alexa Anti-Inflammatory Effects of p-coumaric Acid in LPS-Stimulated RAW264.7 Cells: Involvement of NF-κB and MAPKs Pathways | OMICS International
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Anti-Inflammatory Effects of p-coumaric Acid in LPS-Stimulated RAW264.7 Cells: Involvement of NF-κB and MAPKs Pathways

Claudia E Morales-Martínez1, Ana L Márquez-Aguirre1, Emmanuel Díaz-Martínez1, Jorge A Rodríguez-González2, Juan C Mateos-Díaz2, Hugo Esquivel-Solís1, Carlos Alvarez-Moya3 and Alejandro A Canales-Aguirre1*

1Medical and Pharmaceutical Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Jalisco, Mexico

2Industrial Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Jalisco, Mexico

3Environmental Laboratory Mutagenesis, Cellular and Molecular Department, CUCBA University of Guadalajara, Carr. a Nogales Km 15.5, Zapopan,45020, México

*Corresponding Author:
Alejandro A Canales-Aguirre
Medical and Pharmaceutical Biotechnology
Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ)
Guadalajara 44270, Jalisco, Mexico
Tel: +5213333455200 extn. 1303
E-mail: [email protected]

Received May 18, 2016; Accepted May 23, 2016; Published May 30, 2016

Citation: Morales-Martínez CE, Márquez-Aguirre AL, Díaz-Martínez E, Rodríguez-González JA, Mateos-Díaz JC, et al. (2016) The Prospective Antiobesity Effect of Capsaicin Synthetic Analogs: A Matter of Weight. Med chem (Los Angeles) 6:365-371. doi:10.4172/2161-0444.1000371

Copyright: © 2016 Morales-Martínez CE, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

P-coumaric acid (p-CA), which was widely found in nutritious plant foods, has various anti-inflammatory effects in vivo. In order to clarify the anti-inflammatory mechanisms, the effects on lipopolysaccharide (LPS)-stimulated inflammatory responses in RAW264.7 macrophage cells were examined by pretreated with P-CA (10-100 μg/ml). P-CA significantly inhibited iNOS, COX-2, IL-1β and TNF-α expression at mRNA and/or protein level. Furthermore, P-CA suppressed the phosphorylation of IκB and ERK1/2. The above results suggest that P-CA may inhibit the production of inflammatory cytokines induced by LPS through blocking NF-kB and MAPKs signaling pathways, which further support the anti-inflammatory and immunomodulatory potential of P-CA in different models of inflammation.

Keywords

Capsicum annum; Capsaicinoids; Capsaicin; Capsaicin analogs; Antiobesity; Olvanil; TRPV-1

Introduction

Obesity is caused by an increased intake of highly caloric foods and by a sedentary lifestyle. Therefore, it is important to search for new strategies or therapies that prevent weight gain or are helpful to lose weight. Pharmacological therapy is a complementary strategy to lowcaloric diet and physical activity for weight loss and weight maintenance. There are many drugs approved by the Food and Drug Administration indicated for weight loss in obesity, which can be classified by their mechanism of action: 1) appetite suppression, 2) lipase inhibitors and 3) increased energy expenditure. Nevertheless, such drugs might have many side effects [1].

It has been demonstrated that numerous foods have beneficial effects in body-weight management [2,3] but only a few bioactive elements have been discovered and studied, such as resveratrol from grapes, genistein from soy and quercetin from onion [4,5]. Capsaicin, the bioactive component of red pepper, has been shown potent effects as lipid metabolism modulator [6]. However, its therapeutic use has been limited due to its high pungency. For this reason, the synthesis of capsaicin analogue molecules without pungency, may be an excellent alternative strategy for treating obesity and its associated health complications.

In this review we addressed the compilation and analysis of the most recent studies about the pharmacological effects of natural and synthetic capsaicin analogs in energy balance and adipocyte biology. The scientific data of its possible mechanisms of action is also discussed.

