal, B.B. and B. Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends in pharmacological sciences, 2009. 30(2): p. 85-94. [89] Reddy, A.C.P., et al., Interaction of curcumin with human serum albumin—a spectroscopic study. Lipids, 1999. 34(10): p. 1025-1029. [90] Leung, M.H., H. Colangelo, and T.W. Kee, Encapsulation of curcumin in cationic micelles suppresses alkaline hydrolysis. Langmuir, 2008. 24(11): p. 5672-5675. [91] Barik, A., K.I. Priyadarsini, and H. Mohan, Photophysical Studies on Binding of Curcumin to Bovine Serum Albumin¶. Photochemistry and photobiology, 2003. 77(6): p. 597-603. [92] Mitra, S.P., Binding and stability of curcumin in presence of bovine serum albumin. Journal of Surface Science and Technology, 2007. 23(3/4): p. 91. [93] Zsila, F., Z. Bikádi, and M. Simonyi, Unique, pH-dependent biphasic band shape of the visible circular dichroism of curcumin–serum albumin complex. Biochemical and biophysical research communications, 2003. 301(3): p. 776-782. [94] Hoehle, S.I., et al., Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver. Journal of agricultural and food chemistry, 2006. 54(3): p. 756-764. [95] Volak, L.P., S. Ghirmai, and J.R. Cashman, Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metabolism and Disposition, 2008. 36(8): p. 1594-1605. [96] Ireson, C., et al., Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Research, 2001. 61(3): p. 1058-1064. [97] Cawley, G.F., C.J. Batie, and W.L. Backes, Substrate-dependent competition of different P 450 isoenzymes for limiting NADPH-cytochrome P 450 reductase. Biochemistry, 1995. 34(4): p. 1244-1247. [98] Das, A. and S.G. Sligar, Modulation of the cytochrome P450 reductase redox potential by the phospholipid bilayer. Biochemistry, 2009. 48(51): p. 12104-12112. [99] Shank-Retzlaff, M.L., et al., Membrane topology of cytochrome P450 2B4 in Langmuir–Blodgett monolayers. Archives of biochemistry and biophysics, 1998. 359(1): p. 82-88. [100] Yallapu, M.M., et al., Interaction of curcumin nanoformulations with human plasma proteins and erythrocytes. International journal of nanomedicine, 2011. 6: p. 2779. [101] Bisht, S. and A. Maitra, Systemic delivery of curcumin: 21st century solutions for an ancient conundrum. Current drug discovery technologies, 2009. 6(3): p. 192-199. [102] Wang, Y.-J., et al., Stability of curcumin in buffer solutions and characterization of its degradation products. Journal of pharmaceutical and biomedical analysis, 1997. 15(12): p. 1867-1876. [103] Azeez, S., et al., Virtual screening and in vitro assay of potential drug like inhibitors from spices against glutathione-S-transferase of filarial nematodes. Journal of molecular modeling, 2012. 18(1): p. 151-163. [104] Ota, A., et al., Interactions of p-coumaric, caffeic and ferulic acids and their styrenes with model lipid membranes. Food Chemistry, 2011. 125(4): p. 1256-1261. [105] Shen, L. and H.-F. Ji, The pharmacology of curcumin: is it the degradation products? Trends in molecular medicine, 2012. 18(3): p. 138-144. [106] Tønnesen, H.H. and J. Karlsen, Studies on curcumin and curcuminoids. Zeitschrift für Lebensmittel-Untersuchung und Forschung, 1985. 180(5): p. 402-404. [107] Shen, L. and H.-F. Ji, Contribution of degradation products to the anticancer activity of curcumin. Clinical Cancer Research, 2009. 15(22): p. 7108-7108. [108] Liang, G., et al., Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents. Bioorganic & medicinal chemistry, 2009. 17(6): p. 2623-2631. [109] Jacob, A., et al., Mechanism of the anti-inflammatory effect of curcumin: PPAR-γ activation. PPAR research, 2008. 2007. [110] Epstein, J., I.R. Sanderson, and T.T. MacDonald, Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. British journal of nutrition, 2010. 