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SCIENTIFIC REFERENCES

 

Our references section is divided into three parts. Part one consists of abstracts of three seminal scientific papers published by scientists at UC Berkeley that discuss the molecular biology of DIM in immune response enhancement. Part two consists of other important papers regarding DIM and other ingredients in the Berkeley Immune Support Formula. Part three provides a direct search link on Diindolylmethane to the US National Library of Medicine enabling a comprehensive search of all scientific references on Diindolylmethane dating back to 1975. Together they are designed to be a comprehensive reference source for consumers and healthcare practitiouners investigating the health benefits of the Berkeley Immune Support Formula and Diindolylmethane.

 

Important note for readers: while many of the scientific discoveries and clinical developments listed in this section are extremely exciting, they are stepping stones in the studies of Diindolylmethane (DIM) and some of the other key natural ingredients in the Berkeley Immune Support Formula. The exploration of clinical applications for Diindolylmethane is an emerging science. Only the US FDA has the authority to recognize a compound as a drug or therapeutic for a particular condition in the US and that only occurs after the compound has been thoroughly studied and its efficacy established in four consecutive human clinical trials. At this point in time, Diindolylmethane and the other natural ingredients in the Berkeley Immune Support Formula are regarded as dietary supplements and not therapeutics for any specific condition by the US FDA. The Berkeley Immune Support Formula is a nutritional supplement. The statements on this website have not been evaluated by the US Food and Drug Administration. The Berkeley Immune Support Formula is not intended to diagnose, treat, cure or prevent any disease.

 

Part I: Scientific References on DIM's Enhancement of the Immune Response System

 

3,3′-Diindolylmethane (DIM) stimulates murine immune function in vitro and in vivo,  Xue L, Pestka J, Maoxiang L, Firestone GL, Bjeldanes LF,  Journal of Nutritional Biochemistry, published online, 8-20-07. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 94720-3104, USA.

 

Diindolylmethane (DIM), a major condensation product of indole-3-carbinol, exhibits chemopreventive properties in animal models of cancer. Recent studies have shown that DIM stimulates interferon-gamma (IFN-γ) production and potentiates the IFN-γ signaling pathway in human breast cancer cells via a mechanism that includes increased expression of the IFN-γ receptor. The goal of this study was to test the hypothesis that DIM modulates the murine immune function. Specifically, the effects of DIM were evaluated in a panel of murine immune function tests that included splenocyte proliferation, reactive oxygen species (ROS) generation, cytokine production and resistance to viral infection. DIM was found to induce proliferation of splenocytes as well as augment mitogen- and interleukin (IL)-2-induced splenocyte proliferation. DIM also stimulated the production of ROS by murine peritoneal macrophage cultures. Oral administration of DIM, but not intraperitoneal injection, induced elevation of serum cytokines in mice, including IL-6, granulocyte colony-stimulating factor (G-CSF), IL-12 and IFN-γ. Finally, in a model of enteric virus infection, oral DIM administration to mice enhanced both clearance of reovirus from the GI tract and the subsequent mucosal IgA response. Thus, DIM is a potent stimulator of immune function. This property might contribute to the cancer inhibitory effects of this indole.

 

Activation and potentiation of interferon-gamma signaling by 3,3-Diindolylmethane (DIM) in MCF-7 breast cancer cells. Riby JE, Xue L, Chatterji U, Bjeldanes EL, Firestone GL, Bjeldanes LF. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 94720-3104, USA. Molecular Pharmacology. 2006 Feb;69(2):430-9.

 

3,3-Diindolylmethane, a natural autolytic product in plants of the Brassica genus, including broccoli, cauliflower, and Brussels sprouts, exhibits promising cancer protective activities, especially against mammary neoplasia in animal models. We observed previously that DIM induced a G(1) cell-cycle arrest and strong induction of cell-cycle inhibitor p21 expression and promoter activity in both estrogen-responsive and -independent breast cancer cell lines. We showed recently that DIM up-regulates the expression of interferon gamma (IFNgamma) in human MCF-7 breast cancer cells. This novel effect may contribute to the anticancer effects of DIM because IFNgamma plays an important role in preventing the development of primary and transplanted tumors. In this study, we observed that DIM activated the IFNgamma signaling pathway in human breast cancer cells. DIM activated the expression of the IFNgamma receptor (IFNGR1) and IFNgamma-responsive genes p56- and p69-oligoadenylate synthase (OAS). In cotreatments with IFNgamma, DIM produced an additive activation of endogenous p69-OAS and of an OAS-Luc reporter and a synergistic activation of a GAS-Luc reporter. DIM synergistically augmented the IFNgamma induced phosphorylation of signal transducer and activator of transcription factor 1, further evidence of DIM activation of the IFNgamma pathway. DIM and IFNgamma produced an additive inhibition of cell proliferation and a synergistic increase in levels of major histocompatibility complex class-1 (MHC-1) expression, accompanied by increased levels of mRNAs of MHC-1-associated proteins and transporters. These results reveal novel immune activating and potentiating activities of DIM in human tumor cells that may contribute to the established effectiveness of this dietary indole against various tumor types.
 

DIM stimulates IFNgamma gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Xue L, Firestone GL, Bjeldanes LF. Department of Nutritional Sciences and Toxicology, University of California, 119 Morgan Hall, Berkeley, CA 94720-3104, USA. Oncogene. 2005 Mar 31;24(14):2343-53.

 

3,3-Diindolylmethane (DIM) is a promising anticancer agent derived from Brassica vegetables, but the mechanisms of DIM action are largely unknown. We have shown that DIM can upregulate the expression and stimulate the secretion of interferon-gamma (IFNgamma) in the human MCF-7 breast cancer cell line. This novel effect may provide important clues to explain the anticancer effects of DIM because it is well known that IFNgamma plays an important role in preventing the development of primary and transplanted tumors. Utilizing promoter deletions, we show here that the region between -108 and -36 bp in the IFNgamma promoter, which contains two conserved and essential regulatory elements, is required for DIM-induced IFNgamma expression. DIM activates both JNK and p38 pathways, induces the phosphorylation of c-Jun and ATF-2, and increases the binding of the homodimer or heterodimer of c-Jun/ATF-2 to the proximal AP-1.CREB-ATF-binding element. Moreover, studies with specific enzyme inhibitors showed that up-stream Ca2+-dependent kinase(s) is required for the inducing effects of DIM in MCF-7 cells. These results establish that DIM-induced IFNgamma expression in human breast tumor cells is mediated by activation of both JNK and p38 pathways, which is ultimately dependent on intracellular calcium signaling.

 

Part II: Additional Scientific References on DIM and other Ingredients in Berkeley Immune Support Formula

 

Oral diindolylmethane (DIM): Pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecological Oncology. 2009 Nov 24. Del Priore G, Gudipudi DK, Montemarano N, Restivo AM, Malanowska-Stega J, Arslan AA. Indiana University School of Medicine, Dept of Ob-Gyn, Div Gyn Oncology, Indianapolis, IN, USA; Research Department, New York Downtown Hospital-member NY-Presbyterian Healthcare, New York, NY, USA.

OBJECTIVE: Standard surgical treatment for CIN may impair fertility generating a need for alternative treatment options. We tested the efficacy and toxicity of oral DIM in the treatment of CIN 2 or 3 lesions. METHODS: Patients with biopsy-proven cervical intraepithelial neoplasia (CIN) 2 or 3 scheduled for loop electrosurgical excision procedure (LEEP) were randomized 2:1 to receive diindolylmethane (DIM) orally at approximately 2 mg/kg/day for 12 weeks or placebo. Subjects were evaluated every 3-4 months for 1 year. Analysis of data up to 1 year was assessed including Pap smear, HPV, colposcopy, biopsy and physical examination were performed at follow-up. Central pathology review confirmed all histology diagnoses. RESULTS: To date, 64 subjects (mean age 28 years, range 18-61) have been enrolled (45 in the DIM arm, 19 in the placebo arm), with 60 available for analysis. Average follow-up was 6 months. At enrollment, 58% were diagnosed with CIN 2 and 42% with CIN 3, 57% of subjects were Caucasian, 15% African American, 12% Hispanic and 17% Asian. During treatment 2 subjects (3%) complained of nausea (grade 2) at the 3- to 4-month visit. No systemic toxicities were observed (normal CBC, LFTs, comprehensive metabolic). Forty-six subjects had biopsies at first follow-up (77%). Twenty-one subjects (47%) in the DIM group had improved CIN with a decrease by 1-2 grades or a normal result. Median time to improvement was 5 months. Improved Pap smear was seen in 49% (22/45) with either a less severe abnormality or normal result. Colposcopy improved in twenty-five subjects in the DIM group (56%). Of these 25 subjects, 21 (84%) had improved colposcopic impression, 13 (52%) had a decrease in involved quadrants and 18 (72%) had a decrease in lesion number. Complete colposcopic response was observed in 4 subjects (9%). Stratifying by level of dysplasia, age, race, HPV status, tobacco use, contraceptive used did not alter the results. At median follow-up of 6 months, 85% of subjects have not required LEEP based on routine clinical triage of improving global assessment. CONCLUSION: Oral DIM at 2 mg/kg/day is well tolerated with no significant toxicity. We observed a high rate of clinically significant improvement in confirmed CIN 2 or 3 lesions among both treatment groups in this randomized clinical trial.

