Article pubs.acs.org/jnp
Anti-inflammatory Actions of (+)-3′α-Angeloxy-4′-keto-3′,4′dihydroseselin (Pd-Ib) against Dextran Sulfate Sodium-Induced Colitis in C57BL/6 Mice Huai-Xue Mu,† Jing Liu,†,‡ Sarwat Fatima,† Cheng-Yuan Lin,† Xiao-Ke Shi,† Bin Du,† Hai-Tao Xiao,† Bao-Min Fan,§ and Zhao-Xiang Bian*,† †
School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, People’s Republic of China School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People’s Republic of China § YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming, 650500, People’s Republic of China ‡
S Supporting Information *
ABSTRACT: The immunoregulatory protective properties of (+)-3′α-angeloxy-4′-keto-3′,4′-dihydroseselin (Pd-Ib) isolated from Bupleurum malconense has not been reported. In the present study, the therapeutic effect of Pd-Ib (30, 60, and 120 mg/kg/day) was examined in a mouse model of dextran sulfate sodium (DSS)-induced acute colitis. Administration of Pd-Ib significantly reduced the disease activity index, inhibited the shortening of colon length, reduced colonic tissue damage, and suppressed colonic myeloperoxidase activity and nitric oxide levels in mice with DSS-induced colitis. Moreover, Pd-Ib greatly suppressed the secretion of pro-inflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-17A while enhancing the level of anti-inflammatory cytokine IL-4. The protein levels of phosphorylated STAT3 (p-STAT3) and phosphorylated p38 (p-p38) were down-regulated in the colonic tissues of DSS-treated mice. Importantly, the anti-inflammatory effect of Pd-Ib against acute colitis was comparable to the anti-inflammatory sulfa drug sulfasalazine (300 mg/kg). Furthermore, the in vitro study showed that the inhibitory effect of Pd-Ib on p-STAT3 and IL-6 protein levels was accompanied by the reduction of MAPKs (JNK and p38). In conclusion, this study suggested that Pd-Ib attenuated DSS-induced acute colitis via the regulation of interleukins principally through the STAT3 and MAPK pathways.
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previously reported that Pd-Ib suppressed tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated murine Raw-Blue macrophages via down-regulating the activation of nuclear factor-κB (NF-κB, in press). These results encouraged us to further investigate whether Pd-Ib is efficacious for the treatment of inflammatory conditions, such as UC. This study will evaluate the efficacy of Pd-Ib in a model of dextran sulfate sodium (DSS)-induced acute colitis in mice and its underlying mechanism in LPS-induced RAW264.7 macrophages.
lcerative colitis (UC) is a subtype of inflammatory bowel disease (IBD) that causes inflammation and ulcers in the colonic mucosa.1 Currently, UC has become a major health problem in affluent countries that not only negatively affects the quality of life of sufferers but also leads to an increased risk of colorectal cancer.2 Current primary therapies for UC, including aminosalicylates, biologics, and immunosuppressive agents, suffer from safety issues and/or low efficacy.3−5 Therefore, the research and development of novel drugs is warranted for the prevention and treatment of UC. Peucedanum praeruprorum Dunn is one of the most popular traditional medicinal herbs in China, which has a long history for the treatment of diseases of the respiratory and digestive system.6 Recent studies have demonstrated that pyranocoumarin, a class of coumarin derivate naturally present in many medicinal plant species, exerts versatile biological properties such as antihyperglycemic, anticancer, antiviral, antioxidant, and anti-inflammatory activities.7−12 Pd-Ib [(+)-3′α-angeloxy-4′keto-3′,4′-dihydroseselin], one of the major coumarins of P. praeruprorum Dunn,13,14 is an angular pytanocoumarin compound purified from Bupleurum malconense (Apiaceae). However, little is known about its biological actions. We have © XXXX American Chemical Society and American Society of Pharmacognosy
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RESULTS AND DISCUSSION The DSS-induced acute colitis mouse model is one of the most commonly used models that closely mimics several characteristics of human UC such as diarrhea, bloody stool, mucosal ulceration, and shortened colons.15 It is widely used for the study of the pathology of UC as well as for the development of Received: December 18, 2015