103(11): p. 1545-1557. [111] Henrotin, Y., et al., Biological actions of curcumin on articular chondrocytes. Osteoarthritis and Cartilage, 2010. 18(2): p. 141-149. [112] ABE, Y., S. Hashimoto, and T. HORIE, Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacological Research, 1999. 39(1): p. 41-47. [113] Sugiyama, Y., S. Kawakishi, and T. Osawa, Involvement of the β-diketone moiety in the antioxidative mechanism of tetrahydrocurcumin. Biochemical pharmacology, 1996. 52(4): p. 519-525. [114] Pari, L. and P. Murugan, Antihyperlipidemic effect of curcumin and tetrahydrocurcumin in experimental type 2 diabetic rats. Renal failure, 2007. 29(7): p. 881-889. [115] Kumar, M., et al., Cerebroprotective role of Tetrahydro Curcumin in hyperhomocysteinemic ischemic mice by regulating NF-kappa B. The FASEB Journal, 2009. 23(1_MeetingAbstracts): p. 614.7. [116] Mukhopadhyay, A., et al., Anti-inflammatory and irritant activities of curcumin analogues in rats. Agents and actions, 1982. 12(4): p. 508-515. [117] Sandur, S.K., et al., Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis, 2007. 28(8): p. 1765-1773. [118] Murakami, Y., et al., Comparative anti-inflammatory activities of curcumin and tetrahydrocurcumin based on the phenolic OH bond dissociation enthalpy, ionization potential and quantum chemical descriptor. Anticancer research, 2008. 28(2A): p. 699-707. [119] Yanagisawa, D., et al., Relationship between the tautomeric structures of curcumin derivatives and their Aβ-binding activities in the context of therapies for Alzheimer’s disease. Biomaterials, 2010. 31(14): p. 4179-4185. [120] Payton, F., P. Sandusky, and W.L. Alworth, NMR study of the solution structure of curcumin. Journal of natural products, 2007. 70(2): p. 143-146. [121] Jovanovic, S.V., et al., H-atom transfer is a preferred antioxidant mechanism of curcumin. Journal of the American Chemical Society, 1999. 121(41): p. 9677-9681. [122] Lin, J.-K., M.-H. Pan, and S.-Y. Lin-Shiau, Recent studies on the biofunctions and biotransformations of curcumin. Biofactors, 2000. 13(1): p. 153-158. [123] Martelli, L., et al., A potential role for the vanilloid receptor TRPV1 in the therapeutic effect of curcumin in dinitrobenzene sulphonic acid‐induced colitis in mice. Neurogastroenterology & Motility, 2007. 19(8): p. 668-674. [124] Yamamoto, M., et al., IL-6 is required for the development of Th1 cell-mediated murine colitis. The Journal of Immunology, 2000. 164(9): p. 4878-4882. [125] Ferretti, M., et al., Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis. Journal of Clinical Investigation, 1994. 94(1): p. 449. [126] Neurath, M.F., et al., Local administration of antisense phosphorothiate olignucleotides to the p65 subunit of NF–κB abrogates established experimental colitis in mice. Nature medicine, 1996. 2(9): p. 998-1004. [127] Kim, M.-C., et al., Vanillic acid inhibits inflammatory mediators by suppressing NF-κB in lipopolysaccharide-stimulated mouse peritoneal macrophages. Immunopharmacology and immunotoxicology, 2011. 33(3): p. 525-532. [128] Goel, A., C.R. Boland, and D.P. Chauhan, Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer letters, 2001. 172(2): p. 111-118. [129] Cho, J.-W., et al., Curcumin inhibits the expression of COX-2 in UVB-irradiated human keratinocytes (HaCaT) by inhibiting activation of AP-1. Experimental and molecular medicine, 2005. 37(3): p. 186-192. [130] Kanski, J., et al., Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: structure-activity studies. The Journal of nutritional biochemistry, 2002. 13(5): p. 273-281. [131] Scapagnini, G., et al., Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxidants & redox signaling, 2006. 