Life Extension Magazine®

Issue: Jan 2010

Phytonutrients

Chemistry and health of olive oil phenolics.

The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular disease, and certain types of cancer. The apparent health benefits have been partially attributed to the dietary consumption of virgin olive oil by Mediterranean populations. Most recent interest has focused on the biologically active phenolic compounds naturally present in virgin olive oils. Studies (human, animal, in vivo and in vitro) have shown that olive oil phenolics have positive effects on certain physiological parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet and cellular function, and antimicrobial activity. Presumably, regular dietary consumption of virgin olive oil containing phenolic compounds manifests in health benefits associated with a Mediterranean diet. This paper summarizes current knowledge on the physiological effects of olive oil phenolics. Moreover, a number of factors have the ability to affect phenolic concentrations in virgin olive oil, so it is of great importance to understand these factors in order to preserve the essential health promoting benefits of olive oil phenolic compounds.

Crit Rev Food Sci Nutr. 2009 Mar;49(3):218-36

Daily consumption of a high-phenol extra-virgin olive oil reduces oxidative DNA damage in postmenopausal women.

Extra-virgin olive oils (EVOO), high in phenolic compounds with antioxidant properties, could be partly responsible for the lower mortality and incidence of cancer and CVD in the Mediterranean region. The present study aims to measure oxidative DNA damage in healthy human subjects consuming olive oils with different concentrations of natural phenols. A randomised cross-over trial of high-phenol EVOO (high-EVOO; 592 mg total phenols/kg) v. low-phenol EVOO (low-EVOO; 147 mg/kg) was conducted in ten postmenopausal women in Florence. Subjects were asked to substitute all types of fat and oils habitually consumed with the study oil (50 g/d) for 8 weeks in each period. Oxidative DNA damage was measured by the comet assay in peripheral blood lymphocytes, collected at each visit during the study period. Urine samples over 24 h were collected to measure the excretion of the olive oil phenols. The average of the four measurements of oxidative DNA damage during treatment with high-EVOO was 30 % lower than the average during the low-EVOO treatment (P=0.02). Urinary excretion of hydroxytyrosol and its metabolite homovanillyl alcohol were significantly increased in subjects consuming high-EVOO. Despite the small sample size, the present study showed a reduction of DNA damage by consumption of an EVOO rich in phenols, particularly hydroxytyrosol.

Br J Nutr. 2006 Apr;95(4):742-51

Mediterranean diet and metabolic diseases.

PURPOSE OF REVIEW: The objective of this article is to present evidence illustrating the relationship between Mediterranean diets and metabolic diseases, including obesity, type 2 diabetes, and the metabolic syndrome, and to briefly discuss potential mechanisms by which these diets can help in disease prevention and treatment. RECENT FINDINGS: Although the Mediterranean diet has long been celebrated for its impact on cardiovascular health, mounting evidence indicates a favorable effect on obesity and type 2 diabetes, as well. While health promotion strategies aimed at preventing adult obesity are emphasizing components of Mediterranean dietary patterns, a role for Mediterranean diets in attenuating the inflammatory burden associated with type 2 diabetes is also emerging. Moreover, a lower prevalence of the metabolic syndrome is associated with dietary patterns rich in fruits, vegetables, whole grains, dairy products, and unsaturated fats. Both epidemiological and interventional studies have revealed a protective effect of the Mediterranean diet against mild chronic inflammation and its metabolic complications. SUMMARY: Mounting evidence suggests that Mediterranean diets could serve as an anti-inflammatory dietary pattern, which could help fighting diseases that are related to chronic inflammation, including visceral obesity, type 2 diabetes and the metabolic syndrome.

Curr Opin Lipidol. 2008 Feb;19(1):63-8

Effect of resveratrol, tyrosol and beta-sitosterol on oxidised low-density lipoprotein-stimulated oxidative stress, arachidonic acid release and prostaglandin E2 synthesis by RAW 264.7 macrophages.

