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Keywords:

  • resveratrol;
  • piceatannol;
  • 3,5,4′-trans-trimethoxystilbene;
  • heme oxygenase-1;
  • tumor necrosis factor-α;
  • interleukin-1β;
  • macrophages

Abstract

  1. Top of page
  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References

Resveratrol (Res) and its two natural analogs that are also related to Res metabolism, piceatannol (Pic) and 3,5,4′-trans-trimethoxystilbene (TMS), were compared in their ability to suppress lipopolysaccharide (LPS)-induced production of proinflammatory tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and to induce anti-inflammatory heme oxygenase-1 (HO-1) expression in RAW264.7 macrophages. At non-cytotoxic concentrations, they differentially suppressed LPS-induced production of TNF-α and IL-1β; the relative potency for suppression of TNF-α and IL-1β production was Pic > Res > TMS. Res and Pic differentially induced HO-1 expression; Pic, which possesses four hydroxyl groups, was more active in inducing HO-1 expression than Res that contains three hydroxyl groups. TMS, which has none of hydroxyl groups, failed to induce HO-1 expression. These findings suggest that the hydroxyl groups of Res analogs are important for suppression of TNF-α and IL-1β production and HO-1 expression. Interestingly, protoporphyrin-IX, a competitive inhibitor of HO-1 activity, partly attenuated the inhibitory effects of Res and Pic (but not TMS) on TNF-α and IL-1β production, suggesting that suppression of TNF-α and IL-1β production correlates at least in part with HO-1 expression. Overall, the ability of Res analogs to induce HO-1 expression may provide one of possible mechanisms of their anti-inflammatory action. © 2013 BioFactors, 40(1):138–145, 2014.

1. Introduction

  1. Top of page
  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References

Resveratrol (3,4′,5-trans-trihydroxystilbene; Res), a naturally derived stilbenoid that exist in various foods, beverages, and medicinal plants, has been reported to have a variety of biological and pharmacological activities [1]. These beneficial effects of Res have been supported by observations at the cellular and molecular levels in cellular and in in vivo models; however, Res presents a low bioavailability and a rapid clearance from the circulation via its excessive metabolism [2]. Indeed, Res found in plasma samples constituted less than 2% of the total Res consumed [3], and, therefore, it is most likely that the metabolic forms of Res may reach the target tissues. Thus, it is necessary to investigate the biological mechanisms for which Res metabolites could exert a biological activity. Piceatannol (3,3′,4′,5-trans-tetrahydroxystilbene; Pic), one of such metabolites, is formed in vivo from Res by the cytochrome p450 enzyme CYP1B1 [4]. 3,5,4′-trans-Trimethoxystilbene (TMS), a naturally occurring analog of Res [5], may have higher metabolic stability over Res, because all of its hydroxyl groups, which are subjected to extensive glucuronide or sulfate conjugation in the metabolic pathways of Res, are protected by methylation [6]. Res and its naturally occurring stilbenoids, Pic and TMS, have been reported to possess anti-inflammatory effects [1, 7, 8]. However, the underlying molecular mechanisms are not yet fully understood. Moreover, how these stilbenoids (chemical structures shown in Fig. 1) differ with respect to anti-inflammatory effects is not well understood; and thus was investigated in this study.

image

Figure 1. Chemical structures of resveratrol (Res; upper), piceatannol (Pic; middle), and trnas-3,5,4′-trimethoxystilbene (TMS; lower).