8(3-4): p. 395-403. [132] Suzuki, A., et al., Short-and long-term effects of ferulic acid on blood pressure in spontaneously hypertensive rats. American journal of hypertension, 2002. 15(4): p. 351-357. [133] Hlavačková, L., et al., Spice up the hypertension diet-curcumin and piperine prevent remodeling of aorta in experimental L-NAME induced hypertension. Nutr Metab (Lond), 2011. 8: p. 72. [134] Yang, F., et al., Binding of ferulic acid to cytochrome< i> c enhances stability of the protein at physiological pH and inhibits cytochrome< i> c-induced apoptosis. Chemico-biological interactions, 2007. 170(3): p. 231-243. [135] Kampa, M., et al., Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: potential mechanisms of action. Breast Cancer Res, 2004. 6(2): p. R63-74. [136] Huang, T.-Y., et al., Demethoxycurcumin retards cell growth and induces apoptosis in human brain malignant glioma GBM 8401 cells. Evidence-Based Complementary and Alternative Medicine, 2012. 2012. [137] Reinke, A.A. and J.E. Gestwicki, Structure–activity relationships of amyloid beta‐aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chemical biology & drug design, 2007. 70(3): p. 206-215. [138] Park, S.-Y., et al., Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food and Chemical Toxicology, 2008. 46(8): p. 2881-2887. [139] Hamaguchi, T., et al., Phenolic compounds prevent Alzheimer’s pathology through different effects on the amyloid-β aggregation pathway. The American journal of pathology, 2009. 175(6): p. 2557-2565. [140] Jobin, C., et al., Curcumin blocks cytokine-mediated NF-κB activation and proinflammatory gene expression by inhibiting inhibitory factor I-κB kinase activity. The Journal of Immunology, 1999. 163(6): p. 3474-3483. [141] Menon, V.P. and A.R. Sudheer, Antioxidant and anti-inflammatory properties of curcumin, in The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. 2007, Springer. p. 105-125. [142] Sultana, R., et al., Ferulic acid ethyl ester protects neurons against amyloid β‐peptide (1–42)‐induced oxidative stress and neurotoxicity: relationship to antioxidant activity. Journal of neurochemistry, 2005. 92(4): p. 749-758. [143] Ono, K., M. Hirohata, and M. Yamada, Ferulic acid destabilizes preformed β-amyloid fibrils in vitro. Biochemical and biophysical research communications, 2005. 336(2): p. 444-449. [144] Silverman, R.B. and M.W. Holladay, The organic chemistry of drug design and drug action. 2014: Academic press. [145] Pajouhesh, H. and G.R. Lenz, Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005. 2(4): p. 541-553. [146] Masoudi-Nejad, A., Z. Mousavian, and J.H. Bozorgmehr, Drug-target and disease networks: polypharmacology in the post-genomic era. Silico Pharm, 2013. 1: p. 17. [147] Ma, B., Editorial (Thematic Issue: Protein-protein interaction: from interface to interaction network). Current pharmaceutical design, 2014. 20(8): p. 1171-1172. [148] Flower, D.R., The Immune System as Drug Target. Immunology and Immunogenetics Insights, 2013. 5: p. 1. [149] Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England journal of medicine, 2004. 350(23): p. 2335-2342. [150] Onoue, S., et al., Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability. Journal of pharmaceutical sciences, 2010. 99(4): p. 1871-1881. [151] Canamares, M., J. Garcia-Ramos, and S. Sanchez-Cortes, Degradation of Curcumin Dye in Aqueous Solution and on Ag Nanoparticles Studied by Ultraviolet–Visible Absorption and Surface-Enhanced Raman Spectroscopy. Applied spectroscopy, 2006. 60(12): p. 1386-1391. [152] Bosch, E., et al., Retention of Ionizable Compounds on HPLC. pH Scale in Methanol-Water and the p K and pH Values of Buffers. Analytical Chemistry, 1996. 68(20): p. 3651-3657.


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