Oxidation of LDL is hypothesised as an early and critical event in atherogenesis. Oxidised LDL (oxLDL) favour the transformation of macrophages into foam cells, an important cell involved in atherosclerosis. Furthermore, oxLDL cause multiple changes in macrophage functions. Thus, oxLDL induces certain genes, suppresses others and alters cell lipid metabolism. Consumption of a Mediterranean diet is associated with a low incidence of atherosclerotic disease, but data about the specific dietary constituents involved and mechanisms conferring cardioprotection are still sparse. The aim of the present study was to determine the effect of representative minor components of wine and olive oil on reactive oxygen species and eicosanoid synthesis induced by oxLDL-stimulated macrophages. We observed that exposure to non-toxic oxLDL concentrations leads to the production of H2O2 by RAW 264.7 macrophages and this effect was reverted by apocynin, a NADPH oxidase inhibitor. Moreover, oxLDL induced arachidonic acid (AA) release, cyclo-oxygenase-2 overexpression and subsequent PGE2 release. We observed that resveratrol and tyrosol revert H2O2 production induced by oxLDL as well as AA release and PGE2 synthesis and that these effects were not as a consequence of these compounds interfering with the oxLDL binding to their receptors. Interestingly, beta-sitosterol presence enhances these polyphenol actions. Thus, we found a synergistic action of polyphenols of olive oil and wine and beta-sitosterol of olive oil led to the modulation of the effects of oxLDL on oxidative stress and PGE2 synthesis.

J Nutr. 2008 Jun;99(6):1199-207

Major phenolic compounds in olive oil modulate bone loss in an ovariectomy/inflammation experimental model.

This study was conducted to determine whether the daily consumption for 84 days of tyrosol and hydroxytyrosol, the main olive oil phenolic compounds, and olive oil mill wastewater (OMWW), a byproduct of olive oil production, rich in micronutrients, may improve bone loss in ovariectomized rats (an experimental model of postmenopausal osteoporosis) and in ovariectomized rats with granulomatosis inflammation (a model set up for senile osteoporosis). As expected, an induced chronic inflammation provoked further bone loss at total, metaphyseal, and diaphyseal sites in ovariectomized rats. Tyrosol and hydroxytyrosol prevented this osteopenia by increasing bone formation ( p < 0.05), probably because of their antioxidant properties. The two doses of OMWW extracts had the same protective effect on bone ( p < 0.05), whereas OMWW did not reverse established osteopenia. In conclusion, polyphenol consumption seems to be an interesting way to prevent bone loss.

J Agric Food Chem. 2008 Oct 22;56(20):9417-22

Olive oil consumption and non-alcoholic fatty liver disease.

The clinical implications of non-alcoholic fatty liver diseases (NAFLD) derive from their potential to progress to fibrosis and cirrhosis. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride (TG) accumulation. An olive oil-rich diet decreases accumulation of TGs in the liver, improves postprandial TGs, glucose and glucagon-like peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver. The principal mechanisms include: decreased nuclear factor-kappaB activation, decreased low-density lipoprotein oxidation, and improved insulin resistance by reduced production of inflammatory cytokines (tumor necrosis factor, interleukin-6) and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1. The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids, mainly from olive oil. In this review, we describe the dietary sources of the monounsaturated fatty acids, the composition of olive oil, dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis, clinical and experimental studies that assess the relationship between olive oil and NAFLD, and the mechanism by which olive oil ameliorates fatty liver, and we discuss future perspectives.

World J Gastroenterol. 2009 Apr 21;15(15):1809-15

Effects of olive oil polyphenols on erythrocyte oxidative damage.

Many studies have investigated the protective effects of oleuropein and hydroxytyrosol against cell injury, but few have investigated the protective effects of oleuropein aglycones 3,4-dihydroxyphenylethanol-elenolic acid (3,4-DHPEA-EA) and 3,4-dihydroxyphenylethanol-elenolic acid dialdehyde (3,4-DHPEA-EDA). The present work studied and compared the capacity of these four compounds, found at high concentrations in olive oil, to protect red blood cells (RBCs) from oxidative injury. The in vitro oxidative stress of RBCs was induced by the water-soluble radical initiator 2,2’-azo-bis(2-amidinopropane) dihydrochloride. RBC changes were evaluated either by optical microscopy or by the amount of hemolysis. All compounds were shown to significantly protect RBCs from oxidative damage in a dose-dependent manner. The order of activity at 20 microM was: 3,4-DHPEA-EDA > hydroxytyrosol > oleuropein > 3,4-DHPEA-EA. Even at 3 microM, 3,4-DHPEA-EDA and hydroxytyrosol still had an important protective activity. However, deleterious morphological RBC changes were much more evident in the presence of hydroxytyrosol than with 3,4-DHPEA-EDA. For the first time it was demonstrated that 3,4-DHPEA-EDA, one of most important olive oil polyphenols, may play a noteworthy protective role against ROS-induced oxidative injury in human cells since lower doses of this compound were needed to protect RBCs in vitro from oxidative mediated hemolysis.