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Macrophages play a critical role in the initiation and amplification of inflammation in a variety of inflammatory diseases via the excess production of the proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the generation of other proinflammatory mediators [9]. In models of inflammation where several cytokines are produced, specific blockade of either TNF-α or IL-1β or both results in a reduction in the severity of the inflammation, indicating TNF-α and IL-1β as primary proinflammatory cytokines involved in inflammation [10]. Thus, the suppression of TNF-α and IL-1β production is a promising strategy for reducing the potentially harmful proinflammatory activity of macrophages. Recently, it has been suggested that macrophages possess regulatory pathways where the regulatory mechanisms can operate to control the proinflammatory responses via induction of the anti-inflammatory enzymes and thus limit the destructive potential [11]. Among the anti-inflammatory enzymes expressed in macrophages, inducible heme oxygenase-1 (HO-1) has been shown to play regulatory roles in the production of proinflammatory cytokines [12]. HO-1 is a rate-limiting enzyme that degrades the pro-oxidant heme into carbon monoxide, free iron, and biliverdin that is rapidly converted into bilirubin by cellular biliverdin reductase [13]. This enzyme has been suggested to play a regulatory role in the resolution phase of inflammation and is considered as a potential therapeutic target for treating various inflammatory diseases [14]. Interestingly, some phytochemicals, which occur naturally in many medicinal plants, and some drugs, which are clinically used for treatment of inflammatory diseases, have been reported to induce HO-1 expression and exert their anti-inflammatory effects through HO-1 expression [15-22].

There are several natural stilbenoids that are structurally similar to Res and also related to potential metabolism of Res [23-25]. They may possess some of the beneficial effects of the parent Res and provide even further benefits. In this study, we investigated the comparative effects of Res, Pic, and TMS on the production of the proinflammatory TNF-α and IL-1β and the expression of the anti-inflammatory HO-1 in RAW264.7 macrophages. Whether HO-1 expression could mediate the anti-inflammatory effects of these stilbenoids was also addressed.

2. Materials and Methods

  1. Top of page
  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References

2.1. Reagents and Antibodies

Res, Pic, lipopolysaccharide (LPS), tin protoporphyrin-IX (SnPP), TMS, and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma-Aldrich (St. Louis, MO). Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), and other tissue culture reagents were obtained from Invitrogen-Gibco (Carlsbad, CA). Primary antibodies against HO-1 and β-actin were purchased from StressGen Biotechnologies (Victoria, Canada) and secondary antibodies were obtained from Santa Cruz Biotechnologies (Santa Cruz, CA). Enzyme-linked immunosorbent assay (ELISA) kits for TNF-α and IL-1β were purchased from R & D Systems (Minneapolis, MN).

2.2. Cell Culture and Viability Assay

RAW264.7 cells (a mouse macrophage cell line obtained from American Type Culture Collection) were cultured in DMEM supplemented with 10% heat-inactivated FBS and antibiotic/antimycotic cocktail (Invitrogen-Gibco). The macrophages were maintained at 37°C in a humidified incubator containing 5% CO2. In all experiments, RAW264.7 macrophages were allowed to acclimate for 12 h before any treatments. For determination of cell viability, a modified MTT reduction assay was performed. MTT is a pale yellow substance that is reduced by living cells to yield a dark blue formazan product. This process requires active mitochondria, and even fresh dead cells do not reduce significant amounts of MTT. RAW264.7 macrophages were cultured in a 96-well flat-bottom plate at concentration of 5 × 104 cells/mL. After 12 h precondition, the cells were treated with various concentrations of stilbenoids for 24 h. Thereafter, culture medium was aspirated and 100 µL of MTT dye (1 mg/mL) was added; the cultures, then, were incubated for 4 h at 37°C. The formazan crystals produced through dye reduction by viable cells were dissolved using acidified isopropanol (0.1 N HCl). Index of cell viability was calculated by measuring the optical density of color produced by MTT dye reduction at 570 nm.

2.3. Western Blot Analysis

RAW264.7 macrophages were washed with ice-cold phosphate-buffered saline (PBS), scraped into PBS, and collected by centrifugation. Pellets were resuspended in a lysis buffer containing 50 mM HEPES, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 10% glycerol, 0.5% NP-40, 0.5% Tween 20, 1 mM dithiothreitol, and protease inhibitor cocktail and vortexed for 20 min at 4°C; insoluble material was removed by centrifugation. Protein (30 µg) was separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. After transfer to nitrocellulose membrane, blots were blocked with PBS and nonfat milk (5%) and then incubated with antibodies directed against HO-1 or β-actin. Membranes were washed in PBS, incubated with horseradish peroxidase-conjugated secondary antibodies, developed with commercial chemoluminescence reagents (Amersham Biosciences, Arlington Heights, IL), and exposed to X-ray film.