Pathogeny of Obesity

The abnormal increase of adipose tissue in the body is the cause of overweight and obesity. Despite the complexity of their etiology, the low energy expenditure due to less physical activity and the intake of a High-Caloric Diet, are advised the major causes. Excess in energy balance (blood stream), induces adipocytes to accumulate energy as triglycerides that leads to hypertrophic adipose tissue. The free fatty acid (FFA) flux from adipocyte lysis, together with the metabolic abnormalities of cholesterol in hypertrophied adipocytes cause the obesity-related dyslipidemias, exacerbating the problem. The wellknown lipid master regulators, members of the PPAR (Peroxisome Proliferator-Activated Receptor) family, principally PPAR-gamma, participate in lipid homeostasis abnormalities throughout the body and specifically in adipose tissue during obesity. When PPAR-gamma is over activated it promotes the activation of adipogenic genes and the blockade of anti-adipogenic genes [7]. Thus blocking of PPAR-gamma in obesity is one of the most important drug targets.

Capsaicinoids

Capsaicinoids are bioactive components than can be found in the fruits of the plant genus Capsicum, better known as chilli peppers. They are produced as secondary metabolites that deter consumption by vertebrates and discourage predators without deterring more effective seed dispersers [8]. Currently, capsaicinoids are known as chemicals responsible for the fruit's peppery heat, burning sensation and the hot or spicy flavor they confer [9]. There have been identified nine naturally occurring capsaicinoids in peppers which differences are centered on carbon-carbon double bonds and pungency levels according to Scoville´s heat unit scale [10,11].

An aromatic ring integrates the chemical structure of capsaicinoids, named catechol or vaniloid ring which contains two substituents in the positions 3 and 4. Moreover, capsaicinoids also have a fatty acid hydrophobic side chain linked by an amide bond (Figure 1) [12]. Natural capsaicinoids are N-vanillylamides of fatty acids and their structural conformations depend on the number of lateral chain carbons or the presence/absence of unsaturations. In comparison, capsaicin synthetic analogs may have other modifications as addition/deletion of one or more functional groups [11].

Figure

Figure 1: Capsaicin chemical structure. All capsaicinoids are quite similar to capsaicin, they preserve the catechol/vaniloid ring (A) and the amide bond (B), while they differ on the fatty acid side chain (C).

All these molecules have shown a wide variety of biological and pharmacological properties, as antiobesity on which relies their therapeutic values. On this regard, capsaicin has gained the most scientific interest.

Capsaicin

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the most abundant capsaicinoid in peppers comprising the 50-60% [13]. It was discovered by Tresh in 1846 and its chemical structure was determined by Nelson in 1919. Following years of study, it has been demonstrated that capsaicin is one of the most promissory constituents because its important pharmacological effects of which antinociception was the first evidenced [14]. Capsaicin is currently used for treatment of several pain syndromes, including diabetic neuropathy [15]. Moreover, capsaicin has also demonstrated beneficial effect on osteoarthritis pain relief due to its high capacity to inhibit P substance release, a powerful neuropeptide pain neuromodulator from the sensory nerves to the central nervous system [16].

Capsaicin has also shown potential effects as anti-obesity drug [6]. There is plenty of evidence that capsaicin can induce body weight reduction, [17] increases energy expenditure, [18] improves lipolysis in adipocytes [19] (Table 1). Additionally, some clinical studies support that capsaicin ingestion increased satiety and reduced energy and fat intake during negative energy balance [20]. Similar studies have shown that capsaicin increases the sensation of fullness and decreases the desire to eat [21-27].

CAPSAICIN
2011 Exerts lipolytic action by increasing the mRNA levels of HSL, CPTI-α, UCP2 genes in 3T3-L1 cells [19]
2013 Inhibit the LPL mRNA expression level in 3T3-L1 cells [22]
2013 Topical application reduces weight gain and visceral fat and decreases the expression of TNF-α and IL-6 in high-fat-induced obese mice [17]
2014 Inhibits proliferation and differentiation 3T3-L1 preadipocytes by decreasing the protein expression of LPL, leptin, PPARÉ£ and C/EBPα [23]
2014 Decreases the serum levels of TG, LDL and HDL and UPC2, PPARÉ£, leptin gene expression in high- fat induced obese rats [24]
2014 Increases satiety and sensation of fullness in healthy humans [21]
2015 Inhibits the adipogenic differentiation of mesenchymal stem cells by repressing PPARÉ£, C/ EBPα, FABP4 and SCD-1 gene expression [25]
SYNTHETIC ANALOGS
Nonivamide
2014 Reduces feelings of hunger and carbohydrates intakes in moderately overweight men [26]
2015 Reduces fatty acid uptake and increases the acetyl-coenzyme A synthetase activity by Caco-2 cells [27]
2015 Decreases lipid accumulation in 3T3-L1 cells by reducing the PPARÉ£ protein levels [73]
Olvanil
2015 Improves lipolysis process while decreases the intracellular triglycerides in 3T3-L1 cells [*]
2015 Inhibits adipogenesis by reducing the PPARÉ£ activity in 3T3-L1 cells [*]
Phenylacetylrinvanil
  Induces apoptosis and inhibits in vitro cell proliferation of carcinogenic cell lines HeLa, J774, CasKi, ViBo and P388. [79,80]