Mol Nutr Food Res. 2009 May;53(5):609-16

Phytochemicals in olive-leaf extracts and their antiproliferative activity against cancer and endothelial cells.

Olive oil compounds is a dynamic research area because Mediterranean diet has been shown to protect against cardiovascular disease and cancer. Olive leaves, an easily available natural material of low cost, share possibly a similar wealth of health benefiting bioactive phytochemicals. In this work, we investigated the antioxidant potency and antiproliferative activity against cancer and endothelial cells of water and methanol olive leaves extracts and analyzed their content in phytochemicals using LC-MS and LC-UV-SPE-NMR hyphenated techniques. Olive-leaf crude extracts were found to inhibit cell proliferation of human breast adenocarcinoma (MCF-7), human urinary bladder carcinoma (T-24) and bovine brain capillary endothelial (BBCE). The dominant compound of the extracts was oleuropein; phenols and flavonoids were also identified. These phytochemicals demonstrated strong antioxidant potency and inhibited cancer and endothelial cell proliferation at low micromolar concentrations, which is significant considering their high abundance in fruits and vegetables. The antiproliferative activity of crude extracts and phytochemicals against the cell lines used in this study is demonstrated for the first time.

Mol Nutr Food Res. 2009 May;53(5):600-8

Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation.

Hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC) are two well-known phenolic compounds with antioxidant properties that are present in virgin olive oil (VOO). Because VOO has shown neuroprotective effects in rats, the purpose of the present study was to investigate the possible neuroprotective effect of HT and HT-AC in a model of hypoxia-reoxygenation in rat brain slices after in vitro incubation of these compounds or after 7 days of oral treatment with 5 or 10 mg/kg per day. Lactate dehydrogenase (LDH) efflux to the incubation medium was measured as a marker of brain cell death. HT and HT-AC inhibited LDH efflux in a concentration-dependent manner, with 50% inhibitory concentrations of 77.78 and 28.18 microM, respectively. Other well-known antioxidants such as vitamin E and N-acetyl-cysteine had no neuroprotective effect in this experimental model. After 1 week of treatment, HT (5 and 10 mg/kg per day p.o.) reduced LDH efflux by 37.8% and 52.7%, respectively, and HT-AC reduced LDH efflux by 45.4% and 67.8%. These data are additional evidence of the cytoprotective effect of VOO administration, and provide a preliminary basis for further study of these polyphenols as potential neuroprotective compounds.

Neurosci Lett. 2008 Dec 3;446(2-3):143-6

Phenolic compounds in olive oil: antioxidant, health and organoleptic activities according to their chemical structure.

Hydrophilic phenols are the most abundant natural antioxidants of virgin olive oil (VOO), in which, however, tocopherols and carotenes are also present. The prevalent classes of hydrophilic phenols found in VOO are phenolic alcohols and acids, flavonoids, lignans and secoiridoids. Among these substances the last two classes include the most concentrate phenols of VOO. Secoiridoids, like aglycone derivatives of oleuropein, demethyloleuropein and ligstroside, are present in olive fruit as most abundant VOO phenolic antioxidants. Several important biological properties (antioxidant, anti-inflammatory, chemopreventive and anti-cancer) and the characteristic pungent and bitter tasty properties have been attributed to VOO phenols. Relationships between polyphenols activities and their chemical structures are discussed in this paper.

Inflammopharmacology. 2009 Apr;17(2):76-84

Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey.

One hundred forty-six volunteers were randomized to receive a placebo or an allicin-containing garlic supplement, one capsule daily, over a 12-week period between November and February. They used a five-point scale to assess their health and recorded any common cold infections and symptoms in a daily diary. The active-treatment group had significantly fewer colds than the placebo group (24 vs 65, P < .001). The placebo group, in contrast, recorded significantly more days challenged virally (366 vs 111, P < .05) and a significantly longer duration of symptoms (5.01 vs 1.52 days, P < .001). Consequently, volunteers in the active group were less likely to get a cold and recovered faster if infected. Volunteers taking placebo were much more likely to get more than one cold over the treatment period. An allicin-containing supplement can prevent attack by the common cold virus

Adv Ther. 2001 Jul-Aug;18(4):189-93

Allium sativum potentiates suicide gene therapy for murine transitional cell carcinoma.

