Objective. Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA).Methods. The composition of commercial turmeric dietary supplements was determined by highperformance liquid chromatography. A curcuminoidcontaining turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. Results.A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-B and the subsequent expression of NF-B-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E 2 , and periarticular osteoclast formation were inhibited by turmeric extract treatment.Conclusion. These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.The use of botanical remedies for arthritis treatment is promoted in the US by the lay press and high-profile medical practitioners (1,2). Interest in the use of nonpharmaceutical arthritis treatments has grown with the withdrawal of Food and Drug Administrationapproved antiinflammatory drugs (3). However, scientific data are almost uniformly lacking concerning the antiarthritic efficacy and mechanism of action of popular botanical remedies (4,5). The rational medicinal use of botanical dietary supplements is further complicated by the fact that the composition of over-the-counter botanical dietary supplements is not strictly regulated (4,5). Unfortunately, in the medical literature, the chemical composition and biologic activity of botanicals that are tested for antiarthritic efficacy are frequently also not well characterized (6-9). Therefore, benchmarks are lacking for assessing the potential suitability of commercially available botanical supplements or phytomedicines. 3452Turmeric is one such botanical supplement whose use against arthritis, supported almost exclusively by its traditional, centuries-old use as an antiinflammatory agent in Ayurvedic medicine, has been heavily prom...
Extracts from Boswellia serrata have been reported to have anti-inflammatory activity, primarily via boswellic acid-mediated inhibition of leukotriene synthesis. In three small clinical trials, boswellia was shown to improve symptoms of ulcerative colitis and Crohn's disease, and because of its alleged safety, boswellia was considered superior over mesalazine in terms of a benefit-risk evaluation. The goal of this study was to evaluate the effectiveness of boswellia extracts in controlled settings of dextran sulfate- or trinitrobenzene sulfonic acid-induced colitis in mice. Our results suggest that boswellia is ineffective in ameliorating colitis in these models. Moreover, individual boswellic acids were demonstrated to increase the basal and IL-1beta-stimulated NF-kappaB activity in intestinal epithelial cells in vitro as well as reverse proliferative effects of IL-1beta. We also observed hepatotoxic effect of boswellia with pronounced hepatomegaly and steatosis. Hepatotoxity and increased lipid accumulation in response to boswellia were further confirmed in vitro in HepG2 cells with fluorescent Nile red binding/resazurin reduction assay and by confocal microscopy. Microarray analyses of hepatic gene expression demonstrated dysregulation of a number of genes, including a large group of lipid metabolism-related genes, and detoxifying enzymes, a response consistent with that to hepatotoxic xenobiotics. In summary, boswellia does not ameliorate symptoms of colitis in chemically induced murine models and, in higher doses, may become hepatotoxic. Potential implications of prolonged and uncontrolled intake of boswellia as an herbal supplement in inflammatory bowel disease and other inflammatory conditions should be considered in future clinical trials with this botanical.
The Escherichia coli aadA gene product, which confers resistance to spectinomycin and streptomycin, has been widely used as a dominant selectable marker for chloroplast transformation of Chlamydomonas and tobacco. An aadA transformation cassette was adapted for expression in Euglena gracilis chloroplasts by replacing the Chlamydomonas promoter and 3' untranslated region (UTR) with the E. gracilis psbA promoter and 3' UTR. Transgenic DNA was introduced into E. gracilis chloroplasts by biolistic transformation. Streptomycin- and spectinomycin-resistant colonies were obtained, which screened positively for the presence of the transforming vector by PCR amplification. Although integration of the transforming DNA into the chloroplast genome was not detected, transforming DNA was stably maintained in the chloroplast as an episomal element during continuous selection on antibiotics. The aadA cassette was also inserted into a transformation vector which contained the independently expressed psbK operon from either E. gracilis or a closely related species, E. stellata. The psbK operon contained at least two group III introns and a group III twintron, was highly expressed, and was only 1.5 kb in length. In transgenic E. gracilis chloroplasts, a truncated E. stellata psbK operon was transcribed, and the resultant pre-mRNA was accurately spliced. This system should allow the first direct analysis of group II and group III intron-splicing mechanisms. In addition, it could prove useful in the study of many other Euglena transcription and processing events.
Sodium butyrate (NaB) stimulates sodium and water absorption by inducing colonic Na(+)/H(+) exchange. NaB induces Na(+)/H(+) exchanger (NHE)3 activity and protein and mRNA expression both in vivo and in vitro. Our previously published observations indicated that this induction is Ser/Thr kinase dependent and that NaB-responsive elements were localized within -320/-34 bp of the rat NHE3 promoter. Here we further delineate the mechanism of NaB-mediated NHE3 gene transcription. Transient and stable transfection of Caco-2 cells with NHE3 gene reporter constructs identified Sp binding site SpB at position -58/-55 nt as critical for NaB-mediated induction. Gel mobility shift (GMSA) and DNA affinity precipitation assays indicated NaB-induced binding of Sp3 and decreased binding of Sp1 to SpB element. While no changes in expression of Sp1 or Sp3 were noted, NaB induced phosphorylation of Sp1 and acetylation of Sp3. Sp3 was a more potent inducer of NHE3 gene transcription, which suggested that change in balance, favoring binding of Sp3 to the SpB site, would result in significant increase in NHE3 promoter activity. Small interfering RNA studies in Caco-2 cells and data from NaB-treated SL2 cells used as a reconstitution model confirmed this hypothesis. In addition to the SpB site, which played a permissive role, an upstream novel butyrate response element located at -196/-175 nt was necessary for maximal induction. GMSA identified a protein-DNA complex with a -196/-175 nt probe; this interaction was not affected by NaB treatment, thus suggesting that in response to NaB Sp3 binding to site SpB precedes and results in recruitment of the putative factor to this upstream site.
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