Figure 5). Its 1H- and

Figure 5. Chemical structures of and geldanamycin (2).

13C-NMR spectral data of which were in good agreement with those of geldanamycin (Table 5) previously reported by Ōmura et al. [12] and Qin and Panek [13] .

3.3. Assessment of Cytotoxicity Activity of Crude Extract and Purified Compounds

Crude extract and purified compounds from Streptomyces zerumbet strain W14 were tested for their cytotoxic activities by MTT-assay on L929, RAW264.7, HeLa cells and PBMC. The IC50 values were exhibited in Table 6. In vitro cytotoxicity assays revealed that crude extract exhibited cytotoxicity against RAW264.7 cells and moderated cytotoxicity against L929 and PBMC. The activity of compounds 1 and 2 against RAW264.7 cells exhibited less toxicity with IC50 > 512 µg/ml. However, compound 1 showed cytotoxic activity on HeLa cells and moderate activity to L929 cells, while compound 2 exhibited a cytotoxic activity on PBMC.

3.4. Antibacterial Activity of Purified Compounds

Purified compounds from Streptomyces zerumbet strain W14 were tested for their antibacterial activity by MIC and MBC mehthods. Results in Table 7 showed that compound 1 was the most active against tested bacterial strains. It showed the highest activity against S. aureus with MIC and MBC values of 1 µg/ml and 16 µg/ml, respectively, followed active against MRSA (clinical isolate) with MIC and MBC values of 1 µg/ml and 64 µg/ml, respectively. Interestingly, compound 1 was also active against Bacillus Calmette-Guérin (BCG), vaccine strain, with MIC and MBC values of 128 µg/ml and 128 µg/ml, respectively, while compound 2 showed low activity against tested bacterial strains with MIC and MBC values greater than 512 µg/ml. Gentamicin 10.00 µg/ml and rifampicin (for BCG) 8.00 µg/ml were used as positive control.

Table 4. Comparison of the spectral data of the compound 1 and CFa.

aCF, Curvularia lunata furanoid toxin (data from Liu et al., [11] ). 1H and 13C-NMR assignments for compound 1 [1H (300 MHz), 13C-NMR (75 MHz), CDCl3, J = Hz]; Curvularia lunata furanoid toxin [1H (400 MHz), 13C-NMR (400 MHz), DMSO-d6, J = Hz].

Table 5. Comparison of the spectral data of the compound 2 and GDAa.

aGDA, geldanamycin (data from Ōmura et al. [12] ). 1H and 13C-NMR assignments for compound 2 [1H (400 MHz), 13C-NMR (100 MHz), DMSO-d6, J = Hz]; Geldanamycin [1H, 13C-NMR, DMSO-d6, J = Hz].

Table 6. IC50 of the crude extract and purified compounds against diiference cell lines after 24 using the MTT assay.

aIC50 values represent the concentration causing 50% growth inhibition. They were determined by linear regression analysis. bL929, murine fibroblast cell line; PBMC, human peripheral blood mononuclear cells; RAW 264.7, murine macrophage cell line; HeLa, human cervical carcinoma cell line. -c, Not determine.

Table 7. Antibacterial activity of compound 1.

3.5. Effects of Purified Compounds on NO and PGE2 Production in LPS-Induced RAW 264.7 Cells

LSP caused a significant increase in NO and PGE2 production when compared with the blank control, only compound 2 caused a significant reduction in NO and PGE2 production when compared with LPS-induced control group (p < 0.05). In detail, the production of NO in LPS-induced RAW 264.7 incubated with compound 2 at concentrations of 1, 2.5 and 5 µg/ml for 24 h were 48.72 ± 7.43, 36.51 ± 5.84 and 20.28 ± 4.66 µM, respectively, and the production of PGE2 were 40.74 ± 6.05, 26.62 ± 6.83 and 20.77 ± 4.48 ng/ml, respectively, while the production of NO and PGE2 in the group treated with LPS only was 52.64 ± 6.11 µM and 51.75 ± 6.56 ng/ml, respectively. Therefore, the inhibitory levels of compound 2 on NO and PGE2 production also showed a dose-dependent pattern (Figure 6 (NO) and Figure 7 (PGE2)), while compound 1 did not cause a significant reduction in NO and PGE2 production on LPS-induced RAW 264.7 cells at the concentration of 1 to 5 µg/ml (data not shown). Since compound 2 has inhibitory effect on NO and PGE2 production in LPS-induced RAW 264.7. It was considered on the test of inhibitory effects on iNOS and COX-2 production, proinflammatory cytokine production and also up-regulation of gene expression in LPS-induced RAW 264.7.