This study evaluated the synergistic effect of Allium sativum (AS) with suicide gene therapy for transitional cell carcinoma (TCC) of the bladder. Subcutaneous TCCs were established in syngeneic C3H/He mice with 1 x 10(5) MBT-2 cells. AS liquid extract was injected at the site of tumor transplantation on Day 1 for three weeks (Experiment I) and into the established tumors weekly for five weeks (Experiment II) in combination with or without gene therapy using a replication-defective adenoviral vector containing a herpes simplex virus thymidine kinase (HSV-TK) gene under the transcriptional control of Rous sarcoma virus (RSV) promoter (Ad-RSV-TK, 5 x 10(8) plaque-forming units) plus ganciclovir (20 mg/kg/day i.p.). AS demonstrated a statistically significant reduction in incidence of TCC (cumulative dose 25 mg of AS). Combination AS-suicide gene therapy significantly inhibited the tumor growth compared with the controls, which was evidenced by apoptosis on histomorphological and immunohistochemical studies. These results suggest that AS had a definite antitumor effect in inhibiting tumorigenesis and growth of TCC in a murine model. AS treatment combined with suicide gene therapy had significant additive antitumor effects on TCC and may provide a novel and effective treatment modality for TCC of the bladder.

Nutr Cancer. 2000;38(1):98-105

In vitro virucidal effects of Allium sativum (garlic) extract and compounds.

Garlic (Allium sativum) has been shown to have antiviral activity, but the compounds responsible have not been identified. Using direct pre-infection incubation assays, we determined the in vitro virucidal effects of fresh garlic extract, its polar fraction, and the following garlic associated compounds: diallyl thiosulfinate (allicin), allyl methyl thiosulfinate, methyl allyl thiosulfinate, ajoene, alliin, deoxyalliin, diallyl disulfide, and diallyl trisulfide. Activity was determined against selected viruses including, herpes simplex virus type 1, herpes simplex virus type 2, parainfluenza virus type 3, vaccinia virus, vesicular stomatitis virus, and human rhinovirus type 2. The order for virucidal activity generally was: ajoene > allicin > allyl methyl thiosulfinate > methyl allyl thiosulfinate. Ajoene was found in oil-macerates of garlic but not in fresh garlic extracts. No activity was found for the garlic polar fraction, alliin, deoxyalliin, diallyl disulfide, or diallyl trisulfide. Fresh garlic extract, in which thiosulfinates appeared to be the active components, was virucidal to each virus tested. The predominant thiosulfinate in fresh garlic extract was allicin. Lack of reduction in yields of infectious virus indicated undetectable levels of intracellular antiviral activity for either allicin or fresh garlic extract. Furthermore, concentrations that were virucidal were also toxic to HeLa and Vero cells. Virucidal assay results were not influenced by cytotoxicity since the compounds were diluted below toxic levels prior to assaying for infectious virus. These results indicate that virucidal activity and cytotoxicity may have depended upon the viral envelope and cell membrane, respectively. However, activity against non-enveloped virus may have been due to inhibition of viral adsorption or penetration.

Planta Med. 1992 Oct;58(5):417-23

Immunomodulatory effects of aged garlic extract.

Using various kinds of models, we examined the effects of aged garlic extract (AGE) on immune functions. In the immunoglobulin (Ig)E-mediated allergic mouse model, AGE significantly decreased the antigen-specific ear swelling induced by picryl chloride ointment to the ear and intravenous administration of antitrinitrophenyl antibody. In the transplanted carcinoma cell model, AGE significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in natural killer (NK) and killer activities of spleen cells were observed in Sarcoma-180--bearing mice administered AGE. In the psychological stress model, AGE significantly prevented the decrease in spleen weight and restored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress. These studies strongly suggest that AGE could be a promising candidate as an immune modifier, which maintains the homeostasis of immune functions; further studies are warranted to determine when it is most beneficial.

J Nutr. 2001 Mar;131(3s):1075S-9S

The effect of cimetidine on survival of mice infected with herpes simplex virus type 2, murine encephalomyelitis virus and vesicular stomatitis virus infections.