 

Diindolylmethane (DIM) is a novel topoisomerase II alpha catalytic inhibitor that induces S-phase retardation and mitotic delay in human hepatoma HepG2 cells. Mol Pharmacol. 2006 Apr;69(4):1320-7. Gong Y, Firestone GL, Bjeldanes LF.Department of Nutritional Sciences and Toxicology, 119 Morgan Hall, University of California, Berkeley, CA 94720-3104, USA.

 

Epidemiological evidence suggests that high consumption of Brassica genus vegetables, such as broccoli, cabbage, and Brussels sprouts, is very effective in reducing the risks of several types of cancers. 3,3-Diindolylmethane (DIM), one of the most abundant and biologically active dietary compounds derived from Brassica genus vegetables, displays remarkable antitumor activity against several experimental tumors. In the present study, we demonstrate for the first time that DIM is a novel catalytic topoisomerase IIalpha inhibitor. In supercoiled DNA relaxation assay and kinetoplast DNA decatenation assay, DIM strongly inhibited DNA topoisomerase IIalpha and also partially inhibited DNA topoisomerases I and IIbeta. DIM did not stabilize DNA cleavage complex and did not prevent etoposide-induced DNA cleavage complex formation. Further experiments showed that inhibited topoisomerase IIalpha-catalyzed ATP hydrolysis, which is a necessary step for the enzyme turnover. In cultured human hepatoma HepG2 cells, DIM blocked DNA synthesis and mitosis in a concentration-dependent manner, which was consistent with the outcome of topoisomerase inhibition in these cell-cycle phases. Our results identified a new mode of action for this intriguing dietary component that might be exploited for therapeutic development.

 

3,3-Diindolylmethane (DIM) and Paclitaxel Act Synergistically to Promote Apoptosis in HER2/Neu Human Breast Cancer Cells. Journal of Surgical Research, 2006 May 15;132(2):208-13. K. McGuire, N. Ngoubilly, M. Neavyn, S. Lanza-Jacoby Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.

 

HER2/neu positive breast tumors are difficult to treat. About 25 to 30% of invasive breast tumors overexpress the HER2/neu oncogene. These tumors are aggressive and become resistant to chemotherapeutic drugs. Diindolylmethane (DIM), the active metabolite of indole-3-carbinol, a naturally occurring compound found in cruciferous vegetables, has been found to have anti-cancer properties in both humans and animals. DIM has been shown to induce cell cycle arrest and apoptosis in animal breast cancer models. Because HER2/neu overexpression confers resistance to paclitaxel, and DIM has anti-tumor effects, we hypothesized that DIM will enhance the cytotoxic effects of paclitaxel, a common taxane drug, on human Her2/neu breast cancer cells by potentiating its effect on cell cycle and stimulating apoptosis. METHODS: The MDA-MB-435eB1 human Her2/neu breast cancer cells were treated with varying concentrations of DIM and paclitaxel. The cells were analyzed at different time points (24, 48, and 72 h). Proliferation was measured by a commercial cell proliferation assay (Promega Procheck Assay). Cell-cycle analysis and apoptosis were determined by flow cytometry. Western blot analysis was performed on to determine the effect of DIM and/or paclitaxel on the proteins involved in apoptosis, and epidermal growth factor-induced activation of HER2/neu and ERK1/2 signaling proteins. RESULTS: Both DIM and paclitaxel exhibited time and concentration dependent inhibition of cell proliferation. TUNEL assay indicated that the combination also increased the number of apoptotic cells more than either agent alone. The presence of cleaved poly (ADP-Ribose) polymerase (PARP) significantly increased in the combination treatment, whereas Bcl-2 is decreased. DIM alone decreased the activation of the Her2/neu receptor; the combination decreased the activation of ERK1/ERK2. CONCLUSIONS: DIM in combination with paclitaxel synergistically inhibits growth of Her2/neu human breast cancer cells through G2M phase cell-cycle arrest and induction of apoptosis/necrosis. The Her2/neu receptor and its downstream signaling protein ERK1/2 appear to be involved in DIM's affect on cell growth and differentiation, whereas apoptosis appears to be mediated through the mitochondrial pathway (Bcl-2/PARP). It appears DIM, a naturally occurring, nontoxic compound, may be a beneficial addition to a traditional (taxane-based) chemotherapy regimen.

 

Inactivation of NF-kappaB by 3,3'-Diindolylmethane (DIM) contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Molecular Cancer Therapeutics, 2007 Oct;6(10):2757-65. Rahman KM, Ali S, Aboukameel A, Sarkar SH, Wang Z, Philip PA, Sakr WA, Raz A. Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 715 HWCRC, 4100 John R, Detroit, MI 48201, USA.

 

Constitutive activation of Akt or nuclear factor-kappaB (NF-kappaB) has been reported to play a role in de novo resistance of cancer cells to chemotherapeutic agents, which is a major cause of treatment failure in cancer chemotherapy. Previous studies have shown that 3,3'-diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of indole-3-carbinol, is a potent inducer of apoptosis, inhibitor of tumor angiogenesis, and inactivator of Akt/NF-kappaB signaling in breast cancer cells. However, little is known regarding the inactivation of Akt/NF-kappaB that leads to chemosensitization of breast cancer cells to chemotherapeutic agents, such as Taxotere. Therefore, we examined whether the inactivation Akt/NF-kappaB signaling caused by DIM could sensitize breast cancer cells to chemotherapeutic agents both in vitro and in vivo. MDA-MB-231 cells were simultaneously treated with 15 to 45 micromol/L DIM and 0.5 to 1.0 nmol/L Taxotere for 24 to 72 h. Cell growth inhibition assay, apoptosis assay, electrophoretic mobility shift assay, and Western blotting were done. The combination treatment of 30 micromol/L DIM with 1.0 nmol/L Taxotere elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced greater apoptosis in MDA-MB-231 cells compared with single agents. Moreover, we found that NF-kappaB activity was significantly decreased in cells treated with DIM and Taxotere. We also have tested our hypothesis using transfection studies, followed by combination treatment with DIM/Taxotere, and found that combination treatment significantly inhibited cell growth and induced apoptosis in MDA-MB-231 breast cancer cells mediated by the inactivation of NF-kappaB, a specific target in vitro and in vivo. These results were also supported by animal experiments, which clearly showed that DIM sensitized the breast tumors to Taxotere, which resulted in greater antitumor activity mediated by the inhibition of Akt and NF-kappaB. Collectively, our results clearly suggest that inhibition of Akt/NF-kappaB signaling by DIM leads to chemosensitization of breast cancer cells to Taxotere, which may contribute to increased growth inhibition and apoptosis in breast cancer cells. The data obtained from our studies could be a novel breakthrough in cancer therapeutics by using nontoxic agents, such as DIM, in combination with other conventional therapeutic agents, such as Taxotere.

 

Pilot study: effect of 3,3-Diindolylmethane DIM) supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Journal of Nutrition and Cancer. 2004;50(2):161-7. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF Department of Molecular and Cell Biology, University of California, Berkeley, 94720-3200, USA.

 

Dietary indoles, present in Brassica plants such as cabbage, broccoli, and Brussels sprouts, have been shown to provide potential protection against hormone-dependent cancers. 3,3-Diindolylmethane(DIM) is under study as one of the main protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin County, California, with a history of early-stage breast cancer, were screened for interest and eligibility in this pilot study on the effect of DIM supplements on urinary hormone metabolites. The treatment group received daily DIM (108 mg DIM/day) supplements for 30 days, and the control group received a placebo capsule daily for 30 days. Urinary metabolite analysis included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1), DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol (6beta-OHC), and cortisol in the first morning urine sample before intervention and 31 days after intervention. Nineteen women completed the study,for a total of 10 in the treatment group and 9 in the placebo group. DIM-treated subjects, relative to placebo, showed a significant increase in levels of2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites.

 

Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Department of Social and Preventive Medicine, University at Buffalo, State University of New York at Buffalo, Buffalo, NY, USA, Epidemiology Division of the National Cancer Institute (Istituto Nazionale Tumori), Milan, Italy, Department of Pediatric Hematology and Oncology, Medical School of Hannover, Hannover, Germany.

Experimental and clinical evidence suggests that 16alpha-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the "Hormones and Diet in the Etiology of Breast Cancer" (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degrees C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.

 

Plant-derived 3,3-Diindolylmethane DIM) is a strong androgen antagonist in human prostate cancer cells. Journal of Biological Chemistry.  2003 June 6;278(23);21136-45. Le HT, Schaldach CM, Firestone GL, Bjeldanes LF. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720-3104, USA.