2.4. ELISA for TNF-α and IL-1β

RAW264.7 macrophages on 24-well plate were pretreated for 0.5 h or 6 h with stilbenoids, and then activated with LPS for 24 h. The concentrations of TNF-α and IL-1β in culture supernatant were determined using TNF-α and IL-1β ELISA kits according to the manufacturer's instructions.

2.5. Reverse Transcription Polymerase Chain Reaction

The cells were harvested and total RNA was isolated using RNeasy Mini Kits according to the manufacturer's instructions (Qiagen, Santa Clarita, CA). Two microgram of total RNA was used to synthesis the first stranded cDNA using reverse transcription polymerase chain reaction (RT-PCR) kit (Invitrogen, Carlsbad, CA). For amplification of TNF-α cDNA, the following primers were used: 5′-GCA CAG CCT TCC TCA CAG AG-3′ (sense) and 5′-ACC CGT AGG GCG ATT ACA GT-3′ (antisense). The following primers for IL-1β cDNA amplification were also used: 5′-GCT GTT CCC TTG ACC CAG AC-3′ (sense) and 5′-GGT GAT AAC GGT GGC CTG AC-3′ (antisense). In addition, the cDNA for glyceraldehyde-3-phosphate dehydrogenase was amplified as a control in a similar way using the following primers: 5′-AGG TGG TCT CCT CTG ACT TC-3′ (sense) and 5'-TAC CAG GAA ATG AGC TTG AC-3′ (antisense). For PCR amplification, the following conditions were used: 94°C for 5 min for one cycle and then 94°C for 1 min, 56°C for 30 sec and 72°C for 1 min for 25 cycles. The amplified PCR products were separated with 1.5% agarose gel and then stained with ethidium bromide.

2.6. HO Activity Assay

RAW264.7 macrophages in 150-mm culture dishes were incubated for 6 h in the absence or presence of stilbenoids. Briefly, after the incubation, macrophages were washed twice with PBS, gently scraped off the dish, and centrifuged (1,000g for 10 min at 4°C). The cell pellet was suspended in MgCl2 (2 mM) phosphate (100 mM) buffer (pH 7.4), frozen at −70°C, thawed three times, and finally sonicated on ice before centrifugation at 18,000g for 10 min at 4°C. The supernatant (400 μL) was added to a NADPH-generating system containing 0.8 mM NADPH, 2 mM glucose-6-phosphate, 0.2 U glucose-6-phosphate-1-dehydrogenase, and 2 mg protein of rat liver cytosol prepared from the 105,000g supernatant fraction as a source of biliverdin reductase, potassium phosphate buffer (100 mM, pH 7.4), and hemin (10 μM) in a final volume of 200 μL. The reaction was conducted for 1 h at 37°C in the dark and terminated by addition of 1 mL chloroform. The extracted bilirubin was calculated by the difference in absorption between 464 and 530 nm using a quartz cuvette (extinction coefficient, 40 mM−1 × cm−1 for bilirubin). HO activity was measured as picomoles of bilirubin formed per milligram of cell protein per hour.

2.7. Statistical Analysis

Results are expressed as the means ± SD. Statistical differences between groups were evaluated with Student's two-tailed t-test or by ANOVA with Bonferroni's t-test when multiple groups were compared. Differences were considered to be significant when P < 0.05.

3. Results

  1. Top of page
  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References

The chemical structures of three stilbenoids examined in this study are shown in Fig. 1. While Res contains three hydroxyl groups on its two phenyl rings, Pic contains four, and TMS contains none. In RAW264.7 macrophages, these stilbenoids at concentrations ranging from 1 to 10 μM had no significant effect on cell viability after 24 h incubation (Fig. 2). These non-cytotoxic concentrations of Res, Pic, and TMS were, therefore, used in all subsequent experiments.

image

Figure 2. Effects of Res, Pic, and TMS on cell viability. RAW264.7 macrophages were incubated for 24 h in the absence or presence of Res, Pic, or TMS at indicated concentrations. Cell viability was measured as described under Section 2. Data are expressed as means ± SD from three to four experiments. *P < 0.05 with respect to control group (Con).