3.6. Effects of Compound 2 on iNOS and COX-2 Production in LPS-Induced RAW 264.7 Cells

The effects of compound 2 on iNOS and COX-2 production in LPS-induced RAW 264.7 cells were also carried out by Western blot analysis. Results of relative density ratio from Western blot analysis further indicated that iNOS and

Figure 6. Evaluation of nitrite production by RAW 264.7 cells stimulated for 24 h with LPS alone or in combination with increasing concentrations (1 - 5 µg/ml) of compound 2. The values are the means of at least three determinations ± SEM. Probability level (Student’s t-test): *p < 0.05 vs. LPS-treated group.

Figure 7. Effect of compound 2 on PGE2 production in LPS-induced RAW 264.7 macrophage for 24 h. The values are the means of at least three determinations ± SEM. Probability level (Student’s t-test).

COX-2 production in LPS-induced RAW 264.7 cells were significantly reduced when treated with purified compounds in different concentration (Figure 8). In detail, the relative density ratio of iNOS production in LPS-induced RAW 264.7 incubated with compound 2 at concentrations of 1, 2.5 and 5 µg/ml for 24 h were 84.67, 60.83 and 41.82, respectively, and the relative density ratio of COX-2 production in LPS-induced RAW 264.7 were 81.89, 56.86 and 34.79, respectively. Therefore, the inhibitory levels of compound 2 on iNOS and COX-2 production in LPS-induced RAW 264.7 cells also showed a dose-dependent pattern.

3.7. Effects of Compound 2 on Pro-Inflammatory Cytokine Production in LPS-Induced RAW 264.7 Cells

In this study, data showed that compound 2 decreased production of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in LPS-induced RAW 264.7 cells (p < 0.05) (Figures 9-11). Treatment with LPS alone in RAW 264.7 cells resulted in a significant increase of pro-inflammatory cytokine productions compared with the blank control group. The detailed results of this assay are as follows: TNF-α productions in LPS-induced RAW 264.7 cells incubated with compound 2 at concentrations of 1, 2.5 and 5 µg/ml for 24 h were 36.56 ± 5.51, 22.79 ± 4.80 and

Figure 8. Effect of compound 2 on iNOS protein production (a) and COX-2 protein expression (b) by LPS-induced RAW 264.7 macrophage for 24 h. Probability level (Student’s t-test): *p < 0.05 vs. LPS-treated group.

Figure 9. Effect of compound 2 on LPS-induced TNF-α production by RAW 264.7 cells. The values are the means of at least three determinations ± SEM. Probability level (Student’s t-test): *p < 0.05 vs. LPS-treated group.

Figure 10. Effect of compound 2 on LPS-induced IL-1β production by RAW 264.7 cells. The values are the means of at least three determinations ± SEM. Probability level (Student’s t-test): *p < 0.05 vs. LPS-treated group.

Figure 11. Effect of compound 2 on LPS-induced IL-6 production by RAW 264.7 cells. The values are the means of at least three determinations ± SEM. Probability level (Student’s t-test): *p < 0.05 vs. LPS-treated group.

14.73 ± 4.52 ng/ml, respectively, IL-1β productions in LPS-induced RAW 264.7 cells incubated with compound 2 at different concentrations were 29.57 ± 6.28, 15.64 ± 7.26 and 9.62 ± 4.58 ng/ml, respectively, and IL-6 productions in LPS-induced RAW 264.7 cells incubated with compound 2 at different concentrations were 25.37 ± 4.62, 17.45 ± 3.67 and 9.46 ± 3.34 ng/ml, respectively. Therefore, treatment with compound 2 (1 - 5 μg/ml) clearly inhibited the production of TNF-α, IL-1β and IL-6 in a dose-dependent manner in LPS-induced RAW 264.7 cells.

3.8. Effects of Compound 2 on Up-Regulation of iNOS and Proinflammatory Cytokine Transcriptions in LPS-Induced RAW 264.7 Cells

Since compound 2 inhibited the production of NO and proinflammatory cytokines, the correlation between the concentration of compound 2 and the mRNA expression of iNOS and proinflammatory cytokines was investigated. RAW 264.7 cells were pretreated with different concentrations (1 - 10 μg/ml) of compound 2 for 2 h and then incubated with or without 1 μg/ml of LPS for 6 h, total mRNA was isolated, and the mRNA levels of iNOS and proinflammatory cytokines were examined by RT-PCR. Treatment with LPS also significantly increased the mRNA expression levels of iNOS and proinflammatory cytokines (Figure 12). However, this induction of iNOS and proinflammatory cytokines mRNA expression was significantly inhibited by 5 μg/ml of compound 2. In addition, pretreatment with 10 μg/ml of compound 2 significantly inhibited this upregulation of iNOS and proinflammatory cytokines mRNA expression, particularly of IL-1β and IL-6 mRNA expression.