 

3,3-Diindolylmethane (DIM) is a major digestive product of indole-3-carbinol, a potential anticancer component of cruciferous vegetables. Our results indicate that DIM exhibits potent antiproliferative and antiandrogenic properties in androgen-dependent human prostate cancer cells. DIM suppresses cell proliferation of LNCaP cells and inhibits dihydrotestosterone (DHT) stimulation of DNA synthesis. These activities were not produced in androgen-independent PC-3 cells. Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells. Also, DIM inhibited, in a concentration-dependent manner, the DHT-induced expression of a prostate-specific antigen promoter-regulated reporter gene construct in transiently transfected LNCaP cells. Similar effects of DIM were observed in PC-3 cells only when these cells were co-transfected with a wild-type androgen receptor expression plasmid. Using fluorescence imaging with green fluorescent protein androgen receptor and Western blot analysis, we demonstrated that DIM inhibited androgen-induced androgen receptor (AR) translocation into the nucleus. Results of receptor binding assays indicated further that DIM is a strong competitive inhibitor of DHT binding to the AR. Results of structural modeling studies showed that DIM is remarkably similar in conformational geometry and surface charge distribution to an established synthetic AR antagonist, although the atomic compositions of the two substances are quite different. To our knowledge, DIM is the first example of a pure androgen receptor antagonist from plants.

 

Prospective Study of Fruit and Vegetable Intake and Risk of Prostate Cancer. Journal of the National Cancer Institute. 2007 Jul 24; (Epub ahead of print) Krish VA, Peters U, Mayne ST, Subar AF, Chatterjee N, Johnson CC, Hayes RB. Affiliations for authors: Research Unit, Division of Preventive Oncology, Cancer Care Ontario, Toronto, ON, Canada (VAK); Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT (VAK, STM); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (UP); Department of Epidemiology, University of Washington, Seattle, WA (UP); Divisions of Cancer Epidemiology and Genetics (NC, RBH) and Cancer Control and Population Sciences (AFS), National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Josephine Ford Cancer Center, Henry Ford Health System, Detroit, MI (CCJ).

 

Background Several epidemiologic studies have reported associations between fruit and vegetable intake and reduced risk of prostate cancer, but the findings are inconsistent and data on clinically relevant advanced prostate cancer are limited. Methods We evaluated the association between prostate cancer risk and intake of fruits and vegetables in 1338 patients with prostate cancer among 29361 men (average follow-up = 4.2 years) in the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Participants completed both a general risk factor and a 137-item food-frequency questionnaire at baseline. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results Vegetable and fruit consumption was not related to prostate cancer risk overall; however, risk of extraprostatic prostate cancer (stage III or IV tumors) decreased with increasing vegetable intake (RR = 0.41, 95% CI = 0.22 to 0.74, for high versus low intake; P(trend) = .01). This association was mainly explained by intake of cruciferous vegetables (RR = 0.60, 95% CI = 0.36 to 0.98, for high versus low intake; P(trend) = .02), in particular, broccoli (RR = 0.55, 95% CI = 0.34 to 0.89, for >1 serving per week versus <1 serving per month; P(trend) = .02) and cauliflower (RR = 0.48, 95% CI = 0.25 to 0.89 for >1 serving per week versus <1 serving per month; P(trend) = .03). We found some evidence that risk of aggressive prostate cancer decreased with increasing spinach consumption, but the findings were not consistently statistically significant when restricted to extraprostatic disease. Conclusion: high intake of cruciferous vegetables, including broccoli and cauliflower, may be associated with reduced risk of aggressive prostate cancer, particularly extraprostatic disease.

 

A phase I dose-escalation study of oral DIM (3,3'-Diindolylmethane) in

castrate-resistant, non-metastatic prostate cancer. Am J Transl Res. 2010 Jul 23;2(4):402-11. Heath EI, Heilbrun LK, Li J, Vaishampayan U, Harper F, Pemberton P, Sarkar FH. Karmanos Cancer Institute, Wayne State University Detroit, MI, USA.

 

3, 3'-diindolylmethane (DIM) modulates estrogen metabolism and acts as an anti-androgen which down-regulates the androgen receptor and prostate specific antigen (PSA). We conducted a dose-escalation, phase I study of DIM with objectives to determine the maximum tolerated dose (MTD), toxicity profile, and phar-macokinetics (PK) of DIM, and to assess its effects on serum PSA and quality of life (QoL).PATIENTS AND METHODS: Cohorts of 3-6 patients received escalating doses of twice daily oral DIM providing DIM at 75 mg, then 150 mg, 225 mg, and 300 mg. Toxicity was evaluated monthly. Serum PSA and QoL were measured at baseline, monthly during treatment, and at end of study. RESULTS: 12 patients with castrate-resistant, non-metastatic, PSA relapse prostate cancer were treated over 4 dose cohorts; 2 patients (at 150 mg and 225 mg, respectively) underwent intra-patient dose escalation, by one dose level. After oral administration of the first dose of DIM, the plasma exposure to DIM appeared dose proportional at doses ranging from 75 to 300 mg, with the mean C(max) and mean AUC(last) increasing from 41.6 to 236.4 ng/ml and from 192.0 to 899.0 ng/ml*h, respectively. Continued relatively stable systemic exposure to DIM was achieved following twice daily oral administration of DIM. Minimal toxicity was observed. Two of the four patients treated at 300 mg had grade 3 asymptomatic hyponatremia (AH) discovered on routine blood work. The other 2 patients at this dose had no AH. Therefore, the maximum tolerated dose (MTD) was deemed to be 300 mg and the recommended phase II dose (RP2D) of DIM was 225 mg twice daily. One patient without AH at 225 mg experienced a 50% PSA decline. One patient with DIM dose of 225 mg had PSA stabilization. The other 10 patients had an initial deceleration of their PSA rise (decrease in slope), but eventually progressed based on continual PSA rise or evidence of metastatic disease. Ten patients completed monthly QoL reports for a mean of 6 months (range: 1-13). QoL measures emotional functioning may have held up somewhat better over time than their physical functioning.

 

CONCLUSION: DIM was well tolerated. Increasing systemic exposure to DIM was achieved with the increase of DIM dose. Modest efficacy was demonstrated. Patients' QoL varied over time with length of treatment. Phase II studies are recommended at the dose of 225 mg orally twice daily. Diindolylmethane (DIM) induces a G(1) cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21(WAF1/CIP1) expression.

 

Carcinogenesis 2002 Aug;23(8):1297-305. Hong C, Kim HA, Firestone GL, Bjeldanes LF. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.

 

3,3-Diindolylmethane (DIM) is a promising cancer chemopreventive agent derived from Brassica food plants. To determine whether this natural indole has a direct growth inhibitory effect on human breast cancer cells, we examined the cell cycle regulatory effects of DIM in estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cell lines. Results of flow cytometry studies showed that DIM treatment produced a marked increase (from 51 to 79%) in the proportion of cells in the G(1) phase of the cell cycle, regardless of estrogen-receptor status. Analyses of G(1)-acting cell cycle components indicated that the enzymatic activity of cyclin-dependent kinase (CDK) 2 was also strongly reduced. Western blot analyses showed that, concurrent with the DIM-induced cell cycle arrest, DIM stimulated a rapid and pronounced increase in levels of the CDK inhibitor, p21(WAF1/CIP1) (p21). Northern blot analysis demonstrated that DIM increased p21 mRNA expression with a maximal 6-7-fold induction, and exposure to cycloheximide did not block the response. Similar increases in expression of p21 protein and mRNA were observed in both MCF-7 and MDA-MB-231 human breast cancer cells, suggesting that DIM induction of p21 expression is independent of estrogen-receptor signaling and p53. Transient transfection of 5'-deletion constructs of the p21 promoter demonstrated that the first 291 bp segment of the proximal promoter, which contains six promoter specific transcription factor 1 (Sp1) elements, maintained DIM responsiveness. Consistent with a role for Sp1 in this response, a reporter construct driven by three consensus Sp1 binding sites was responsive to DIM. In addition, electrophoretic mobility shift assays showed that DIM induced the binding of Sp1 and Sp3 to the consensus Sp1 responsive element. Thus, our observations have uncovered an antiproliferative pathway for DIM that implicates Sp1/Sp3-induced expression of p21 as a target for cell cycle control in human breast cancer cells.

 

Lycopene. Advances in Food and Nutrition Research 2006;51:99-164. Rao AV, Ray MR, Rao LG, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

 

Oxidative stress is now recognized as an important etiological factor in the causation of several chronic diseases including cancer, cardiovascular diseases, osteoporosis, and diabetes. Antioxidants play an important role in mitigating the damaging effects of oxidative stress on cells. Lycopene, a carotenoid antioxidant, has received considerable scientific interest in recent years. Epidemiological, tissue culture, and animal studies provide convincing evidence supporting the role of lycopene in the prevention of chronic diseases.

 

Combined lycopene and vitamin E treatment suppresses the growth of PC-346C human prostate cancer cells in nude mice. The Journal of Nutrition. 2006 May;136(5):1287-93. Limpens J, Shroder FH, de Ridder CM, Bolder CA, Wildhagen MF, Obermuller-Jevic UC, Kramer K., Van Weerden WM. Department of Urology, Erasmus MC, Rotterdam, The Netherlands.