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3.1. Res, Pic, and TMS Differentially Suppress LPS-Induced Production of TNF-α and IL-1β

The first objective of the present study was to determine whether Res, Pic, and TMS could differ in their ability to suppress the production of the proinflammatory TNF-α and IL-1β in RAW264.7 macrophages activated with the endotoxin LPS. It was shown that in vitro activation with LPS dramatically increased the expression of TNF-α mRNA and IL-1β mRNA and the production of TNF-α and IL-1β in RAW264.7 macrophages (Fig. 3). Pretreatment of macrophages with Res, Pic, and TMS for 6 h suppressed LPS-induced expression of TNF-α mRNA and IL-1β mRNA and LPS-induced production of TNF-α and IL-1β in a dose-dependent manner, but the potency varied. At the same concentration (10 μM), Pic was the most potent, followed by Res and TMS (Fig. 3). Interestingly, the suppression of TNF-α and IL-1β production was much higher when the macrophages were pretreated with Res and Pic for 6 h prior to LPS activation, as compared to when they were pretreated for 0.5 h prior to LPS activation (Fig. 4). However, the suppression of TNF-α and IL-1β production by TMS was independent of the pretreatment time (Fig. 4).

image

Figure 3. Effects of Res, Pic, and TMS on TNF-α mRNA and IL-1β mRNA expression and TNF-α and IL-1β production. RAW264.7 macrophages were pretreated for 6 h in the absence or presence of Res, Pic, or TMS at indicated concentrations, and then activated with 1 µg/mL of LPS for 4 h or 24 h. A: After stimulation with LPS for 4 h, the levels of TNF-α mRNA were determined by RT-PCR. B: After stimulation with LPS for 24 h, the concentrations of TNF-α in culture supernatant were determined using a commercial TNF-α ELISA kit. C: After stimulation with LPS for 4 h, the levels of IL-1β mRNA were determined by RT-PCR. D: After stimulation with LPS for 24 h, the concentrations of IL-1β in culture supernatant were determined using a commercial IL-1β ELISA kit. Blots shown are representative of three independent experiments. Data are expressed as means ± SD from three to four experiments. *P < 0.05.

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image

Figure 4. Effects of pretreatment with Res, Pic, and TMS on TNF-α and IL-1β production. RAW264.7 macrophages were pretreated for 0.5 h or 6 h in the absence or presence of 10 µM of Res, Pic, or TMS, and then activated for 24 h with 1 µg/mL of LPS. A: The concentrations of TNF-α in culture supernatant were determined using a commercial TNF-α ELISA kit. B: The concentrations of IL-1β in culture supernatant were determined using a commercial IL-1β ELISA kit. Data are expressed as means ± SD from three to four experiments. *P < 0.05.

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3.2. Res, Pic, and TMS Differentially Induce HO-1 Expression

The second objective of the present study was to determine whether Res, Pic, and TMS could differ in their ability to induce the expression of the anti-inflammatory HO-1 in RAW264.7 macrophages. We found that Res and Pic (but not TMS) significantly increased HO-1 expression after 6 h of incubation (Fig. 5A). However, despite displaying a similar basic chemical structure, these compounds affected the pattern of HO-1 protein expression in a different fashion. Pic was more active in inducing HO-1 expression than Res, whereas TMS failed to induce HO-1 expression (Fig. 5A). Consistent with these findings, HO activity also differed for each stilbenoid tested in this study. Pic had higher activity than Res, but TMS had no effect on HO activity (Fig. 5B).

image

Figure 5. Effects of Res, Pic, and TMS on HO-1 expression. RAW264.7 macrophages were incubated for 6 h in the absence or presence of indicated concentrations of Res, Pic, or TMS. A: HO-1 expression was determined by Western blot analysis which is described under Section 2. Blots shown are representative of three independent experiments. B: HO activity was determined as described under Section 2. Data are expressed as means ± SD from three to four experiments. *P < 0.05.