The effect of cimetidine on survival was investigated in mice infected with herpes simplex virus type 2 (HSV-2), murine encephalomyelitis virus (GD-VII), and vesicular stomatitis virus (VSV). BALB/c mice, 5 weeks of age, were injected intraperitoneally (i.p.) with 5.5 x 10(5) plaque-forming units (PFU) of virus/0.5 ml, and cimetidine (1 mg/0.5 ml) was administered simultaneously. The survival rates of 80% and 85% in the cimetidine groups were significantly greater than the 10% and 23% for the control groups. The GD-VII- and VSV-infected control mice were dead at 3 days after virus inoculation. However, more cimetidine-treated mice survived than control mice. When anti-mouse T-cell serum or cyclosporine, which is a helper T-cell suppressor, was administered to BALB/c mice; the effect of cimetidine against the HSV-2 infection could be observed. When injected with anti-asialo GM1, BALB/c mice or beige mice with low natural killer (NK) cell activity were not affected by cimetidine. Lastly, cimetidine was shown to activate the cytotoxic action on NK cells. The above results indicate that the antiviral effects of cimetidine depend on NK cell activation.

Kurume Med J. 1989;36(3):95-9

Dehydroepiandrosterone enhances influenza immunization in aged mice.

The effect of DHEA administration on the age-associated decline in immunity against influenza vaccine was studied. Increased humoral response was observed in 16- and 24-month-old mice immunized by live A/PR/8/34 (H1N1) influenza virus following DHEA treatment (a single injection adjacent to immunization). Furthermore, DHEA-treated mice demonstrated increased resistance to postvaccination intranasal challenge with live influenza virus. Thus, DHEA treatment overcomes the age-related defect in the immunity of old mice against influenza.

Ann N Y Acad Sci. 1995 Dec 29;774:297-9

Dehydroepiandrosterone (DHEA) treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection.

Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity. Recently it was suggested that its age-associated decline is related with immunosenescence. To examine whether DHEA administration could effectively reverse the age-associated decline of immunity against influenza vaccine, aged mice were simultaneously vaccinated and treated with DHEA. Reversal of the age-associated decline and a significant constant increase of humoral response was observed in treated mice. Increased resistance to post-vaccination intranasal challenge with live influenza virus was observed in DHEA-treated aged mice. Thus, DHEA treatment overcame the age-related defect in the immunity of old mice against influenza.

Vaccine. 1995;13(15):1445-8

Dehydroepiandrosterone treatment is not beneficial to the immune response to influenza in elderly subjects.

BACKGROUND: Dehydro-epiandrosterone (DHEA) is a native steroid with an immunomodulating activity that was suggested to counter-regulate some phenomena of immunosenescence. Recently, it was shown to reverse the age-associated decline of immune response against influenza vaccine in aged mice. The present study was designed to evaluate the effect of DHEA on the immunization of elderly volunteers against influenza. METHODS: Seventy-one elderly volunteers age 61-89 yr were enrolled in a prospective randomized, double-blind study to receive either DHEA (50 mg qd p.o. for four consecutive days starting two days before immunization) or placebo. Antibody response to the vaccine was measured before and 28 days after vaccination. RESULTS: DHEA treatment significantly increased serum DHEA-sulfate (DHEA-S). No enhancement in established immunity was observed. A significant decrease in attainment of protective antibody titer (1:40 or higher) against the A/Texas strain in subjects with nonprotective baseline antibody titer was recorded following DHEA treatment compared with placebo (52% vs. 84%, P < 0.05). Baseline DHEA-S serum levels were inversely related to attainment of immunization in DHEA-treated subjects. Influenza-like morbidity during the winter was low in the study group with no difference between the DHEA and placebo groups. CONCLUSIONS: Although highly effective in aged rodents, a short course of DHEA treatment did not improve the age-related declined response to immunization against influenza in human subjects. Higher baseline DHEA-S levels are not predictive of better immunization against influenza in the elderly.

J Clin Endocrinol Metab. 1997 Sep;82(9):2911-4

Endocrine regulation of the immune response to influenza virus infection with a metabolite of DHEA-androstenediol.