 

Epidemiologic studies have repeatedly associated a high intake of lycopene and vitamin E with reduced prostate cancer risk. The present study examined the ability of the 2 compounds to reduce tumor growth and prostate-specific antigen (PSA) plasma levels in the PC-346C orthotopic mouse model of human prostate cancer. Three days after intraprostatic tumor injection, NMRI nu/nu mice were administered a daily oral dose of synthetic lycopene [5 or 50 mg/kg body weight (BW)], vitamin E in the form of alpha-tocopheryl acetate (5 or 50 mg/kg BW), a mixture of lycopene and vitamin E (5 mg/kg BW each), or vehicle. Intraprostatic tumor volume and plasma PSA concentrations were measured at regular intervals. Mice were killed when the tumor load exceeded 1000 mm(3) or on d 95 when the study was terminated. Prostate and liver were analyzed by HPLC for lycopene isomers and alpha- and gamma, delta-tocopherol concentrations. None of the single treatments significantly reduced tumor volume. In contrast, combined treatment with lycopene and vitamin E, at 5 mg/kg BW each, suppressed orthotopic growth of PC-346C prostate tumors by 73% at d 42 (P < 0.05) and increased median survival time by 40% from 47 to 66 d (P = 0.02). The PSA index (PSA:tumor volume ratio) did not differ between experimental groups, indicating that PSA levels were not selectively affected. Lycopene was detected only in mice supplemented with lycopene. As in humans, most tissue lycopene was in the cis-isomer conformation, whereas 77% trans-lycopene was used in the dosing material. Liver alpha-tocopherol concentrations were increased in mice supplemented with both 50 mg/kg (226%, P < 0.05) and 5 mg/kg vitamin E (41%, P < 0.05), whereas prostate alpha-tocopherol concentrations were increased only by the higher dose (83%, P < 0.05). Our data provide evidence that lycopene combined with vitamin E may inhibit the growth of prostate cancer and that PSA can serve as a biomarker of tumor response for this treatment regimen.

 

Tomato lycopene and its role in human health and chronic diseases. CMAJ 2000 Sep 19;163(6):739-44 Agarwal S., Rao AV., Department of Nutritional Sciences, Faculty of Medicine, University of Toronto.

 

Lycopene is a carotenoid that is present in tomatoes, processed tomato products and other fruits. It is one of the most potent antioxidants among dietary carotenoids. Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease. Serum and tissue lycopene levels have been found to be inversely related to the incidence of several types of cancer, including breast cancer and prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial effects, evidence is accumulating to suggest that other mechanisms may also be involved. In this article we outline the possible mechanisms of action of lycopene and review the current understanding of its role in human health and disease prevention.

 

Combinations of Tomato and Broccoli Enhance Antitumor Activity in Dunning R3327-H Prostate Adenocarcinomas. Canene-Adams K, Lindshield B, Wang S, Jeffery E, Clinton S, Erdman J.,  Cancer Res 2007; 67: (2). January 15, 2007

 

The consumption of diets containing 5 to 10 servings of fruits and vegetables daily is the foundation of public health recommendations for cancer prevention, yet this concept has not been tested in experimental models of prostate cancer. We evaluated combinations of tomato and broccoli in the Dunning R3327-H prostate adenocarcinoma model. Male Copenhagen rats (n=206) were fed diets containing 10% tomato, 10% broccoli, 5% tomato plus 5% broccoli (5:5 combination), 10% tomato plus 10% broccoli (10:10 combination) powders for approximately 22 weeks starting 1 month prior to receiving s.c. tumor implants. We compared the effects of diet to surgical castration (2 weeks before termination) or finasteride (5 mg/kg body weight orally, 6 d/wk). Castration reduced prostate weights, tumor areas, and tumor weight (62%, P<0.001), whereas finasteride reduced prostate weights (P<0.0001), but had no effect on tumor area or weight. Tomato reduced tumor weight by 34% (P<0.05). Broccoli decreased tumor weights by 42% (P<0.01) whereas the 10:10 combination caused a 52% decrease (P<0.001). Tumor growth reductions were associated with reduced proliferation and increased apoptosis, as quantified by proliferating cell nuclear antigen immunohistochemistry and the ApopTag assay. The combination of tomato and broccoli was more effective at slowing tumor growth than either tomato or broccoli alone and supports the public health recommendations to increase the intake of a variety of plant components.

 

Selenium inhibition of survivin expression by preventing Sp1 binding to its promoter. Chun JY, Hu Y, Pinder E, Wu J, Li F, Gao AC, Molecular Cancer Therapeutics. 2007 Sep;6(9):2572-80. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

 

Survivin, an antiapoptotic protein highly expressed in cancer, regulates multiple cellular network associated with cancer cell viability and drug resistance. Inhibition of survivin expression has been pursued as a valid cancer therapeutic target. In this study, we showed that selenium, an effective chemopreventive agent for many types of cancers, down-regulated survivin expression. Selenium inhibited survivin expression in both mRNA and protein levels in a dose- and time-dependent manner. Using a series of survivin promoter-luciferase constructs, a 37-bp DNA element in the survivin core promoter region that mediates the ability of selenium to inhibit survivin transcription was identified. Gel mobility shift assays and chromatin immunoprecipitation analyses revealed that selenium prevents the binding of Sp1 or Sp1-like proteins to the 37-bp cis-acting DNA element in the survivin promoter. Furthermore, inhibition of survivin expression by small interfering RNA enhanced selenium's inhibitory effects on cell growth, whereas overexpression of survivin in LNCaP human prostate cancer cells desensitized cancer cells to selenium effect, suggesting that the expression of survivin plays an important role in determining the response of cancer cells to selenium. Taken together, these results suggest that selenium down-regulated survivin expression by preventing the binding of Sp1 or Sp1-like proteins to the promoter of survivin, which contributes at least in part to the inhibitory effect of selenium on survivin gene transcription. In addition, down-regulation of survivin expression may account for one of the molecular mechanisms of the anticancer effects of selenium.

 

High selenium reduces NF-kappaB-regulated gene expression in uninduced human prostate cancer cells. Christensen MJ, Nartey ET, Hada AL, Legg RL, Barzee BR, Journal of Nutrition and Cancer, 2007;58(2):197-204. Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA.

 

Nuclear factor kappa B (NF-kappaB) induces expression of antiapoptotic and pro-inflammatory genes and is constitutively activated in prostate cancer. We tested the hypothesis that a biologically and physiologically relevant form and concentration of selenium (Se) may alter NF-kappa B activation in early prostate cancer cells in the absence of exogenously added inducers of the NF-kappaB pathway. LNCaP cells were cultured in medium without added tumor necrosis factor alpha or lipopolysaccharide but with methylseleninic acid added to provide final concentrations of Se of 30 nM-7.6 microM. Compared to 50 nM Se, treatment with 7.6 microM Se virtually eliminated NF-kappaB binding to its DNA response element and reduced transcription rates and mRNA levels by half for NF-kappaB-regulated genes. There were no differences due to Se in tyrosine phosphorylation, inhibitor of kappa B alpha (I kappa B alpha) levels, or NF-kappaB translocation from cytosol to nucleus. The observation in these basal, unstimulated cells of altered NF-kappaB binding to DNA in the absence of effects on the NF-kappaB activation pathway suggests an interaction of Se with the NF-kappaB protein or an effect on recruitment of NF-kappaB coactivators or corepressors. Inhibition of transcription factor binding and anti-apoptotic gene expression may be one mechanism for the chemopreventive effects of Se against prostate cancer.

 

Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion. Zeng H, Combs GF Jr., 2007 Jun 22, Journal of Nutritional Biochemistry. United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, P.O. Box 9034, Grand Forks, ND 58202-9034, USA.

 

Selenium is an essential dietary component for animals including humans, and there is increasing evidence for the efficacy of certain forms of selenium as cancer-chemopreventive compounds. In addition, selenium appears to have a protective effect at various stages of carcinogenesis including both the early and later stages of cancer progression. Mechanisms for selenium-anticancer action are not fully understood; however, several have been proposed: antioxidant protection, enhanced carcinogen detoxification, enhanced immune surveillance, modulation of cell proliferation (cell cycle and apoptosis), inhibition of tumor cell invasion and inhibition of angiogenesis. Research has shown that the effectiveness of selenium compounds as chemopreventive agents in vivo correlates with their abilities to affect the regulation of the cell cycle, to stimulate apoptosis and to inhibit tumor cell migration and invasion in vitro. This article reviews the status of knowledge concerning selenium metabolism and its anticancer effects with particular reference to the modulation of cell proliferation and the inhibition of tumor cell invasion.

 

Selenomethionine induction of DNA repair response in human fibroblasts. Oncogene (2002) 21, 3663-3669. Seo Y, Sweeney C, and Smith M. Indiana University Cancer Center, Department of Microbiology, Walther Oncology Center, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, IN 46202, USA. Department of Medicine, Section of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Selenium compounds have a long history in chemoprevention of mammary and colon cancers in rodent models. Selenium compounds are in current clinical trials, having shown promise in prevention of prostate and other human cancers. In human tissues, it has been estimated that each cell sustains approximately 10 000 potentially mutagenic (if not repaired) lesions per day due to endogenous DNA damage. Almost no studies have addressed the potential for selenium compounds to induce DNA repair, a potential mechanism for their cancer-preventive actions. We show that selenium in the form of selenomethionine induces a DNA repair response in normal human fibroblasts in vitro, and protects cells from DNA damage. We show a possible mechanism for the inducible DNA repair response, in which enhanced repair complex formation was observed in selenomethionine-treated cells.