Table 1: Antiobesity effect of capsaicin and their synthetic analogs.

Despite the wide evidence of the favorable capsaicin effects in metabolism regulation, applications of this molecule are limited by its pungency. For the same reason, the doses employed in clinical trials are lower than those reported in vitro and in vivo preclinical tests. Thus it has been difficult to achieve similar effects in clinical research until date.

Mechanism of action

Binding of capsaicin to its receptor TRPV1: Capsaicin is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), better known as vanilloid receptor 1. This receptor is a nonselective cation channel that allows the transient influx of Ca2+ when is activated during the detection and transduction of nociceptive stimuli [28]. Its structure and topology have been well characterized [29]. This receptor was initially found on key sensory afferents neurons and it has recently been shown expressed in hepatocytes, kidney cells and adipocytes [30]. Several studies have focused on elucidating how capsaicin interacts and regulates TRP channels. Such may help as model of the capsaicin-channel complex for pharmacological applications and would potentially guide further developments of capsaicin analogs. These experimental reports have shown that capsaicin binds to a pocket of TRPV1 in a conformation where the vanillyl ring points toward the S4-S5 linker, while the lipid tail points upward in the direction of the S4 helix, [31] where Tyr511 was critical for vanilloid sensitivity [32] Yang et al. proposed that, though matching with the ‘tail-up, head-down’ model, the specificity for ligand binding is bestowed by hydrogen bonds that formed between its vanillyl head with residues E571 and Tyr511 of the TRPV1 channel [33].

Capsaicin molecular target in adipocyte: It has not yet been clarified in detail the mechanism by which capsaicin exerts its antiadipogenic effect, however, some findings suggest the possible signaling pathways, which are described in Figure 2.

Figure

Figure 2: Putative signaling pathways of capsaicin in the adipocyte. It has been described that capsaicin and its analogs bind the Transient Receptor Potential Vanilloid 1 (TRPV1), a non-specific cation channel located in the cellular membrane which comprises six putative transmembrane segments (S1-S6), intracellular N- and C-termini, and a cation-selective pore-forming reentrant loop between S5 and S6 with high permeability to calcium. Capsaicin and its analogues pass through the cell membrane by their lipophilic properties and bind their vanilloid ring to theresidue Tyr511 located on the intracellular loop between S2 and S3 of TRPV1 leading to a conformational change that opens the cation-selective pore.This triggers an influx of extracellular Ca2+ resulting in a high cytosolic concentration. As it is well known that Ca2+ is one of the most versatile second messengers that can activate several Ca2+-binding proteins, we suggest that capsaicin and its analogues might activate calmodulin-calcineurinand then the MAPK pathway, which this has been reported to blockadePPARÉ£- and C/EBPα-dependent adipogenesis by PPARÉ£-phosphorylation, ubiquitination and degrading. In addition, since AMP-activated protein kinase (AMPK), a metabolic regulator that reduces the PPARÉ£-mediated transcriptional activity, can be activated by calmodulin-dependent protein kinase kinase-β (CaMMKKβ) through elevated intracellular Ca2+ levels, we propose this as an additional signaling pathway of capsaicin and its analogues.Furthermore, it has been found that the increase of intracellular Ca2+activates connexin43 (Cx43), a major gap junction protein that should be degraded through the phosphorylation-ubiquitination course to allow the differentiation of adipocytes. We suggest thatCx43 is up-regulated by the Ca2+ influx after capsaicin and its analogues bound TRPV1, thus preventing adipogenesis by an unknown mechanism.