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sulfasalazine (SASP), an agent effective in preventing colitis in animal models,16,17 was utilized as a reference drug for the evaluation of the anticolitis efficacy of Pd-Ib. As shown in Figure 2A, the loss of body weight was significantly reduced in mice treated with Pd-Ib at 120 mg/kg, but not at 30 or 60 mg/ kg when compared with the DSS-induced mice only after 9 days of colitis induction. Administration of Pd-Ib also reduced the severity of clinical symptoms in mice with DSS-induced colitis, as reflected by the scores of disease activity index (DAI). As shown in Figure 2B, the DAI score of mice treated with PdIb at 120 mg/kg and SASP at 300 mg/kg was significantly lower than that of the DSS group alone; by contrast, the DAI score of the control group was nil. On the other hand, shortening of colon length was significantly attenuated with PdIb treatment at 60 and 120 mg/kg (Figure 2C and D). Further, oral administration of Pd-Ib significantly ameliorated the aforementioned signs and symptoms of colonic inflammation. When compared to the non-DSS-treated control, mucosal ulceration, damage of crypts, interstitial edema, and immune cell infiltration were observed in mice with acute colitis (Figure 3A and B). Administration of Pd-Ib provided remarkable improvement in the aspect of mucosal architectural distortion (Figure 3D−F). Importantly, the protective effect of Pd-Ib (120 mg/kg, Figure 3F) against mucosal injury was comparable to that of SASP (300 mg/kg, Figure 3C), a well-established therapeutic drug for UC patients. During mucosal inflammation, a complex array of inflammatory mediators, including NO, prostaglandins, and cytokines, impair the function of the
therapeutic strategies. A schematic presentation of our experimental design is shown in Figure 1. In this study,
Figure 1. Experimental design. Mice were randomly assigned into 6 groups. DSS was dissolved in distilled water at a concentration of 2% (w/v) and given to mice other than the control group. The first day and the last day of drug treatment were designated as day 5 and day 12, respectively. Mice were monitored daily for the change of body weight, stool consistency, and gross fecal bleeding. The SASP treatment group (300 mg/kg) served as a positive control, and PdIb treatment groups were given different doses (30, 60, or 120 mg/kg).
Figure 2. Effects of Pd-Ib on body weight change (A), disease activity index (B), and colon length (C and D) of mice with DSS-induced colitis. Colitis was induced in all groups except the control group. Pd-Ib and SASP were administered to mice from day 5 to day 12. The change in body weight was taken as the difference between the body weight before induction of colitis and sacrifice on day 13. The DAI score was determined by combining scores of (i) body weight loss, (ii) stool consistency, and (iii) stool bleeding. On day 13, the mice were sacrificed and the colon lengths were measured. Data are expressed as mean ± SD, n = 8 (####p < 0.0001, compared with the control group; *p < 0.05, **p < 0.01, ***p < 0.001, compared with the DSS group). B
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Figure 3. Effects of Pd-Ib on histological manifestation, MPO activity, and NO production in DSS-induced colitis mice. (A−F) H&E staining images of representative colons are shown at a magnification of 10× (A, control group; B, DSS group; C, DSS + SASP group, 300 mg/kg; D, DSS + Pd-Ib 30 mg/kg group; E, DSS + Pd-Ib 60 mg/kg group; F, DSS + Pd-Ib 120 mg/kg group). (G) Histological scores. (H) MPO activity. (I) NO production. Colitis was induced in all groups except the control group. Pd-Ib and SASP were administered to mice from day 5 to day 12. On day 13, the mice were sacrificed. MPO activity and NO production in colon homogenates were determined. Data are expressed as mean ± SD, n = 8 (###p < 0.001, compared with the control group; *p < 0.05, **p < 0.01, ***p < 0.001, compared with the DSS group).