Low serum selenium and total carotenoids predict mortality among older women living in the community. Journal of Nutrition. 2006 Jan;136(1):172-6. Ray AL, Semba RD, Walston J., Ferrucci L, Cappola AR, Ricks MO, Xue QL, Fried LP. The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Selenium and the carotenoids play an important role in antioxidant defenses and in the redox regulation involved in inflammation. We tested the hypothesis that low selenium and carotenoids predict mortality in older women living in the community. Women who were enrolled in the Women's Health and Aging Studies I and II in Baltimore, MD (n = 632; 70-79 y old) had serum selenium and carotenoids measured at baseline and were followed for mortality over 60 mo. Median (minimum, maximum) serum selenium and carotenoids were 1.53 (0.73, 2.51) micromol/L and 1.67 (0.13, 9.10) micromol/L; 14.1% of the women died. The 5 major causes of death were heart disease (32.6%), cancer (18.0%), stroke (9.0%), infection (6.7%), and chronic obstructive pulmonary disease (5.6%). Adjusting for age, education, smoking, BMI, poor appetite, and chronic diseases, higher serum selenium [hazard ratio (HR) 0.71, 95% CI 0.56-0.90/1 SD increase in log(e) selenium; P = 0.005] and higher serum total carotenoids (HR 0.77, 95% CI 0.64-0.84/1 SD increase in log(e) total carotenoids; P = 0.009) were associated with a lower risk of mortality. Women living in the community who have higher serum selenium and carotenoids are at a lower risk of death.

 

From dietary antioxidants to regulators in cellular signaling and gene regulation: Sulforaphane and selenium, partners in adaptive response and prevention of cancer. Free Radical Research. 2006 Aug;40(8):775-87. Brigelius-Flohe R., Banning A. German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114 - 116, D-14558, Nuthetal, Germany.

 

The association of decreased cancer risk with intake of cruciferous vegetables and selenium is stronger than that reported for fruits and vegetables in general. An active constituent in cruciferae is sulforaphane. Chemopreventive effects of both, sulforaphane and selenium have been attributed to an antioxidant action which certainly is too simplicistic. Sulforaphane induces via activation of the Nrf2/Keap1 system phase 2 enzymes that protect against carcinogens and oxidants. Induced enzymes comprise the selenoproteins thioredoxin reductase-1 (TrxR1) and gastrointestinal glutathione peroxidase (GI-GPx, GPx2), which contain antioxidant response elements (ARE) in their promoter regions. Translational realisation of the enhanced transcripts depends on adequate selenium supply, which explains the synergism of Nrf2 activators and selenium. Regarding tumorigenesis the role of TrxR1 is ambiguous: it is essential for fast tumor cell growth but also diminishes vascularisation of tumors. The anticarcinogenic role of GI-GPx is evident from enhanced gastrointestinal tumor formation in gpx2/gpx1 double KO mice.

 

Synergy between sulforaphane and selenium in the induction of thioredoxin reductase 1 requires both transcriptional and translational modulation. Carcinogenesis, 2003 Mar;24(3):497-503. Nutrition Division, Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, UK. Zhang J, Svehikova V., Bao Y, Howie AF, Beckett GJ, Williamson G.

 

Thioredoxin reductases (TrxRs) catalyse the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis and cell signaling. We have used human hepatoma HepG2 cells to examine the regulation of TrxRs by isothiocyanate (sulforaphane) and selenium (Se). We show that TrxR1 mRNA, but not TrxR2 mRNA, is induced up to 4-fold by sulforaphane, and this increase was abolished by actinomycin D, a transcription inhibitor. Se, in the form of sodium selenite, induced TrxR1 at the translational level, as shown by an increase in protein (2.1-fold) and activity (4.8-fold), but not mRNA. In combination, sulforaphane and Se synergistically induced TrxR1 protein (5.5-fold), activity (13-fold) and mRNA (6.5-fold). Although Se does not induce TrxR1 mRNA, Se can delay the degradation of sulforaphane-induced TrxR1 mRNA. Modulation of TrxR1 mRNA by sulforaphane was glutathione and protein kinase C-dependent, as L-buthionine-S,R-sulfoximine (a specific inhibitor of glutathione synthesis), and the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine, significantly reduced the induction. The combination of sulforaphane and Se also efficiently protected HepG2 cells from paraquat-induced cell death, whereas sulforaphane-only and Se-only treatments showed very little if any protective effect. These results demonstrate that synergy can result from a combination of induction at the levels of transcription and translation.

Selenium in the maintenance and therapy of HIV-infected patients. Chemical and Biological Intaractions. 1994 Jun;91(2-3):199-205. Schrauzer GN, Sacher J. University of California, San Diego, Department of Chemistry and Biochemistry, La Jolla 92093.

Due to its antiviral effects and its importance for all immunological functions, the administration of selenium is suggested as a supportive measure in early as well as in advanced stages of HIV-induced disease. Initial observations on the effects of selenium supplementation in HIV-infected patients indicate that selenium causes symptomatic improvements and possibly slows the course of the disease. As selenium inhibits reverse transcriptase activity in RNA-virus-infected animals, supplemental selenium could also prevent the replication of HIV and retard the development of AIDS in newly HIV-infected subjects. An adequate supply of selenium and of antioxidant vitamins is also proposed as a measure to reduce the probability of the placental transmission of HIV in pregnancy.

 

Suppression of human immunodeficiency virus type 1 viral load with selenium supplementation: a randomized controlled trial. Archives of Internal Medicine. 2007 Jan 22;167(2):148-54. Hurwitz BE, Klaus JR, Lllabre MM, Gonzalez A, Lawrence PJ, Maher KJ, Greenson JM, Baum MK, Shor-Posner G, Skyler JS, Schneiderman N.

 

Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking. METHODS: High selenium yeast supplementation (200 mug/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean +/- SD. RESULTS: Of the 450 HIV-1-seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0% +/- 24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change (Delta) in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (Delta = 32.2 +/- 24.5 vs 0.5 +/- 8.8 microg/L; P<.001), and greater levels predicted decreased HIV-1 viral load (P<.02), which predicted increased CD4 count (P<.04). Findings remained significant after covarying age, sex, ethnicity, income, education, current and past cocaine and other drug use, HIV symptom classification, antiretroviral medication regimen and adherence, time since HIV diagnosis, and hepatitis C virus coinfection. Follow-up analyses evaluating treatment effectiveness indicated that the nonresponding selenium-treated subjects whose serum selenium change was less than or equal to 26.1 microg/L displayed poor treatment adherence (56.8% +/- 29.8%), HIV-1 viral load elevation (Delta = +0.29 +/- 1.1 log(10) units), and decreased CD4 count (Delta = -25.8 +/- 147.4 cells/microL). In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 microg/L evidenced excellent treatment adherence (86.2% +/- 13.0%), no change in HIV-1 viral load (Delta = -0.04 +/- 0.7 log(10) units), and an increase in CD4 count (Delta = +27.9 +/- 150.2 cells/microL). CONCLUSIONS: Daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease.

 

Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. Yoshizawa K, Willett WC, Morris SJ, et al.  J Natl Cancer Inst. 1998;90(16):1219-1224. 

 

In a recent randomized intervention trial, the risk of prostate cancer for men receiving a daily supplement of 200 microg selenium was one third of that for men receiving placebo. By use of a nested case-control design within a prospective study, i.e., the Health Professionals Follow-Up Study, we investigated the association between risk of prostate cancer and prediagnostic level of selenium in toenails, a measure of long-term selenium intake. METHODS: In 1986, 51,529 male health professionals aged 40-75 years responded to a mailed questionnaire to form the prospective study. In 1987, 33,737 cohort members provided toenail clippings. In 1988, 1990, 1992, and 1994, follow-up questionnaires were mailed. From 1989 through 1994, 181 new cases of advanced prostate cancer were reported. Case and control subjects were matched by age, smoking status, and month of toenail return. Selenium levels were determined by neutron activation. All P values are two-sided. RESULTS: The selenium level in toenails varied substantially among men, with quintile medians ranging from 0.66 to 1.14 microg/g for control subjects. When matched case-control data were analyzed, higher selenium levels were associated with a reduced risk of advanced prostate cancer (odds ratio [OR] for comparison of highest to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25-0.96; P for trend = .11). After additionally controlling for family history of prostate cancer, body mass index, calcium intake, lycopene intake, saturated fat intake, vasectomy, and geographical region, the OR was 0.35 (95% CI = 0.16-0.78; P for trend = .03). CONCLUSIONS: Our results support earlier findings that higher selenium intakes may reduce the risk of prostate cancer.

 

Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance. Ophthalmic & Physiological Optics. Kvansakul J, Rodriguez-Carmona M., Edgar DF, Barker FM, Kapcke W., Schalch W., Barbur JL. Applied Vision Research Centre, Department of Optometry and Visual Science, City University, London, UK.