Because capsaicin and its analogues are lipophilic, they pass through the cell membrane and act on binding site located in the intracellular portion of the TRPV1 receptor. The interaction of vanillyl head of capsaicin with residue Tyr 511 (located between the second and third transmembrane domain) of the TRPV1 receptor leads to a conformational change that opens the channel by the pore-forming S5–S6 transmembrane helix. Because TRPV1 is a Ca2+ channel with high permeability its activation triggers an influx of Ca2+, resulting in increased cytosolic concentration [34]. It is known that calcium in the cell is one of the most versatile second messengers in numerous intracellular signaling pathways, and a change in the intracellular Ca2+ levels, actives a number of intracellular Ca2+-binding proteins, including calmodulin (CaM), calcineurin B, protein kinase A (PKA), S100B and DREAM [35]. Calcineurin mediates the calcium-dependent inhibition of adipogenesis in 3T3-L1 cells by preventing the expression of the pro-adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARÉ£) and CCAAT/enhancer-binding protein alpha (C/EBPα) by a still unknown mechanism [36]. These results were tested again and found that the increase of extracellular Ca2+ influx activates connexin43 (Cx43) [37], a major gap junctions protein that should be phosphorylated and degraded to allow the differentiation of adipocytes [38]. Therefore, calcium influx induced by the action of capsaicin might probably act on the maintaining of Cx43 thus interrupting the adipocyte differentiation and adipogenesis. Additional work suggests that activation of AMP-activated protein kinase (AMPK), a regulator pathway of metabolism, reduces the PPARÉ£- mediated transcriptional activity [39,40]. Reports supported that AMPK can be activated by an elevated intracellular Ca2+ level mediated by calmodulin-dependent protein kinase kinase-β (CaMMKKβ) [41].

Despite these investigations, there are still some questions about the intracellular downstream signaling targets of capsaicin in adipocytes and thus the real mechanism is still unknown.

Capsaicin Analogs

Capsaicin analogs are molecules that preserve all or part of the aromatic catechol ring in its chemical structure, which are clearly demonstrated to be TRPV1 receptor agonists [42]. Nevertheless, they may or may not have similar effects due to different functional groups and variable number of carbon-carbon double bonds located in different positions along the chain, which may modify its pungency level and biological activity [43]. Here we present the current knowledge of some of the most studied.

Natural analogs

Capsiate: It was the first natural capsaicin analogue characterized in the CH-19 sweet pepper variety (Capsicum annum L.) [44]. Similar to capsaicin, is the most abundant capsinoid in peppers of this variety. The main difference between capsiate and capsaicin is the pungency level; capsiate is a non-pungent capsinoid. Capsiate is structurally identical to capsaicin, except that it has an ester bond rather than an amide bond between the vanilloid ring and the fatty acid chain (Figure 3). It is known that this molecule exerts some of the same effects as capsaicin, such as the increase in swimming endurance capacity of mice by raising fat oxidation, thus improving carbohydrate utilization [45] and glucose homeostasis while, decreasing fat accumulation in diabetic rats [46] and suppressing fat accumulation in adipocytes 3T3-L1 [47]. Capsiate, also increases energy expenditure and enhances fat oxidation at high doses in humans [48]. Additionally, recent research has shown that capsiate also activates TRPV1 and other TRP channels by an as yet unknown mechanism by which evokes its action [49].

Figure

Figure 3: Names and chemical structure of natural and synthetic analogs of capsaicin.

Resiniferatoxin (RTX): RTX is also a natural ultra-pungent capsaicin analogue found in the latex of Euphorbia resinifera, a cactuslike plant and is ten times as pungent as capsaicin. This molecule preserves the aromatic catechol ring and contains an ester bond rather than an amide bond in its chemical structure (Figure 3). It has been shown that unlike the capsaicin-induced adrenaline increase, RTX produced only a slowly initiated adrenaline reaction [50]. However, it preserves the analgesic effect because it diminishes thermal pain sensitivity but increases the sensitivity to tactile stimulation in adult rats [51]. Studies on the potential role of RTX in the regulation of lipid metabolism are limited.