In these studies the influence of androstenediol on the course of an experimental virus infection was examined. Pretreatment with 320 mg/kg AED protected male mice from lethal influenza virus infection. In addition, AED enhanced antigen-induced trafficking of mononuclear cells into the draining lymph node and augmented antigen-specific activation of helper-T cells, which are important for control of viral pathogenesis. Furthermore, AED prevented the characteristic increase in serum corticosterone noted during influenza A virus infection. Although steroid hormones, at least corticosteroids, typically suppress host immune and inflammatory responses in vivo, these data suggest that AED may function to augment host immune and inflammatory responses in contrast to corticosteroids.

J Neuroimmunol. 1997 Sep;78(1-2):203-11

Relationship between the response to influenza vaccination and the nutritional status in institutionalized elderly subjects.

BACKGROUND: Influenza is a major health problem among elderly people in industrialized countries. Nursing homes may be a particularly good setting for outbreaks of influenza. Thus, the aim of the present study was to evaluate some aspects of the nutritional status of institutionalized elderly subjects in relation to their response to influenza vaccination. Certain aspects of the cellular immune response were also investigated. METHODS: Twenty-three patients participated in this cross-sectional study. All patients were vaccinated on day 0 with FluviralR, 1994-95 preparation: A/Shangdong/09/93, A/Texas/36/91, B/Panama/45/90. At the same time the prevaccination antibody titer, the nutritional status by the Mini Nutritional Assessment, biochemical parameters, and lymphocyte proliferation were assessed. On day 28, the postvaccination antibody titer was determined. The determination of pre- and postvaccination antibody titers against the various influenza antigens was carried out by the hemagglutination inhibition test. An increase of 4x for any of the virus antigens was considered as a seroconversion. A titer higher than 40 at the prevaccination period was considered as protective. RESULTS: Eleven elderly subjects were responsive and 12 were not. We have shown that the nutritional parameters such as hemoglobin, hematocrit, total protein, iron and vitamin E levels, as well as the DHEA level and the cellular immune response were significantly lower in the nonresponsive group as compared to the responsive group. Thus, they might be associated with the influenza vaccine responsiveness of institutionalized elderly subjects. CONCLUSIONS: These results will help design intervention studies for improving the immune response by achieving an optimal nutritional status, mainly in the frail elderly population, that could have a great public health impact.

J Gerontol A Biol Sci Med Sci. 1999 Feb;54(2):M59-64

Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy.

OBJECTIVE: To evaluate the use of oral cyanocobalamin therapy in the treatment of cobalamin (vitamin B(12))-deficient anemia. DATA SOURCES: Primary and review articles were identified by MEDLINE search (1966-May 2000) and through secondary sources. DATA SYNTHESIS: Cobalamin-deficient anemia is among the most common diagnoses in older populations. Cobalamin-deficient anemia may be diagnosed as pernicious anemia, resulting from the lack of intrinsic factor required for cobalamin absorption or as protein malabsorption from the inability to displace cobalamin from protein food sources. Several studies provide evidence that daily oral cyanocobalamin as opposed to monthly parenteral formulations may adequately treat both types of cobalamin-deficient anemias. CONCLUSIONS: Daily oral cyanocobalamin at doses of 1000-2000 microg can be used for treatment in most cobalamin-deficient patients who can tolerate oral supplementation. There are inadequate data at the present time to support the use of oral cyanocobalamin replacement in patients with severe neurologic involvement.

Ann Pharmacother. 2002 Jul-Aug;36(7-8):1268-72

Hematological response to short-term oral cyanocobalamin therapy for the treatment of cobalamin deficiencies in elderly patients.

OBJECTIVES: The aim of this trial was to demonstrate the efficacy of one month of oral cobalamin (vitamin B12) therapy in elderly patients with cobalamin deficiency related to food-cobalamin malabsorption (FCM). PATIENTS AND METHOD: Twenty elderly patients (mean age: 78+/-17 years) with established cobalamin deficiency related to FCM were included in an open-label, non-randomized, non-placebo trial. They were treated with a maximum of 1,000 microgram per day of oral crystalline cyanocobalamin for at least 1 month. Serum cobalamin levels (primary endpoint), blood count abnormalities and reticulocytes count (secondary endpoints) were determined at baseline and during the first month of treatment. RESULTS: 85% of the patients normalized their serum cobalamin levels with a mean increase of+167 pg/ml (p<0.001 compared with baseline). 100% of the patients corrected their initial macrocytosis and 25% their anemia; 100% of the patients had medullar regeneration with a mean increase of reticulocytes count of 32+/-11.3 x 106/l (p=0.03 compared with baseline). CONCLUSIONS: Our findings support the view that one month of oral crystalline cyanocobalamin is effective to correct serum vitamin B12 levels and to obtain hematological responses in elderly patients with cobalamin deficiency related to FCM.