 

Macular pigment (MP) is found in diurnal primate species when vision spans a range of ambient illumination and is mediated by cone and rod photoreceptors. The exact role of MP remains to be determined. In this study we investigate two new hypotheses for possible MP functions. OBJECTIVE: As MP absorption coincides partly with that of rhodopsin, MP may reduce rod signal effectiveness in the mesopic range, thus extend the usefulness of cone-mediated vision into the mesopic range. Forward light scatter in the eye can reduce retinal image contrast. If blue light contributes significantly to intraocular scatter, selective blue light absorption by MP could reduce the effects of scatter. DESIGN: We investigated 34 subjects from a carotenoid supplementation trial. The measurements included high mesopic contrast acuity thresholds (CATs), macular pigment optical density (MPOD), wavefront aberrations, and scattered light. The measurements were made after 6 months of daily supplementation with zeaxanthin (Z), lutein (L), a combination of the two (C), or placebo (P), and again after a further 6 months of doubled supplementation. RESULTS: The data reveal a trend toward lower CATs in all groups supplemented, with a statistically significant improvement in the lutein group (p = 0.001), although there was no correlation with MPOD. Light scattering in the eye and the root-mean-square wavefront aberrations show decreasing trends as a result of supplementation, but no correlation with MPOD. CONCLUSIONS: The results suggest that supplementation with L or Z increases MPOD at the fovea and at 2.5 degrees , and that supplementation can improve CATs at high mesopic levels and hence visual performance at low illumination.

 

Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. Journal of the American Medical Association.1994 Nov 9;272(18):1413-20. Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD, Gragoudas ES, Haller J., Miller DT. Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Boston 02114.

 

OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. DESIGN--The multicenter Eye Disease Case-Control Study. SETTING--Five ophthalmology centers in the United States. PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001).

 

Lutein and zeaxanthin in eye and skin health. Clin Dermatol. 2009 Mar-Apr;27(2):195-201. Roberts RL, Green J, Lewis B. Kemin Health, LC, 600 E Court Avenue, Suite A, Des Moines, IA 50309-2058, USA.

Less than 20 of the hundreds of carotenoids found in nature are found in the human body. These carotenoids are present in the body from the foods or dietary supplements that humans consume. The body does not synthesize them. Among the carotenoids present in the body, only lutein and its coexistent isomer, zeaxanthin, are found in that portion of the eye where light is focused by the lens, namely, the macula lutea. Numerous studies have shown that lutein and zeaxanthin may provide significant protection against the potential damage caused by light striking this portion of the retina. In the eye, lutein and zeaxanthin have been shown to filter high-energy wavelengths of visible light and act as antioxidants to protect against the formation of reactive oxygen species and subsequent free radicals. Human studies have demonstrated that lutein and zeaxanthin are present in the skin, and animal studies have provided evidence of significant efficacy against light-induced skin damage, especially the ultraviolet wavelengths. Little was known about the protective effects of these carotenoids in human skin until recently. This article reviews the scientific literature pertaining to the effects that lutein and zeaxanthin exhibit in the human eye and skin.

 

Vitamin E and immune response in the aged: molecular mechanisms and clinical implications. Immonology Reviews. 2005 June;205:269-84. Meydani SN, Han SN, Wu D. Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA

 

Nutritional status has been indicated as a contributing factor to age-related dysregulation of the immune response. Vitamin E, a lipid-soluble antioxidant vitamin, is important for normal function of the immune cells. The elderly are at a greater risk for vitamin E intake that is lower than recommended levels. Vitamin E supplementation above currently recommended levels has been shown to improve immune functions in the aged including delayed-type hypersensitivity skin response and antibody production in response to vaccination, which was shown to be mediated through increased production of interleukin (IL)-2, leading to enhanced proliferation of T cells, and through reduced production of prostaglandin E(2), a T-cell suppressive factor, as a result of a decreased peroxynitrite formation. Vitamin E increased both cell-dividing and IL-producing capacities of naive T cells, but not memory T cells. The vitamin E-induced enhancement of immune functions in the aged was associated with significant improvement in resistance to influenza infection in aged mice and a reduced risk of acquiring upper respiratory infections in nursing home residents.

 

Vitamin E supplementation reverses the age-associated decrease in effective immune synapse formation in CD4+ T cells. Annals of the New York Academy of Sciences. 2004 December; 1031:412-4. Ahmed T, Marko M, Wu D, Chung H, Huber B, Meydani SN. Nutritional Immunology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.

 

Aging is associated with impairment of T cell function. We demonstrate here that age-associated declines in T cell signaling are due to the inability to form effective immune synapses at the site of the T cell receptor and antigen interaction. On the basis of our previous research with vitamin E (VE), we hypothesized that VE supplementation of old CD4(+) T cells enhances effective immune synapse formation through increased translocation of signaling proteins. Using confocal microscopy, we found that when exposed to antigen-presenting cells, CD4(+) T cells from old mice have a lower percentage of effective immune synapses compared to those from young mice. Furthermore, we show that in vitro and in vivo VE supplementation increases the percentage of old CD4(+) T cells capable of forming a functional immune synapse.

 

Carotenoid action on the immune response. Journal of Nutrition.2004 Jan;134(1):257S-261S. Chew BP, Park JS. Washington State University, Pullman, WA 99164-6351, USA.

 

Early studies demonstrating the ability of dietary carotenes to prevent infections have left open the possibility that the action of these carotenoids may be through their prior conversion to vitamin A. Subsequent studies to demonstrate the specific action of dietary carotenoids have used carotenoids without provitamin A activity such as lutein, canthaxanthin, lycopene and astaxanthin. In fact, these nonprovitamin A carotenoids were as active, and at times more active, than beta-carotene in enhancing cell-mediated and humoral immune response in animals and humans. Another approach to study the possible specific role of dietary carotenoids has used animals that are inefficient converters of carotenoids to vitamin A, for example the domestic cat. Results have similarly shown immuno-enhancement by nonprovitamin A carotenoids, based either on the relative activity or on the type of immune response affected compared to beta-carotene. Certain carotenoids, acting as antioxidants, can potentially reduce the toxic effects of reactive oxygen species (ROS). These ROS, and therefore carotenoids, have been implicated in the etiology of diseases such as cancer, cardiovascular and neurodegenerative diseases and aging. Recent studies on the role of carotenoids in gene regulation, apoptosis and angiogenesis have advanced our knowledge on the possible mechanism by which carotenoids regulate immune function and cancer.

Relationship between plasma carotenoids and prostate cancer. Nutritional Cancer. 2005;53(2):127-34. Hursting SD. Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Carotenoids, particularly lycopene, are thought to decrease prostate cancer risk, but the relationship between plasma carotenoid concentrations and risk in various populations has not been well characterized. Comparing 118 non-Hispanic Caucasian men mainly from southeast Texas with nonmetastatic prostate cancer with 52 healthy men from the same area, we conducted a case-control analysis evaluating associations between risk and plasma levels of total carotenoids, beta-cryptoxanthin, alpha- and trans-beta-carotene, lutein and zeaxanthin, total lycopenes, trans-lycopene, total cis-lycopenes, and cis-lycopene isoforms 1, 2, 3, and 5. Risk for men with high plasma levels of alpha-carotene, trans-beta-carotene, beta-cryptoxanthin, and lutein and zeaxanthin was less than half that for those with lower levels. In contrast, we observed no significant associations for total lycopenes, all-trans-lycopene, and cis-lycopene isomer peaks 2, 3, and 5, although high levels of cis-lycopene isomer peak 1 were inversely associated with risk. Analysis of men with aggressive disease (Gleason scores of > or =7, n = 88) vs. less aggressive cases (Gleason scores of <7, n = 30) failed to reveal significant associations between carotenoid levels and the risk of diagnosis with aggressive disease. These findings suggest that, in these men, higher circulating levels of alpha-cryptoxanthin, alpha-carotene, trans-beta-carotene, and lutein and zeaxanthin may contribute to lower prostate cancer risk but not to disease progression.

Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. 2002 May 28;99(11):7610-5. Proclamation of the National Academy of Sciences. Fahey JW, Haristoy X, Dolan PM, Kensler TW, Sholtus I, Stephenson KK, Talalay P, Lozniewski A. Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-2185, USA.

 

Gastric infection with Helicobacter pylori is a cosmopolitan problem, and is especially common in developing regions where there is also a high prevalence of gastric cancer. These infections are known to cause gastritis and peptic ulcers, and dramatically enhance the risk of gastric cancer. Eradication of this organism is an important medical goal that is complicated by the development of resistance to conventional antimicrobial agents and by the persistence of a low level reservoir of H. pylori within gastric epithelial cells. Moreover, economic and practical problems preclude widespread and intensive use of antibiotics in most developing regions. We have found that sulforaphane [(-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane], an isothiocyanate abundant as its glucosinolate precursor in certain varieties of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3 reference strains and 45 clinical isolates of H. pylori [minimal inhibitory concentration (MIC) for 90% of the strains is <or=4 microg/ml], irrespective of their resistance to conventional antibiotics. Further, brief exposure to sulforaphane was bactericidal, and eliminated intracellular H. pylori from a human epithelial cell line (HEp-2). In complementary experiments, sulforaphane blocked benzo[a]pyrene-evoked forestomach tumors in ICR mice. This protection resulted from induction of phase 2 detoxication and antioxidant enzymes, and was abrogated in mice lacking the nrf2 gene, which regulates phase 2 enzymes. Thus, the dual actions of sulforaphane in inhibiting Helicobacter infections and blocking gastric tumor formation offer hope that these mechanisms might function synergistically to provide diet-based protection against gastric cancer in humans.