Piperine: Piperine is the molecule responsible for the pungency of black pepper and is also considered a capsaicin analogue due to its capacity to produce a clear agonist activity at the TRPV1 receptor [52]. Nevertheless, piperine contains a benzodioxole ring rather than an aromatic catechol ring present in capsaicin (Figure 3), it is considered a capsaicin analogue due to its high TRPV1 affinity [53]. A number of studies have been addressed to elucidate the biological roles and physiological effects of piperine, such as the enhancement of the digestive capacity, the reduction of the gastrointestinal transit time for food, its ability to protect against oxidative damage and increasing the bioavailability of a number of therapeutic drugs, and some anti-tumoral effects as well [54]. To date, piperine has been reported to exhibit similar biological activities as capsaicin, including inhibition of adipogenesis by antagonizing PPARÉ£ activity in 3T3-L1 cells [55], reduction of HFD-induced hepatic steatosis by decreasing triglycerides, free fatty acids and cholesterol in liver, as well decrease of hepatic lipogenic markers such as LXR, SREBP1c, Leptina, aP2 y CD36 in mice [56]. Nevertheless, other in vivo studies reported that piperine consumption does not amplify beneficial effects of caloric restriction in obese mice [57].

Gingerol: 6-gingerol is the bioactive constituent of the rhizome of fresh ginger (Zingiber officinale). Chemically, gingerol contains the characteristic vanilloid ring without the amide bond and the double bond in the carbon chain. It has an insertion of a hydroxyl group at C-5 (Figure 3) and has been used as a medicinal plant since ancient times because it possesses several pharmacological activities, including the effect on lipid metabolism [58]. Previous research has shown that 6-gingerol may reduce adiposity by promoting the catabolism of lipid through the increase of acetyl-coenzyme A acyl-transferase in high-fat diet mice [59]. It has also been shown a decrease in glucose levels, body weight, leptin, insulin and tissue lipids in high-fat diet-induced obese rats treated with 6-gingerol [60,61]. Furthermore, gingerol prevents adipogenesis in 3T3-L1 through the significant down-regulation of PPARÉ£ and C/EBPα [62,63].

Synthetic analogs

Since the discovery of multiple capsaicinoid effects, a number of researchers have focused in the chemical characterization of these molecules [64,65]. However, the development of additional potential of capsaicinoids as drugs has been restricted by their limited natural availability and low structural variability. At the moment, chemical synthesis has been an alternative tool to discover new capsaicin analogs without the inherent and undesirable effects [66,67]. In this section, we described the knowledge on synthetic analogs molecules that have shown similar effects to capsaicin, emphasizing the effect on lipid metabolism and energy balance.

Palvanil: N-Palmitoyl-vanillamide is a non-pungent capsaicin analogue, which is currently obtained by enzymatic synthesis [68]. It contains the aromatic catechol ring linked to a palmitic acid (CH3 (CH2)14COOH) by an amide bond in its chemical structure (Figure 3). Recent studies have shown that Palvanil is an antinociceptive agent because it inhibits inflammatory and neuropathic pain by activating TRPV1 receptor, besides, it has been demonstrated that this molecule produced significantly less side effects such as hypothermia and bronchoconstriction than capsaicin [69]. The use of Palvanil in the treatment of pathologies such as inflammatory and neuropathic hyperalgesia and other types of pain has been protected for commercial purposes [70]. However, there is a lack of studies regarding the potential effects of Palvanil in the regulation of lipid metabolism.

Nonivamide (VAMC9): The chemical name of Nonivamide is N-vanillylamide of nonanoic acid and is also obtained by enzymatic synthesis through a direct lipase-catalyzed reaction [71]. It contains the aromatic catechol ring linked to a pelargonic acid (CH3 (CH2)14COOH) by an amide bond (Figure 3). Nonivamide is a capsaicin analogue with two times less pungency than capsaicin (9,200,000 SHU compared to 16,100,000 SHU for capsaicin). It has been reported to exhibit similar biological activities as capsaicin, including the increase in intracellular Ca2+ levels via the activation of vanilloid receptors in some cell types [72], the reduction of lipid accumulation in adipocytes by decreasing PPARÉ£ protein levels in a similar way than capsaicin [73]. In the report of the only clinical trial performed with Nonivamide to our knowledge, is been shown that the addition of nonivamide to a glucose solution ad libitum, reduced the energy intake from a standardized breakfast in moderately overweight men [26]. This suggests that Nonivamide has a therapeutic potential as anti-obesity drug with better efficacy than capsaicin but without the undesirable effects of pungency.