4. Discussion

Strain W14 was isolated from the rhizome tissue of Zingiber zerumbet (L.) Smith, a medicinal plant containing several compounds, for example, polyphenols, alkaloids and terpenes [14] . This microbe produced secondary metabolites after inoculation onto ISP-2 medium for 14 days. Based on morphological observation as well as on the presence of LL-type diaminopimelic acid in the whole-cell extracts and 16S rDNA sequence, the strain W14 was identified as belonging to the genus Streptomyces. Although, the level of 16S rDNA sequence similarity between this isolate and the type strain (S. malaysiensis) of its closest relatives in the genus Streptomyces was 99.65%, but the physiological characterization clearly differentiated this isolate from its closest neighbours, implying that this isolate was distinctive. It is therefore concluded that this isolate represents a novel species of the genus Streptomyces, for which the name Streptomyces zerumbet is proposed.

Two major compounds were isolated from the Streptomyces zerumbet W14 crude extract, and were identified to be methyl 5-(hydroxymethyl)furan-2-carboxylate (1) and geldanamycin (2). To the best of our knowledge, compound 1 is furanoid toxin, which had been isolated from Curvularia lunata, the pathogen that causes Curvularia leaf spot on maize [11] . This compound has been synthesized and shown antibacterial activity with MIC value of 100 μg/ml against Streptococcus

Figure 12. Effect of compound 2 on LPS-induced mRNA expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in RAW 264.7 cells.

pyogenes, Proteus vulgari, and E. coli [15] . In this study, compound 1 exhibited better antibacterial activity especially towards S. aureus ATCC 25923 with MIC and MBC values of 1.00 μg/ml and 16.00 μg/ml, respectively. It also exhibited significant cytotoxicity against HeLa cells with IC50 value of 64 μg/ml. The results were in agreement with furan-2-carboxylic acid, 5-3-(hydroxymethyl)-4,5-dimethoxyphenyl]-3-methylfuran-2-carboxylic acid isolated from the bark of Cassia alata, which displayed cytotoxicity against NB4 (acute promyelocytic leukemia cell line), A549 (adenocarcinomic alveolar basal epithelial cell line), SHSY5Y (neuroblastoma cell line), PC3 (prostate cancer cell line) and MCF 7 (breast adenocarcinoma cell line) cell lines with IC50 values of 2.5, 1.2, 2.2, 3.6 and 1.9 μmol/l, respectively [16] . Compound 2 (geldanamycin) had been discovered in the culture filtrates of Streptomyces hygroscopicus var. geldanus var. nova. It was moderately active in vitro against protozoa, bacteria and fungi [17] . In this study, it exhibited low antibacterial activity with MIC and MBC values greater than 512 μg/ml. It also exhibited significant cytotoxicity against PBMC, but no cytotoxicity against L929, RAW 264.7 and HeLa cells which differed from those reports of geldanamycin was extremely active against KB cells; an ubiquitous keratin-forming HeLa cell line (<0.001 μg/ml), L1210 cells; a mouse lymphocytic leukemia cell line (<0.002 μg/ml) [17] , SKBr3; a human breast cancer cell line (IC50 value of 37 nM) [18] and A431; human epidermoid carcinoma cell line and BC; breast cancer cell line with IC50 value of 0.15 and 0.01 μg/ml, respectively [19] .

During our investigations of the anti-inflammatory compounds, biphenyls were isolated from Streptomyces sp. BO-07 which had anti-inflammatory activities [20] . Geldanamycin has been reported as a potent anti-inflammatory compound that target heat-shock protein 90 and glucose-related protein 96 [21] [22] , which act as intracellular chaperones that maintain the structural integrity of cytoplasmic and endoplasmic reticulum-associated proteins, respectively. It binds to, and inactivates the function of, an Hsp90-Hsp70 multichaperone machine [23] . This multisubunit complex maintains the conformation and activity of regulatory kinases (e.g. c-src, cyclin-dependent protein kinase 4 [CDK4], Raf-1, and p38) [24] [25] [26] , and nitric oxide synthase (NOS) [27] in eukaryotic cells. Because several Hsp90 substrates promote cellular activation and cell growth by maintanining the structural integrity of kinases such as c-Src, Raf-1, CDK4, extracellular signal-regulated kinase 1, JNK, p38 MAPK, lymphocyte-specific protein tyrosine kinase, protein kinase R [28] [29] [30] [31] , and transcription factors (e.g. NF-κB), steroid hormone receptors [32] [33] [34] , these proteins have potent antiproliferative effects both in vitro and in vivo [35] . Other Hsp90 substrates (e.g. NOS) promote inflammation. Because of this, geldanamycin has potent anti-inflammatory effects [36] [37] by binding to the amino-terminal ATPase domain of Hsp90 and inactivates its function [21] [38] . Inhibition of the function of Hsp90 substrates with the use of geldanamycin has antiproliferative and anti-inflammatory effects [22] [39] [40] [41] [42] . Thus, the anti-inflammatory effects of geldanamycin are produced, in part, by inhibiting the production of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, and pro-inflammatory mediator such as NO and PGE2, and also iNOS and COX-2 in LPS-induced RAW 264.7 cells were investigated.