 

Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proclamations of the National Academy of Sciences. 1997 Sep 16;94(19):10367-72. Fahey JW, Zhang Y, Talalay P. Brassica Chemoprotection Laboratory and Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

 

Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2 enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10-100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at -50 degrees C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal enzyme inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats.

 

Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol Carcinog. 2010 Dec 28. Saw CL, Huang MT, Liu Y, Khor TO, Conney AH, Kong AN. Center for Cancer Prevention Research, Rutgers, The State University of New Jersey, Piscataway, New Jersey.

Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and others have shown that broccoli sprout extracts containing high SFN protected against UV-induced skin carcinogenesis in SKH-1 hairless mice. A recent study showed that there was no difference between Nrf2 knockout (Nrf2 KO) and Nrf2 wild-type (WT) BALB/C mice after exposing to high dose of UVB. Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against UV. In this context, the role of Nrf2 in UVB-induced skin inflammation in Nrf2 WT and Nrf2 KO C57BL/6 mice was studied. A single dose of UVB (300 mJ/cm(2)) resulted in skin inflammation in both WT and Nrf2 KO (-/-) mice (KO mice) at 8 h and 8 d following UVB irradiation. In the WT mice inflammation returned to the basal level to a greater extent when compared to the KO mice. SFN treatment of Nrf2 WT but not Nrf2 KO mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin.

 

Dose-dependent modulation of the T cell proteome by ascorbic acid. British Journal of Nutrition. 2007 Jan;97(1):19-26. Grant MM, Mistry N, Lunec J, Griffiths HR. Aston University, Birmingham, UK.

 

To investigate the hypothesis that the micronutrient ascorbic acid can modulate the functional genome, T cells (CCRF-HSB2) were treated with ascorbic acid (up to 150 microM) for up to 24 h. Protein expression changes were assessed by two-dimensional electrophoresis. Forty-one protein spots which showed greater than two-fold expression changes were subject to identification by matrix-assisted laser desorption ionisation time of flight MS. The confirmed protein identifications were clustered into five groups; proteins were associated with signalling, carbohydrate metabolism, apoptosis, transcription and immune function. The increased expression of phosphatidylinositol transfer protein (promotes intracellular signalling) within 5 min of ascorbic acid treatment was confirmed by Western blotting. Together, these observations suggest that ascorbic acid modulates the T cell proteome in a time- and dose-dependent manner and identify molecular targets for study following antioxidant supplementation in vivo.

Smoking-induced monocyte dysfunction is reversed by vitamin C supplementation in vivo. Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):120-6. Epub 2006 Oct 19 Stadler N, Eggermann J, Voo S, Kranz A, Waltenberger J. Department of Cardiology, University of Maastricht, Cardiovascular Research Institute of Maastricht, P. Debyelaan 25, NL-6202 AZ Maastricht, The Netherlands.

OBJECTIVE: The role of antioxidants in preventing vascular disease remains controversial. Vascular endothelial growth factor (VEGF-A) is important for endothelial and monocyte function. This study investigated the negative effects of smoking on monocyte migratory responsiveness to VEGF-A and the usefulness of vitamin C to prevent smoking-induced monocyte dysfunction. METHODS AND RESULTS: The chemotactic response of isolated monocytes from a cohort of 17 non-smokers and 10 smokers toward VEGF-A was assessed. VEGF-A significantly stimulated the migration of monocytes in non-smokers; the monocytes from smokers failed to respond to VEGF-A. Repeated analysis after 2 weeks of vitamin C intake (2 g/d) showed a fully restored VEGF-A-induced monocyte migration in smokers. VEGF-A serum levels were not altered by vitamin C. VEGF-A-inducible kinase activity was intact in monocytes from smokers as assessed by in vitro kinase assay. Monocyte dysfunction can be mimicked in vitro by challenging monocytes with a range of reactive oxygen species (ROS). CONCLUSIONS: Stimulation of monocyte migration by VEGF-A was severely attenuated in smokers, and the deficit observed was surmounted by vitamin C supplementation. The negative effects of smoking on monocyte function may translate into adverse impacts on VEGF-A-dependent repair processes such as arteriogenesis. These results propose a causative role of oxidative stress in smoking-induced monocyte dysfunction.

 

Vitamin C deficiency increases the lung pathology of influenza virus-infected gulo-/- mice. Journal Nutrition. 2006 Oct;136(10):2611-6. Li W, Maeda N, Beck MA.

 

This study was designed to determine the effects of vitamin C deficiency on the immune response to infection with influenza virus. l-Gulono-gamma-lactone oxidase gene-inactivated mice (gulo-/- mice) require vitamin C supplementation for survival. Five-wk-old male and female gulo-/- mice were provided water or water containing 1.67 mmol/L vitamin C for 3 wk before inoculation with influenza A/Bangkok/1/79. There were no differences in lung influenza virus titers between vitamin C-adequate and -deficient mice; however, lung pathology in the vitamin C-deficient mice was greater at 1 and 3 d after infection but less at d 7 compared with vitamin C-adequate mice. Male vitamin C-deficient mice had higher expression of mRNA for regulated upon activation normal T expressed and secreted (RANTES), IL-1beta, and TNF-alpha in the lungs at d 1 after infection compared with male controls. However, at d 3 after infection, male vitamin C-deficient mice had less expression of mRNA for RANTES, monocyte chemotactic protein-1 (MCP-1), and IL-12 compared with male controls. None of these differences were observed in female mice. Vitamin C-deficient male mice also had greater nuclear factor-kappaB activation as early as 1 d after infection compared with male controls. These data suggest that vitamin C is required for an adequate immune response in limiting lung pathology after influenza virus infection.

 

Effect of Vitamin C on common cold: randomized controlled trial. European Journal of Clinical Nutrition. 2006 Jan;60(1):9-17. Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S. Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Chuo-ku, Tokyo, Japan.

 

OBJECTIVE: To investigate the relationship between the common cold and vitamin C supplementation. DESIGN: A double-blind, 5-year randomized controlled trial. SETTING: A village in Akita prefecture, one of the regions in Japan with the highest mortality from gastric cancer. SUBJECTS: Participants in annual screening programs for circulatory diseases conducted under the National Health and Welfare Services Law for the Aged, and diagnosed as having atrophic gastritis. Of the 439 eligible subjects, 144 and 161 were assigned to receive 50 or 500 mg of vitamin C, respectively, after protocol amendment. During the supplementation phase, 61 dropped out, and 244 completed the trial. Intervention: Daily vitamin C supplementation of 50 mg (low-dose group) or 500 mg (high-dose group). RESULTS: Total number of common colds (per 1000 person-months) was 21.3 and 17.1 for the low- and high-dose groups, respectively. After adjustment for several factors, the relative risks (95% confidence interval (CI)) of suffering from a common cold three or more times during the survey period was 0.34 (0.12-0.97) for the high-dose group. No apparent reduction was seen for the severity and duration of the common cold. CONCLUSION: A randomized, controlled 5-year trial suggests that vitamin C supplementation significantly reduces the frequency of the common cold but had no apparent effect on the duration or severity of the common cold.

 

Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1985;1:307-9. Garland C, Shekelle R B, Barrett-Connor E, Criqui MH, Rossof A H and Paul O. 

 

Mortality rates from colon cancer in the USA are highest in populations exposed to the least amounts of natural sunlight; differences in endogenous vitamin D production and calcium absorption could be responsible. To investigate this possibility, the association of dietary vitamin D and calcium with 19-year risk of colorectal cancer was examined in 1954 men who had completed detailed, 28-day dietary histories in the period 1957-59. Risk of colorectal cancer was inversely correlated with dietary vitamin D and calcium. In the quartiles of a combined index of dietary vitamin D and calcium, from lowest to highest, observed risks of colorectal cancer were 38.9, 24.5, 22.5, and 14.3/1000 population. This association remained significant after adjustment for age, daily cigarette consumption, body mass index, ethanol consumption, and percentage of calories obtained from fat.

 

Vitamin D: its role in cancer prevention and treatment. Prog Biophys Mol Bio. 2006 Sep;92(1):49-59. Epub 2006 Mar 10. Holick MF,  Boston University Medical Center, 715 Albany Street, M-1013, Boston, MA 02118, USA.