inflammatory cytokines.21 High levels of TNF-α, interferon-γ (IFN-γ), IL-6, and IL-17A have been observed in UC patients as well as in mouse models of colitis.22,23 Therefore, the inhibition of pro-inflammatory cytokines is a promising strategy for the development of novel anti-IBD therapies. In the present study, levels of TNF-α, IFN-γ, IL-6, and IL-17A in the DSSinduced mice were found positively correlated to the severity of colitis and were significantly suppressed by the administration of Pd-Ib in a dose-dependent manner (Figure 4A−D). Interestingly, both medium- and high-dosage Pd-Ib treatment groups (60 and 120 mg/kg) exerted a significantly greater inhibitory effect on the expression of IL-6 and IL-17A compared to the SASP group (300 mg/kg, Figure 4C and D). IL-17, a major pro-inflammatory cytokine that is secreted by T helper 17 (Th17) cells, has attracted interest for its role in IBD.24 Meanwhile, the role of IL-6 in the differentiation of Th17 cells together with TGF-β also has been identified.25 Our
intestinal epithelia and lead to a robust recruitment of immune cells to the site of injury.18,19 Previous studies have shown that neutrophil infiltration facilitates the formation of potent cytotoxic oxidants, causing colonic tissue damage via the activation of myeloperoxidase activity (MPO) and nitric oxide.20 Therefore, neutrophil sequestration is often reflected by an increase of MPO activity and NO production. Our results demonstrate that MPO activity and NO production in colonic tissues of the Pd-Ib- and SASP-treated mice were significantly lower than those in the DSS group. Pd-Ib treatment notably ameliorated ultrastructural changes and inflammatory cell infiltration, as indicated by the lowered histological scores (Figure 3G), MPO activity (Figure 3H), and NO production (Figure 3I). Collectively, these results provide evidence for the potential use of Pd-Ib as a preventive measure for UC patients. Numerous experimental and clinical data have suggested that UC may result from the imbalance between the pro- and antiC
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Figure 4. Effects of Pd-Ib on the production of cytokines in the colonic tissue of animals with DSS-induced colitis. (A) IFN-γ levels. (B) TNF-α levels. (C) IL-6 levels. (D) IL-17A levels. (E) IL-4 levels. (F) IL-10 levels. Colitis was induced in all groups except the control group. Pd-Ib and SASP were administered to mice from day 5 to day 12. On day 13, the mice were sacrificed. Data are expressed as mean ± SD, n = 8 (#p < 0.05, ##p < 0.01, ### p < 0.001, compared with the control group; *p < 0.05, **p < 0.01, ***p < 0.001, compared with the DSS group).
finding suggests that the protective effect of Pd-Ib against colonic injury may relate to the regulation of Th17 cells via inhibition of IL-6 and IL-17A. On the contrary, the present result showed that the Pd-Ib treatment remarkably promoted the level of anti-inflammatory cytokine IL-4, but not IL-10, in the colonic tissues when compared to the DSS group (Figure 4E and F). The increased level of IL-4 indicated a possible therapeutic mechanism of Pd-Ib on DSS-induced colitis. IL-4 has been reported by others to have a protective function in the intestinal tract of experimental colitis model.26 Indeed, IL-4 is known to inhibit both antigen presentation of monocytes and the subsequent production of pro-inflammatory cytokines in IBD patients, e.g., IL-1β and TNF-α.27,28 STAT3 (signal transducer and activator of transcription 3) activation is believed to be a critical step in the propagation of proinflammatory responses. Previous findings have shown that nuclear p-STAT3 protein expression is remarkably elevated in the colonic tissues of mice with colitis.29,30 In fact, IL-6 plays a pathogenic role in colitis by activating STAT3 predominantly in the acquired immune cells.31 Conversely, the initiation of IL-6 response was found highly correlated with the activation of the p38 MAPK (mitogen-activated protein kinase) signaling cascade in UC conditions.32,33 The present data showed that p-p38 and p-STAT3 levels were up-regulated in DSS-treated mice, but they were notably repressed by the Pd-Ib treatment (Figure 5). These results indicated that the administration of Pd-Ib dose-dependently inhibited the phosphorylation of p38 and STAT3, and its effects were associated with a reduction of the pro-inflammatory cytokines TNF-α, IFN-γ, IL-6, and IL17A and an enhancement of anti-inflammatory cytokine IL-4 in colonic tissues of DSS-treated mice. To verify the possible mechanism of the in vivo study, the anti-inflammatory effect of Pd-Ib in LPS-stimulated RAW264.7 cells was examined. Our finding revealed that Pd-Ib markedly
Figure 5. Effect of Pd-Ib on protein expression of STAT3 and p38 in the colonic tissue of animals with DSS-induced colitis. Colitis was induced in all groups except the control group. Pd-Ib and SASP were administered to mice from day 5 to day 12. On day 13, the mice were sacrificed. Representative Western blot images of STAT3, p-STAT3, p38, and p-p38 expression in colonic tissue extracts. β-Actin was used as an internal control.