Arvanil: The Arvanil´s chemical name is N-Vanillylarachidonamide. It contains the aromatic catechol ring linked to an arachidonic acid by an amide bond in its structure (Figure 3). It is also obtained by enzymatic synthesis and it has been demonstrated that only one modification in its chemical structure changes its biological activity. For example, methylation of the amide group decreases the affinity to TRPV1, and the substitution of the 3-methoxy group with a chlorine atom on the aromatic ring, increases its capacity to inhibit fatty acid amide hydrolase [74]. It has been shown that Arvanil has a beneficial effect in a rat model of Huntington´s disease, reducing ambulatory and stereotypic activity, and increasing the activity [75]. Moreover, it has been demonstrated the beneficial potential of Arvanil in neuronal affectations such as astrocytomas and mild cognitive impairment [76]. However, there is a lack of evidence about the Arvanil effects on the regulation of lipid metabolism.

Olvanil: Olvanil is a non-pungent capsaicin analogue that is also obtained by enzymatic synthesis through a direct lipase-catalyzed reaction [66,77]. It contains the aromatic catechol ring linked to an oleic acid by an amide bond (Figure 3).

Although its antinociceptive effect was discovered in 1990, no more studies on its potentially actions have been published to date. In our group, we found that olvanil treatment improves lipolysis while decreases the amount of intracellular triglycerides in 3T3-L1 cells in a similar manner to capsaicin. We also found that olvanil inhibits adipogenesis by reducing the activity of PPARÉ£ and preventing the maturation of 3T3-L1 preadipocytes (data send for publication).

Phenylacetylrinvanil (PhAR): PhAR is a capsaicin analogue, without pungency but with one thousand more affinity to TRPV1 receptors than capsaicin [78]. It contains an insertion of a hydroxyl group at C-12 of the chemical structure of olvanil and the presence of an additional functional group (Figure 3). About the potentials of this molecule, only the anti-carcinogenic effect has been evidenced. Recent studies have proven that PhAR induces apoptosis in leukaemia cell lines, such as P388, J774 and WEHI-3 [79] and it also inhibits in vitro cell proliferation of carcinogenic cells such as HeLa, CasKi and ViBo [80]. However, no evidence was found of its possible role in energy metabolism regulation.

Conclusions

Synthesis of capsaicin analogs and its chemical variants are a very useful alternative tool for drug therapy of obesity. Besides, their study might be helpful to understand the structural-activity relationship of molecules that have shown a highly medicinal value but with undesirable side effects, like capsaicin. Information found in scientific literature about the biological activity on metabolic disease of capsaicin analogs synthetized until now, adds knowledge about the plausible molecular mechanisms and possible portion of the capsaicin chemical structure responsible for its effect that is not completely understood.

Vanillyl structure was considered very important for activation of the TRPV1 receptors, however, as can be seen in the available data, it has been recently found that molecules lacking the vanillyl structure can also activate the TRPV1 receptors and in some cases magnify the affinity to these receptors, higher than capsaicin itself. This could lead to the conclusion that there are other structural moieties or functional groups than can activate TRPV1 receptors, inducing the same or enhanced biological effects, therefore, the concept “capsaicin analogue” can be difficult to define. Another important subject is the fact that many capsaicin analogs, despite having different pungency levels, have the same receptor affinity and different antinociception capacity but some preserve, and in some cases increase, their potential benefits in the regulation of metabolism, like nonivamide and olvanil compared to capsaicin. The majority of evidence provided suggest that the pungency level of these molecules does not determine the biological effect discussed here. Additional work should be conducted on synthetizing different analog molecules with some structural modifications, based in previous research to obtain a better molecule with the highest potential therapeutic effect but with less inherent undesirable side effects.

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  1. Jemima
    Posted on Sep 29 2016 at 9:57 pm
    In general, the study has its significance to elucidate the biological mechanism of P-CA.
 

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