Shikonin Prevents Early Phase Inflammation Associated with Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer and Induces Apoptosis in Human Colon Cancer Cells.

Shikonin is the main active principle in the root of Lithospermum erythrorhizon, widely used in traditional Chinese medicine for its anti-inflammatory and wound healing properties. Recent research highlights shikonin's antitumor properties and capacity to prevent acute ulcerative colitis. The aim of the present study was to evaluate the ability of shikonin to prevent, in vivo, the early phases of colorectal cancer development, with special focus on its cytotoxic mechanism in vitro. We employed the azoxymethane/dextran sulfate sodium model of colitis in Balb/C mice. Body weight and drinking were monitored throughout the experiment, and length of colon and lesions of the colon were recorded on termination of the experiment in all of the experimental groups. Colons underwent histological evaluation and biochemical analyses [myeloperoxidase activity assay, measurement of interleukin-6, evaluation of proinflammatory enzymes (cyclooxygenase-2 and inducible nitric oxide synthase), and nuclear factor-κB activation by Western blot]. Caco-2 cells were used to evaluate, in vitro, the effect of shikonin on proliferation, cytotoxicity, cell cycle, and apoptosis. Our results reveal that shikonin significantly protected the intestinal tissue of our animals by preventing the shortening of the colorectum and ulcer formation in a dose-dependent manner. Shikonin attenuated the expression of cyclooxygenase-2 and inducible nitric oxide synthase, and myeloperoxidase activity, and inhibited the production of interleukin-6 and activation of nuclear factor-κB. It induced Bcl-2 and inhibited caspase 3. In conclusion, shikonin acts as a chemopreventive agent in the azoxymethane/dextran sulfate sodium model through inhibition of the proinflammatory milieu generated during the disease, an important risk factor in cancer development.

Immunmodulatory and Antiproliferative Properties of Rhodiola Species.

The traditional medicines of Asia and Europe have long used various Rhodiola species, which are endemic to the subarctic areas of the northern hemisphere, as tonic, adaptogen, antidepressant, and anti-inflammatory drugs. In order to establish the therapeutic uses of these plants in modern medicine, the pharmacological effects of Rhodiola sp. have been widely studied. Indeed, the most amply researched species, Rhodiola rosea, has been shown to possess antioxidant, adaptogenic, antistress, antimicrobial, immunomodulatory, angiomodulatory, and antitumoral effects. Salidroside (p-hydroxyphenethyl-ß-D-glucoside), a major compound in Rhodiola, seems to be responsible for many of the effects observed with Rhodiola extracts.The aim of this paper is to review the pharmacological effects not only of various Rhodiola species, mainly R. rosea along with Rhodiola imbricata, Rhodiola algida, and Rhodiola crenulata, but also of salidroside, focusing especially on its antioxidant, immunomodulatory, antitumoral, and antiproliferative activities, as well as to describe their therapeutic significance in disease management. Although previous pharmacological studies have established a scientific basis for possible therapeutic uses of Rhodiola extracts and salidroside, high-quality, randomized, controlled clinical trials are still needed.

Chemopreventive effect of oleuropein in colitis-associated colorectal cancer in c57bl/6 mice.

SCOPE: The main phenolic secoiridoid oleuropein and active constituent from olive tree (Olea europaea, Oleaceae), has demonstrated anti-inflammatory properties in intestinal inflammation and anti-tumoral effects in different cancer cells. In this study, we evaluated the chemoprevention of oleuropein in a model of azoxymethane (AOM)/Dextran sulfate sodium (DSS)-induced colorectal cancer (CRC) in C57BL/6 mice and the modulatory effect on the Th17 response in DSS acute colitis. METHODS AND RESULTS: Oleuropein protected from AOM/DSS-induced CRC by improving clinical symptoms, disease activity index score as well as suppressed the growth and multiplicity of colonic tumors. Treatment with oleuropein reduced intestinal IL-6, IFN-γ, TNF-α, and IL-17A concentration, and decreased cyclooxygenase-2, Bax and proliferating cell nuclear antigen protein expression. Western blot analysis also showed a markedly downregulation of CRC-related pathways as nuclear factor-κB (NF-κB), Wnt/ß-catenin, phosphatidylinositol-3-kinase (P3IK)/Akt, and signal transducer and activators of transcription (STAT)3. In DSS acute model, oleuropein inhibited Th17 response, by decreasing CD4(+) Rorγt(+) IL-17(+) IFN-γ(+) T-cell subsets in the lamina propria, as well as IL-17A and IFN-γ expression. CONCLUSION: Oleuropein as a dietary supplementation could be a promising protective agent against colitis-associated CRC.

Protective effect of apocynin in a mouse model of chemically-induced colitis.

Apocynin, a constituent of Picrorhiza kurroa, successfully inhibits NADPH oxidase and shows promise as an anti-inflammatory drug. Now, we report anti-inflammatory effects of apocynin in an experimental colitis model induced by dextran sulfate sodium as well as the effects on the mediators involved in this process. Apocynin reduced the colitis induced in mice by administration of 5 % dextran sulfate sodium during 7 days. Mice were fed a control diet or a diet supplemented with 2 % of apocynin or 2 % of rutin. Sulfasalazine (50 mg/kg, p. o.) was used as a positive control. Treatment with apocynin and rutin ameliorated the course of colonic inflammation with results similar to those of the reference drug, as could be seen by reductions in the disease activity index scores and colon length. NO and PGE2 production as well as the iNOS and COX-2 expression were reduced by apocynin and rutin. Moreover, the activation of NF-κB p65 as well as STAT3 in dextran sulfate sodium-treated colon tissues was significantly reduced by apocynin. These results are promising for further experimental studies on treating gastrointestinal diseases and on the potential protective effects of apocynin.