inhibited IL-6-induced STAT3 phosphorylation in a timedependent manner while suppressing p-STAT3 expression in a dose-dependent manner. As shown in Figure 6A, p-STAT3 activation was highest at 3 h after LPS (1 μg/mL) treatment, but it was reduced after 6 h. After 12 h it was expressed again and stabilized until 24 h. Following the treatment with Pd-Ib (20 μg/mL), the LPS-induced STAT3 phosphorylation was significantly diminished after 12 h. Meanwhile, the same phenomenon was observed for the production of IL-6 (Figure 6B). The Western blot analysis showed that Pd-Ib treatment at 20 μg/mL significantly inhibited p-STAT3 expression; thus a higher Pd-Ib concentration did not cause a further reduction in p-STAT3 expression in LPS-stimulated RAW264.7 cells D
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Figure 6. Pd-Ib modulated the activation of p-STAT3 and IL-6 in LPS-stimulated RAW264.7 cells. (A) Representative Western blot images of macrophages. After macrophages were treated with 1 μg/mL of LPS in the absence or presence of 20 μg/mL of Pd-Ib for 0−24 h, cells were harvested and lysed. The levels of p-STAT3 and β-actin were analyzed by Western blot. (B) The time course effect of Pd-Ib on IL-6 production in LPS-stimulated RAW264.7 cells was analyzed by ELISA. After macrophages were treated with 1 μg/mL of LPS in the absence or presence of 20 μg/ mL of Pd-Ib for 0−24 h, cells were harvested. Release of IL-6 in the supernatant was analyzed by ELISA. (C) Representative Western blot images of macrophages. RAW 264.7 cells were treated with 1 μg/mL of LPS alone or with various concentrations of Pd-Ib (5, 10, 20, 40 μg/mL) for 24 h; protein levels of p-STAT3 and STAT3 in the cell extracts were detected by Western blot. β-Actin was used as an internal control. (D) The dosage effect of Pd-Ib on IL-6 production in LPS-stimulated RAW264.7 cells was analyzed by ELISA. Cells were treated with different doses of Pd-Ib (0, 5, 10, 20, 40 μg/mL) in the absence or presence of LPS (1 μg/mL) for 24 h (##p < 0.01, ###p < 0.001 compared with control group; **p < 0.01 compared with LPS-alone group).