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3.3. Suppression of LPS-Induced Production of TNF-α and IL-1β Correlates with HO-1 Expression

To assess the potential role of HO-1 in inhibition of LPS-induced expression of TNF-α mRNA and IL-1β mRNA and LPS-induced production of TNF-α and IL-1β, RAW264.7 macrophages were pretreated with 10 μM of Res, Pic, or TMS for 6 h in the presence or absence of SnPP, a competitive inhibitor of HO-1 activity, followed by LPS activation. As shown in Fig. 6, SnPP treatment partly attenuated the inhibitory effects of Res and Pic (but not TMS) on LPS-induced expression of TNF-α mRNA and IL-1β mRNA and LPS-induced TNF-α and IL-1β production. SnPP alone had no effect on cell viability (not shown).

image

Figure 6. Effects of SnPP on the inhibitory actions of Res, Pic, and TMS in TNF-α mRNA and IL-1β mRNA expression and TNF-α and IL-1β production. RAW264.7 macrophages were pretreated for 6 h with 10 µM of Res, Pic, or TMS in the absence or presence of 20 µM of SnPP, and then activated with 1 µg/mL of LPS for 4 h or 24 h. A: After stimulation with LPS for 4 h, the levels of TNF-α mRNA were determined by RT-PCR. B: After stimulation with LPS for 24 h, the concentrations of TNF-α in culture supernatant were determined using a commercial TNF-α ELISA kit. C: After stimulation with LPS for 4 h, the levels of IL-1β mRNA were determined by RT-PCR. D: After stimulation with LPS for 24 h, the concentrations of IL-1β in culture supernatant were determined using a commercial IL-1β ELISA kit. Blots shown are representative of three independent experiments. Data are expressed as means ± SD from three to four experiments. *P < 0.05.

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4. Discussion

  1. Top of page
  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References

In the present study, we determined whether Res and its two naturally occurring analogs that are related to Res metabolism, Pic and TMS, could differ in their ability to suppress the production of the proinflammatory TNF-α and IL-1β and also to induce the expression of the anti-inflammatory HO-1 in RAW264.7 macrophages. This study demonstrates that at noncytotoxic concentrations, pretreatment with the stilbenoids examined in this study differentially suppressed the expression of TNF-α mRNA and IL-1β mRNA and the production of TNF-α and IL-1β in LPS-stimulated macrophages; the relative potency for suppression of TNF-α and IL-1β production was Pic > Res > TMS. This study also demonstrates that Res and Pic, one of Res metabolites, differentially induced HO-1 expression in macrophages; Pic was more active in inducing HO-1 expression than Res. Interestingly, TMS that may have higher metabolic stability over Res failed to induce HO-1 expression in macrophages. In structural comparison with Res that contains three hydroxyl groups on its two phenyl rings (chemical structures shown in Fig. 1), Pic has an additional hydroxyl group and TMS possesses three methoxyl groups in lieu of the hydroxyl groups. These structural differences, together with our present findings, suggest that the hydroxyl groups on the phenyl rings has been shown to be one of important structural features necessary to suppress LPS-induced production of TNF-α and IL-1β and induce HO-1 expression in RAW264.7 macrophages. Our results are in agreement with the previous findings of Murias et al. [26] who showed that synthetic hydroxylated (but not methoxylated) analogs of Res showed a high rate of inhibition of cyclooxygenase-2, a proinflammatory enzyme.