Oleuropein protects against dextran sodium sulfate-induced chronic colitis in mice.

The anti-inflammatory effect of oleuropein (1), the major phenolic secoiridoid in Olea europaea, was evaluated in an experimental model of chronic colitis in mice. Animals were exposed to four repeated cycles of dextran sodium sulfate in drinking water followed by a 7-day rest period. Animals receiving a standard diet supplemented with 0.25% of 1 (equivalent to 500 mg/kg/day) for 56 days exhibited a decrease of inflammatory symptoms, as reflected by improvement of disease activity index and histopathological changes. It was found that 1 decreased inflammatory cell recruitment and the release of inflammatory cytokines interleukin (IL)-1ß and IL-6 with increased IL-10 levels in colon tissue. Colon expression of cyclooxygenase-2 and inducible nitric oxide synthase was reduced significantly by 1. The anti-inflammatory molecular mechanism of 1 was associated with the suppression of the phosphorylation of p38 mitogen-activated protein kinase and might be mediated by up-regulation of annexin A1. In addition, 1 ameliorated intestinal wound healing in IEC-18 monolayers. Therefore, oleuropein seems to be a promising active molecule in experimental ulcerative colitis.

Lanostanoids from fungi: a group of potential anticancer compounds.

Lanostanes are a group of tetracyclic triterpenoids derived from lanosterol. They have relevant biological and pharmacological properties, such as their cytotoxic effects via induction of apoptosis. This review compiles the most relevant lanostanoids studied from 2000 to 2011, principally those isolated from Ganoderma lucidum and other related fungi, such as Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and Elfvingia applanata, which have great potential as anticancer agents because of their cytotoxic or apoptotic effects. The compounds were selected on the basis of their proapoptotic mechanisms, through their ability to modify transcriptional activities via nuclear factors or genes and the activation or inhibition of pro- or antiapoptotic proteins; studies based only on their cytotoxicity were excluded from this review in the absence of complementary studies on their mechanisms of action. A total of 81 compounds from Ganoderma lucidum and other species from this genus are included, as well as 96 compounds isolated from other fungi, principally Poria cocos. Some of these compounds were found to arrest the cell cycle in the G1 phase, increase levels of p53 and Bax, or inhibit the phosphorylation of Erk1/2 or the activation of NF-κB and AP-1. Other lanostanes have inhibitory effects on the growth of androgen prostate carcinoma through increasing the expression of p21, which activates the tumor suppressor protein p53, while other compounds have been shown to selectively inhibit topo II activity without affecting topo I. General considerations concerning the chemical structure-biological activities of these compounds are also discussed.

Modulation of protein tyrosine nitration and inflammatory mediators by isoprenylhydroquinone glucoside.

The nitration of tyrosine caused by peroxynitrite and other reactive nitrogen species is clearly detrimental for some physiological processes; however, its signalling role is still open to controversy. Among the natural phenolics known for their ability to oppose free tyrosine nitration, isoprenylhydroquinone glucoside is investigated due to its unusual structure, which contains a simple hydroxybenzene alkylated by a hemiterpenoid moiety. This hydroquinone was shown to be an effective inhibitor of peroxynitrite-induced protein tyrosine nitration in 3T3 fibroblasts. When tested on bovine seroalbumin nitration, however, the potency was reduced by half and the effect was almost abolished in the presence of bicarbonate. In contrast, addition of this anion had no effect on the nitrite/hydrogen peroxide/hemin system. Isoprenylhydroquinone glucoside was also active in the microM range on intra- and extracellular protein-bound tyrosine nitration by phorbol 12-myristate 13-acetate-stimulated neutrophils. The effects on nitric oxide synthase expression, interleukin-1beta and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages were quite moderate. Thus, isoprenylhydroquinone glucoside is an inhibitor of protein nitration in situ, but lacks effect on the generation of either nitric oxide or inflammatory cytokines.

Dihydrocucurbitacin B, isolated from Cayaponia tayuya, reduces damage in adjuvant-induced arthritis.

23,24-Dihydrocucurbitacin B, from the anti-rheumatic plant Cayaponia tayuya, was tested on arthritis induced by adjuvant to corroborate the anti-inflammatory properties of this plant. Arthritis was induced in Lewis rats; the resulting arthritic rats were then treated with dihydrocucurbitacin B (1 mg/kg orally, daily, 1 week). The effect of dihydrocucurbitacin B on the synthesis, release, and activity of pro-inflammatory enzymes (elastase, cyclooxygenase-2, and nitric oxide synthase-2) as well as its effect on different mediators (tumor necrosis factor-alpha and interleukin-1beta) were determined. Dihydrocucurbitacin B modified the evolution of the clinical symptoms, reducing the swelling and bone and tissue damage along with the development of the disease, modifying the cell infiltration and the expression of both nitric oxide synthase-2 and cyclooxygenase-2. In addition, it decreased the tumor necrosis factor-alpha and interleukin-1beta production in lymphocytes, but did not modify it in macrophages.