J Nutr Health Aging. 2006 Jan-Feb;10(1):3-6

Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial.

BACKGROUND: Supplement-ation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B(12) deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. METHODS: We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B(12) deficiency in older people with mild vitamin B(12) deficiency, defined as a serum vitamin B(12) level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 mumol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 mug of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B(12) deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration. RESULTS: Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 mug was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 mug of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration. CONCLUSION: The lowest dose of oral cyanocobalamin required to normalize mild vitamin B(12) deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 mug daily.

Arch Intern Med. 2005 May 23;165(10):1167-72

Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.

BACKGROUND: Vitamin B12 deficiency is common and rises with age. Most people with vitamin B12 deficiency are treated in primary care with intramuscular vitamin B12 which is a considerable source of work for health care professionals. Several case control and case series studies have reported equal efficacy of oral administration of vitamin B12 but it is rarely prescribed in this form, other than in Sweden and Canada. Doctors may not be prescribing oral formulations because they are unaware of this option or have concerns regarding effectiveness. OBJECTIVES: To assess the effectiveness of oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. SEARCH STRATEGY: Searches were undertaken of The Cochrane Library, MEDLINE, EMBASE and Lilacs in early 2005. The bibliographies of all relevant papers identified using this strategy were searched. In addition we contacted authors of relevant identified studies and Vitamin B12 research and pharmaceutical companies to enquire about other published or unpublished studies and ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) examining the use of oral or intramuscular vitamin B12 to treat vitamin B12 deficiency. DATA COLLECTION AND ANALYSIS: All abstracts or titles identified by the electronic searches were independently scrutinised by two reviewers. When a difference between reviewers arose, we obtained and reviewed a hard copy of the papers and made decisions by consensus. We obtained a copy of all pre-selected papers and two researchers independently extracted the data from these studies using piloted data extraction forms. The whole group checked whether inclusion and exclusion criteria were met, and disagreement was decided by consensus. The methodological quality of the included studies was independently assessed by two researchers and disagreements were brought back to the whole group and resolved by consensus. MAIN RESULTS: Two RCT’s comparing oral with intramuscular administration of vitamin B12 met our inclusion criteria. The trials recruited a total of 108 participants and followed up 93 of these from 90 days to four months. High oral doses of B12 (1000 mcg and 2000 mcg) were as effective as intramuscular administration in achieving haematological and neurological responses. AUTHORS’ CONCLUSIONS: The evidence derived from these limited studies suggests that 2000 mcg doses of oral vitamin B12 daily and 1000 mcg doses initially daily and thereafter weekly and then monthly may be as effective as intramuscular administration in obtaining short term haematological and neurological responses in vitamin B12 deficient patients.

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004655

Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills?

OBJECTIVE: To estimate savings, using a third-party payer perspective, if all elderly patients currently receiving vitamin B12 (cobalamin) injections were switched to high-dose oral therapy. DESIGN: We modeled high-dose oral B12 supplement costs to include drugs, pharmacists’ fees, and one-time conversion costs consisting of two physician visits and laboratory monitoring. The number of vitamin-injection visits avoided by switching to oral therapy was predicted using a multivariate model that considered covariates for overall patient illness. SETTING: Ontario family physicians’ and internists’ practices. PARTICIPANTS: Population-based administrative databases for Ontario were used to identify all people between 65 and 100 years who received parenteral vitamin B12 during 1995 and 1996. MAIN OUTCOME MEASURES: The cost of parenteral vitamin B12 for each patient, including drugs, injections, pharmacists’ fees, and injection-associated physician visits, was measured directly from the databases. RESULTS: The annual cost of parenteral vitamin B12 therapy averaged $145.88 per person and totaled a maximum $25 million over 5 years. Converting all patients to high-dose oral B12 and treating them for 5 years would cost $7.4 million. Depending on how many vitamin-injection visits are avoided by switching to oral therapy, between $2.9 million and $17.6 million would be saved. Switching to oral B12 administration saved costs as long as 16.3% of injection-associated visits were avoided. CONCLUSION: Switching all patients from B12 injections to oral cobalamin therapy could result in substantial savings.