(Figure 6C). As postulated, cytokine production of IL-6 by LPS-induced RAW264.7 cells was found to be inhibited in a dose-dependent manner with a Pd-Ib concentration range from 5 to 20 μg/mL. When the concentration was higher than 20 μg/mL, unexpectedly, IL-6 levels increased sharply (Figure 6D). Moreover, we found that various MAPK, suggested to be involved in pro-inflammatory signaling cascades,34 were activated by the LPS treatment in RAW264.7 cells. As shown in Figure 7, treatment of Pd-Ib markedly suppressed the phosphorylation levels of p38 and JNK, but not ERK, in the LPS-stimulated RAW264.7 macrophages. This observation indicated that Pd-Ib inhibited inflammation via an inhibition of the p38 and JNK signaling pathways. Together the in vivo and in vitro results demonstrated that Pd-Ib provided significant anti-inflammatory action, which may be correlated with the p38/JNK-dependent regulation of IL-6 and p-STAT3. In summary, this is the first report about the protective effect of Pd-Ib on acute DSS-induced colitis. In this study, we revealed that Pd-Ib alleviated various symptoms of colitis mainly by mediating inflammatory cytokines, although other mechanisms may be involved. Furthermore, this finding indicated that Pd-Ib regulates inflammation through the IL-6/ STAT3 and MAPK signaling pathways, a finding verified by the in vitro results. Therefore, this study has provided the foundation for developing Pd-Ib as a therapeutic drug specifically for UC patients.
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Figure 7. Effect of Pd-Ib on protein expression of components of the MARK pathway in LPS-stimulated RAW264.7 cells. Representative Western blot images of macrophages. After macrophages were treated with 1 μg/mL of LPS in the absence or presence of various concentrations of Pd-Ib (5, 10, 20, 40 μg/mL) for 24 h, the expression levels of p-JNK, JNK, p-ERK, ERK, p-p38, and p38 in the cell extracts were determined by Western blot. β-Actin was used as a loading control. S2, respectively). SASP, LPS (L3129), and Griess reagent were purchased from Sigma Corp. (St. Louis, MO, USA). DSS (molecular weight: 36 to 50 kDa) was purchased from MP Biomedical (Santa Ana, CA, USA). Dulbecco’s modified Eagle’s medium (DMEM), ECL reagent, FBS, penicillin, and streptomycin were purchased from Life Technologies (Carlsbad, CA, USA). The BCA protein assay kit was supplied by Thermo Fisher Scientific (Waltham, MA, USA). AntiSTAT3, p-STAT3, p38, p-p38, ERK, p-ERK, JNK, and p-JNK were purchased from Cell Signaling Technology (Beverly, MA, USA). Anti-
EXPERIMENTAL SECTION
Reagents and Chemicals. Pd-Ib was provided by YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University (purity >98%), and extracted as described previously (in press). The 1H NMR and 13C NMR spectra of Pd-Ib in CDCl13 are recorded (Bruker 400 Hz NMR spectrometer; Figure S1 and Figure E
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β-actin mouse antibody, anti-rabbit IgG, and anti-mouse IgG were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). ELISA kits for mouse IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ were purchased from Merck Millipore (Darmstadt, Germany). The ELISA kit for mouse IL-6 was purchased from eBioscience (San Diego, CA, USA). Animals. Six-week-old male C57BL/6 mice weighing 18−20 g were purchased from the Laboratory Animal Services Center, The Chinese University of Hong Kong. All animals were provided with standard chow and water during the experimental period according to the protocol approved by the Committee for Care of Laboratory Animals of Hong Kong Baptist University, Hong Kong SAR, China. Cell Culture. Murine RAW264.7 macrophages were maintained in DMEM supplemented with 100 U/mL penicillin, 100 μg/mL streptomycin, and 10% FBS in an incubator at 37 °C in a humidified atmosphere with 5% CO2. Cells were subcultured every 3 days at a dilution of 1:6. Induction of Acute Colitis and Intervention. The animals were randomly assigned into six groups (n = 8). Mice in the control group were supplied with distilled water, whereas all other experimental groups were given 2.0% (w/v) DSS for 5 days. Thereafter, the mice of the DSS, SASP-treated (300 mg/kg/day)35−37 and Pd-Ib (30, 60, or 120 mg/kg/day)-treated groups were administered by gavage with saline, SASP, or Pd-Ib from day 6 to day 12, respectively. Evaluation of Disease Activity Index. The DAI was determined by scoring the changes of body weight loss, diarrheal condition, and fecal bleeding. The scoring system of each DAI component is shown in Table 1.38 The dynamic DAI score is the sum of the score of these