One of interesting findings is that 6-h pretreatment with Res and Pic (but not TMS) augmented their ability to suppress TNF-α and IL-1β production in RAW264.7 macrophages, and this suggests that Res and Pic may activate other additional anti-inflammatory pathways that may not be activated by TMS. Because HO-1 expression has been reported to exert significant anti-inflammatory effects in macrophages [27], we explored the potential involvement of HO-1 in the anti-inflammatory effects of Res and Pic in RAW264.7 macrophages. We found that Res and Pic varied in their ability to suppress the expression of TNF-α mRNA and IL-1β mRNA and the production of TNF-α and IL-1β and also to induce HO-1 expression; Pic was more active in suppressing LPS-induced production of TNF-α and IL-1β and inducing HO-1 expression than Res. Thus, the level of HO-1 expression by Res and Pic correlated with their suppression of TNF-α and IL-1β production. At equimolar concentrations, pretreatment with TMS was minimally effective in suppression of TNF-α and IL-1β production in our study, which correlated with their inability to induce HO-1 expression. In support of this, inhibition of HO-1 activity by SnPP partly (but not completely) reversed Res- and Pic-induced suppression of the expression of TNF-α mRNA and IL-1β mRNA and the production of TNF-α and IL-1β. However, SnPP had no effect on TMS-induced suppression of the expression of TNF-α mRNA and IL-1β mRNA and the production of TNF-α and IL-1β, which may account in part for its lack of the effect on HO-1 expression. Overall, our results strongly suggest that the anti-inflammatory effects of Res and Pic are associated, at least in part, with their ability to induce HO-1 expression. However, it should be noted that besides HO-1 pathway, Res, Pic, and TMS may also activate other anti-inflammatory pathways, such as their direct modulation of nuclear factor-κB (NF-κB) activity [8, 28, 29] and sirtuins [30], and overall anti-inflammatory effects could be achieved by virtue of the concerted actions of the multiple pathways being activated. The beneficial effects of HO-1 expression have been attributed to several factors, including the degradation of pro-oxidant heme, formation of biliverdin and/or bilirubin with their antioxidant properties, as well as the release of carbon monoxide, which has cytoprotective and anti-inflammatory effects [31]. Although the exact mechanisms involved in anti-inflammatory actions of the HO-1 system have not been fully elucidated, one or more of the HO-1 reaction products may mediate anti-inflammatory effects of Res and Pic under our experimental conditions. Interestingly, it has been reported that HO-1-derived carbon monoxide inhibits LPS-induced production of proinflammatory cytokines, including TNF-α and IL-1β, in RAW264.7 macrophages [32]. It has been also reported that HO-1-derived bilirubin reduces proinflammatory cytokine production and other inflammatory mediators in mice challenged with LPS [33]. These studies, to some extent, support our conclusion that HO-1 expression by Res and Pic may be one of possible mechanisms by which they can exert inhibitory effects on TNF-α and IL-1β production.

Together, our observations suggest that the hydroxyl groups on the phenyl rings of naturally occurring Res analogs that are also related to Res metabolism is important for suppression of LPS-induced production of TNF-α and IL-1β and HO-1 expression in RAW264.7 macrophages. The ability of Res analogs to induce HO-1 expression may provide one of possible mechanisms by which they can exert anti-inflammatory effects. As Pic is more potent than Res, Pic may have therapeutic potential in the treatment of inflammatory diseases accompanied by macrophage activation. In addition, considering that Pic is one of Res metabolites, our results may explain why Res, in spite of its extensive metabolism, can also have in vivo anti-inflammatory effects in animal models of inflammatory diseases. It has been demonstrated that Res is effective for protecting mice against LPS-induced acute lung injury, which may be related to its suppression of NF-κB activation and suppression of proinflammatory cytokines, such as IL-1β, and other inflammatory mediators [34]. It has been also demonstrated that Pic is capable of protecting mice from septic shock after LPS challenge, presumably by its suppression of proinflammatory cytokines, such as TNF-α, and other inflammatory mediators [35]. To our best knowledge, there is no comparative study on in vivo effects of Res and its two natural analogs on proinflammatory cytokine production. Further study is warranted to investigate whether Res and its two analogs would be also effective in inhibiting proinflammatory cytokine production in animal model. Finally, we provide a glance of the structure-activity relationships of Res analogs for the anti-inflammatory HO-1 expression in macrophages; this information may be useful to design more efficacious HO-1 inducers which can provide better therapeutic implications for various inflammatory diseases.

Acknowledgements

  1. Top of page
  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST) (No. 2012M3A9C3048686).

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  2. Abstract
  3. 1. Introduction
  4. 2. Materials and Methods
  5. 3. Results
  6. 4. Discussion
  7. Acknowledgements
  8. References
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