Our results indicate that compound 2 inhibits the TNF-α, IL-1β and IL-6 mRNA transcription. The results were in agreement with geladanamycin inhibits the production of TNF-α in taxol, LPS, or CpG DNA-activated RAW 264.7 cells [43] [44] , indicating that compound 2 has more general anti-inflammatory properties. This is consistent with a previous report showing that inhibition of Hsp90 by radicicol (which its structure related to geldanamycin) repressed the mRNA transcription TNF-α, IL-1β and IL-6 genes in LPS-stimulated THP-1 cells, a human macrophage-like cell line [45] and geldanamycin inhibited the translation of TNF-α and IL-6 transcription in LPS-activated RAW 264.7 cells, but did not appear to inhibit the translation of IL-1β [46] , which was difference from this study. This is important because previous work by Wax et al. [46] showed that a low dose of geldanamycin (300 nM). In contrast, the higher does of geldanamycin (5 μg/ml) used in this study inhibit the transciption and translation of the pro-inflammatory cytokines. Furthermore, compound 2 also suppressed the expression of COX-2 and iNOS induced by LPS, implying that this compound activation negatively regulates the expression of these pro-inflammatory mediators. Our results indicate that Hsp90 is critical to the transcriptional control of these pro-inflammatory cytokines and mediators in LPS-activated macrophages. It is thus possible that the function of Hsp90 is also critical to inflammatory cytokine and mediator production in autoimmune inflammatory diseases and that inhibition of Hsp90 could be a useful target for future drug development.

In addition, previous work by Igarashi et al. [47] showed that zerumbone (which its structure related to radicicol and geldanamycin) in Zingiber zerumbet Smith, increased cellular protein aggregates and promoted nuclear translocation of heat shock factor 1 (HSF1), which down-regulation attenuated the suppressive effects of zerumbone on mRNA and protein expressions of pro-inflammatory genes, including inducible nitric oxide synthase and IL-1β. In this study, geldanamycin isolated from Streptomyces zerumbet; an endophyte of Zingiber zerumbet, has structure related to zerumbone from Zingiber zerumbet. Since, some endophyte promoted the accumulation of secondary metabolites of host plants, which influenced the quantity and quality of compounds, or could produce diverse classes of phytochemicals, secondary metabolites originally from plants, including the structural analog compounds [48] [49] [50] [51] [52] . It was suggested that compound relationship between endophyte and host plants should be further studied in the future. This knowledge can be applied for the production of better and new drugs from endophytes and their medicinal plants.

The results obtained here demonstrate that Streptomyces zerumbet, a novel species isolated from Zingiber zerumbet (L.) Smith could produce methyl 5-(hydroxymethyl)furan-2-carboxylate (1) and geldanamycin (2). The compound 1 had antibacterial activity against Staphylococus aureus ATCC 25923 and Methicillin-resistant S. aureus with the MIC and MBC values of 1 µg/ml and 16 - 64 µg/ml, respectively, while the compound 2 at the concentration of 1 - 5 µg/ml had in vitro anti-inflammatory activity on LPS-induced RAW 264.7 cells by inhibition of mRNA expression and production of inducible NO synthase (iNOS), nitric tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). These results indicate that the compounds 1 and 2 exhibited promising antibacterial and anti-inflammatory activities, respectively. In conclusion we suggest that the future studies on these compounds could be useful for the management of bacterial infections and inflammatory diseases. And the compound relationship between endophyte and host plants should be also further studied in the future.

Acknowledgements

The authors are grateful to Ms Sopita Rattanopas and Ms Siwaporn Inpang in the Department of Chemistry, Faculty of Science, Silpakorn University, Thailand, for measuring NMR and MS data, respectively. This work was supported by the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, Thailand.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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