 

Vitamin D, the sunshine vitamin, has been recognized for almost 100 years as being essential for bone health. Vitamin D provides an adequate amount of calcium and phosphorus for the normal development and mineralization of a healthy skeleton. Vitamin D made in the skin or ingested in the diet, however, is biologically inactive and requires obligate hydroxylations first in the liver to 25-hydroxyvitamin D, and then in the kidney to 1,25-dihydroxyvitamin D. 25-Hydroxyvitamin D is the major circulating form of vitamin D that is the best indicator of vitamin D status. 1,25-dihydroxyvitamin D is the biologically active form of vitamin D. This lipid-soluble hormone interacts with its specific nuclear receptor in the intestine and bone to regulate calcium metabolism. It is now recognized that the vitamin D receptor is also present in most tissues and cells in the body. 1,25-dihydroxyvitamin D, by interacting with its receptor in non-calcemic tissues, is able to elicit a wide variety of biologic responses. 1,25-dihydroxyvitamin D regulates cellular growth and influences the modulation of the immune system. There is compelling epidemiologic observations that suggest that living at higher latitudes is associated with increased risk of many common deadly cancers. Both prospective and retrospective studies help support the concept that it is vitamin D deficiency that is the driving force for increased risk of common cancers in people living at higher latitudes. Most tissues and cells not only have a vitamin D receptor, but also have the ability to make 1,25-dihydroxyvitamin D. It has been suggested that increasing vitamin D intake or sun exposure increases circulating concentrations of 25-hydroxyvitamin D, which in turn, is metabolized to 1,25-dihydroxyvitamin D(3) in prostate, colon, breast, etc. The local cellular production of 1,25-dihydroxyvitamin D acts in an autocrine fashion to regulate cell growth and decrease the risk of the cells becoming malignant. Therefore, measurement of 25-hydroxyvitamin D is important not only to monitor vitamin D status for bone health, but also for cancer prevention.

 

Vitamin D in defense of the human immune response. Ann NY Acad Sci. 2007 Nov;1117:94-105. Epub 2007 Jul. Adams JS, Liu PT, Chun R, Modlin RL, Hewison M.  Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room B-131, Los Angeles, CA 90048, USA

 

Defensin is a generic name reserved for an endogenously synthesized antimicrobial agent. The purpose of this review is to describe a series of discoveries that led to the proposal that 25-hydroxylated metabolites of vitamin D are key, intracellular regulators of the synthesis and action of naturally occurring defensin molecules against bacterial antigens. The discussion will (1) highlight the basic elements of human immune response that is responsive to vitamin D, (2) recount work relevant to the extrarenal expression of the vitamin D-1-hydroxlase (CYP27b1) in the macrophage as an initiator of the innate immune response, and (3) describe recent work on the relevance of the vitamin D intracrine-autocrine-paracrine system in a model of a common and devastating human disease, tuberculosis.

 

Vitamin D compounds: activity against microbes and cancer. Anticancer research 2006 Jul-Aug;26(4A):2531-42. Gombart AF, Luong QT, Koeffler HP. Division of Hematology / Oncology, Cedars-Sinai Medical Center, Burns and Allen Research Institute, David Geffen School of Medicine at UCLA, 8700 Beverly Blvd., Los Angeles, CA 90048, USA

 

Vitamin D3 is produced in skin and is sequentially metabolized by the liver and kidney to the biologically active form 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. It is a seco-steroid hormone that regulates calcium homeostasis within the body. The genomic actions of 1,25(OH)2D3 are modulated through the vitamin D receptor (VDR). VDR belongs to a superfamily of nuclear receptors that transduce hormonal signals from the immediate environment and transactivate genes in response to these signals. Target genes contain hormone response elements (VDREs) in their promoters to which heterodimers of VDR and retinoid X receptors (RXR) can bind and transactivate expression of the target genes. The VDR is expressed in at least 30 different target tissues including bone, kidney, blood, breast, prostate, gut, activated B- and T- lymphocytes, monocytes and keratinocytes). Most dividing cell types, normal and malignant, can express VDR and respond to 1,25(OH)2D3. Although 1,25(OH)2D3 and its analogs (termed deltanoids) are important regulators of calcium and bone metabolism, their non-calciotropic activities that include inhibition of cell proliferation, promotion of cell differentiation and modulation of immune cell function have spurred interest in therapeutic applications in a wide variety of diseases. In this report, the anticancer and newly discovered antimicrobial actions of 1,25(OH)2D3 and deltanoids are reviewed.

 

Vitamin D and Calcium supplementation reduces cancer risk: results of a randomized trial. American Journal of Clinical Nutrition. 2007 Jun:85(6): 1586-91. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA.

 

BACKGROUND: Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. OBJECTIVE: The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. DESIGN: This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. RESULTS: When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. CONCLUSIONS: Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00352170.

 

A Single Dose of Vitamin D Enhances Immunity to Mycobacteria. Am. J. Respir. Crit. Care Med., Volume 176, Number 2, July 2007, 208-213. Martineau AR

 

Rationale: Vitamin D was used to treat tuberculosis in the pre-antibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed. Objectives: To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status. Methods: A double-blind randomized controlled trial was conducted in 192 healthy adult tuberculosis contacts in London, UK. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. Measurements and Main Results: The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay) that measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the read-out is expressed as a luminescence ratio (luminescence post-infection/baseline luminescence). Interferon-gamma responses to the M. tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared to placebo (mean luminescence ratio at follow-up 0.57 vs. 0.71 respectively, 95% CI for difference 0.01 to 0.25; P=0.03) but did not affect antigen-stimulated Interferon-gamma secretion. Conclusions: A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated Interferon-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent tuberculosis infection.

 

Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006 Mar 24;311(5768):1770-3. Epub 2006 Feb. Liu PT, Stenger S, Li H. Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, CA 90095, USA

 

In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

 

Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005 Jul;19(9):1067-77. Gombart AF, Borregaard N, Koeffler HP. Department of Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA

 

The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.

 

Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986 Jan;57(1):159-63. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J, Stanford J.

 

Previous studies have shown that recombinant interferon gamma (IFN-gamma), crude T cell supernatants, or appropriate T-cell lines can cause total inhibition of the growth of M. tuberculosis inside murine peritoneal macrophages. In similar experiments with human monocytes much smaller effects are seen. This could be due to the relative immaturity of these cells. Because dihydroxy vitamin D3 (1,25-(OH)2 D3) can cause phenotypic differentiation of immature leukemic lines into macrophage-like cells, we have explored the possibility that exposure to cholecalciferol metabolites in vitro might increase the ability of monocytes to control proliferation of M. tuberculosis, or cause monocytes to mature into cells able to respond appropriately to IFN-gamma. Incubation of monocytes with three cholecalciferol metabolites induced anti-tuberculosis activity to an extent that correlated with their binding affinities to the intracellular receptor protein for the derivatives. 1,25-(OH)2 D3 also primed monocytes for phorbol myristate acetate-triggered reduction of nitroblue tetrazolium. The effects were additive rather than synergistic with those of IFN-gamma. Monocytes incubated with IFN-gamma developed 25-OH D3 1-hydroxylase activity, detected by conversion of tritiated 25-(OH) D3 to a more polar metabolite which coeluted with 1,25-(OH)2 D3 on straight and reverse-phase HPLC. The latter is a more active form in vivo. These findings help to explain claims for the efficacy of vitamin D in the treatment of some forms of tuberculosis, and also the occasional finding of raised serum calcium, and disturbed vitamin D metabolism in these patients.

 

Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Trang HM et al. 1998. Am J Clin Nutr 68:854-858. Department of Laboratory Medicine, University of Toronto, and The Wellesley Hospital, Canada.

 

In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact. To test the presumption of equivalence in humans, we compared the ability of equal molar quantities of vitamin D2 or D3 to increase serum 25-hydroxyvitamin D [25(OH)D], the measure of vitamin D nutrition. Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d. 25(OH)D was assayed with a method that detects both the vitamin D2 and D3 forms. With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41.3+/-17.7 nmol/L before to 64.6+/-17.2 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 43.7+/-17.7 nmol/L before to 57.4+/-13.0 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23.3+/-15.7 nmol/L, or 1.7 times the increase obtained with vitamin D2 (13.7+/-11.4 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration. The lowest 2 tertiles for basal 25(OH)D showed larger increases in 25(OH)D: 30.6 and 25.5 nmol/L, respectively, for the first and second tertiles. In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.

 

Recombinant human interferon gamma in the treatment of rheumatoid arthritis: double blind placebo controlled study. Ann. Machold KP, Neumann K, Smolen. Rheum Dis.1992 Sep;51(9):1039-43.

 

Interferon gamma (IFN gamma) has been advocated in open studies as a beneficial remission inducing drug for the treatment of rheumatoid arthritis (RA). The work reported here was designed to assess the therapeutic potential of IFN gamma in the treatment of RA in a double blind placebo controlled study. It was found that patients treated with IFN gamma improved significantly with respect to morning stiffness, grip strength, swelling of an index joint, and erythrocyte sedimentation rate. Furthermore significantly more responders (according to predetermined response criteria) were found in the group treated with IFN gamma. Only minor adverse effects and no significant toxicity with respect to clinical or laboratory parameters were observed.

 

Part III: Link to Comprehensive List of All Scientific Papers Published on Diindolylmethane Dating back to 1975

To review all published scientific literature on Diindolylmethane at the US National Library of Medicine dating back to 1975 please click here.

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