Table 2. Histological Scoring System for DSS-Induced Colitis
body weight loss (%)
0 1 2 3 4
none 1−5 6−10 10−15 >15
diarrhea
none
loose stools
slight
diarrhea
fecal blood
description
severity of inflammation
0 1 2 3 0 1 2 3 0 1 2 3 4
none mild moderate severe none mucosa mucosa and submucosa transmural none 1/3 damaged 2/3 damaged crypt loss by surface epithelium present both crypt and surface epithelium lost
crypt damage
in the supernatants were determined using MILLIPLEX MAP mouse cytokines kits (Merck Millipore, Darmstadt, Germany). The concentration of IL-6 in the supernatant of LPS-stimulated RAW264.7 cells was detected by an ELISA kit (eBioscience). The amount of protein in each sample was measured using the Bradford method, and bovine serum albumin was used as a concentration reference. The levels of cytokines were expressed as pg/mL. Western Blot Analysis. Protein lysates were extracted using RIPA buffer [150 mM NaCl, 1 mM EDTA, 1% NP-40, 2 mM EGTA, 50 mM Tris (pH 7.4)] with phosphatase and protease inhibitors (Roche, Mannheim, Germany) and then separated by 10% SDS-PAGE. Bands were detected immunologically using antibodies against STAT3, pSTAT3, p38, p-p38, ERK, p-ERK, JNK, and p-JNK. All blots were stripped and reprobed with β-actin antibody to ascertain equal loading of proteins. Statistical Analysis. The data are presented as mean ± standard deviation (SD). Statistical significances were evaluated using one-way ANOVA, followed by Duncan’s new multiple range tests. GraphPad Prism 5.0 software (GraphPad Software Inc., San Diego, CA, USA) was used for all calculations, and p < 0.05 was considered statistically significant.
rectal bleeding
normal
score
extent of inflammation
Table 1. Disease Activity Index Scores Based on Disease Marker Intensities score
feature
three parameters. At the end of the experiment, mice were killed. Colon was dissected from each mouse, and the length between the ileo-cecal junction and anal verge was measured. Histological Analysis. The colons of mice were harvested, gently washed with ice-cold PBS, fixed in 4% paraformaldehyde overnight, and embedded in paraffin. Paraffin sections of 5 μm were stained with hematoxylin and eosin (H&E) according to a standard procedure to evaluate colonic architectural damage.39 The epithelial morphological characteristics were observed using a Nikon (ECLIPSE 80i, Japan) microscope under varying magnifications. The histological scoring system with grading 0 to 10 is shown in Table 2.40 Assessment of Neutrophil Infiltration in Colonic Tissue (MPO Assay). MPO is an enzyme mainly released by neutrophils, and its activity is directly associated with the severity of inflammation in a given tissue. In this study, MPO activity was measured as described in our previous study.41 In brief, MPO activity was calculated from the rate of optical density changes, whereas one unit of MPO activity was defined as the amount of enzyme present that produced a change in optical density of 1.0 U/min at 25 °C. The results were normalized to the wet weight of colon tissue and quantified as units/mg tissue. Determination of NO Production. The frozen colonic tissues kept at −80 °C were weighed and homogenized in 0.5% hexadecyltrimethylammonium bromide (100 mg colonic tissue/mL). The homogenates were centrifuged at 16000g at 4 °C for 15 min. The nitrite content in the supernatant was measured using the Griess reagent following the manufacturer’s instructions.42 Measurement of Cytokines. Colonic tissues were homogenized with lysis buffer to extract total protein according to our previous report.43 Briefly, the homogenate was centrifuged at 16000g at 4 °C for 15 min. The amounts of IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.5b01071. 1 H NMR spectra of Pd-Ib (PDF) 13 C NMR spectra of Pd-Ib (PDF)
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AUTHOR INFORMATION
Corresponding Author
*Tel/Fax: +852-3411 2905. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by Hong Kong Baptist University research grant no. IRMS-HKBU2011. REFERENCES
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DOI: 10.1021/acs.jnatprod.5b01071 J. Nat. Prod. XXXX, XXX, XXX−XXX