Can Fam Physician. 2001 Jan;47:79-86

Vitamin B12 status and rate of brain volume loss in community-dwelling elderly.

OBJECTIVES: To investigate the relationship between markers of vitamin B(12) status and brain volume loss per year over a 5-year period in an elderly population. METHODS: A prospective study of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment. Volunteers were assessed yearly by clinical examination, MRI scans, and cognitive tests. Blood was collected at baseline for measurement of plasma vitamin B(12), transcobalamin (TC), holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), and serum folate. RESULTS: The decrease in brain volume was greater among those with lower vitamin B(12) and holoTC levels and higher plasma tHcy and MMA levels at baseline. Linear regression analysis showed that associations with vitamin B(12) and holoTC remained significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, ApoE epsilon4 status, tHcy, and folate. Using the upper (for the vitamins) or lower tertile (for the metabolites) as reference in logistic regression analysis and adjusting for the above covariates, vitamin B(12) in the bottom tertile (<308 pmol/L) was associated with increased rate of brain volume loss (odds ratio 6.17, 95% CI 1.25-30.47). The association was similar for low levels of holoTC (<54 pmol/L) (odds ratio 5.99, 95% CI 1.21-29.81) and for low TC saturation. High levels of MMA or tHcy or low levels of folate were not associated with brain volume loss. CONCLUSION: Low vitamin B(12) status should be further investigated as a modifiable cause of brain atrophy and of likely subsequent cognitive impairment in the elderly.

Neurology. 2008 Sep 9;71(11):826-32

Vitamin B12 deficiency neurological syndromes: correlation of clinical, MRI and cognitive evoked potential.

OBJECTIVE : To evaluate cognitive function in B12 deficiency neurological syndromes and response to B12 therapy. METHODS : Patients were diagnosed on the basis of low serum B12 or megaloblastic bone marrow or both. Detailed neurological examination was performed and mental status was evaluated by the Mini Mental State Examination (MMSE). Hemoglobin, RBC indices, blood counts, serum chemistry, HIV, thyroid profile, antiparietal cell antibody and craniospinal MRI were done. Cognitive evoked potential was carried out using the odd ball auditory paradigm and recording was achieved from Fz, Cz and Pz referred to mastoid. P3 latency and amplitude were measured and compared with 33 age and sex matched controls. Three months following B12 therapy, clinical and P3 values were reevaluated and compared with the baseline values. RESULTS : 36 patients, aged 16-80 years were included; 32 patients were above 40 years of age. Their median education level was 14 years. The presenting syndrome was myeloneurocognitive in 9, myeloneuropathy in 10, myelocognitive in 8,myelopathy in 8 and only cognitive in 1 patient.MMSE was abnormal in 17; between 28-19 in 14 and 18-11 in 3 patients. Cranial MRI carried out in 14 patients revealed multiple white matter hyperintensity in T2 in 3 and cortical atrophy in 1. P3 was unrecordable in 7 and latency was prolonged in 8 out of 33 patients. P3 latency was significantly prolonged in patients compared to controls and both MMSE and P3 latency improved significantly at the 3-month follow-up. CONCLUSION : MMSE was abnormal in 47 % and P3 in 45.5% of patients with B12 deficiency neurological syndromes which improved following treatment. SIGNIFICANCE : There is high incidence of reversible cognitive impairment and P3 abnormalities in B12 deficiency neurological syndromes.

J Neurol. 2008 Mar;255(3):353-9

Cobalamin: a critical vitamin in the elderly.

Vitamin B(12) deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol/L (200 pg/mL) is considered normal, 10-15% of the elderly are deficient. Today, however, a threshold of 220-258 pmol/L (300-350 pg/mL) is recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid (MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20-50% of the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B(12). An already moderately reduced vitamin B(12) level is associated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore, a poor vitamin B(12) status is assumed to be involved in the development and progression of dementia (e.g., Alzheimer’s dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of elderly persons (>/=60 years) should be regularly controlled and a general supplementation with vitamin B(12) (>50 microg/day) should be considered.

Prev Med. 2004 Dec;39(6):1256-66

Vitamin B12 deficiency in the aged: a population-based study.

BACKGROUND: vitamin B12 deficiency is common in the aged, but it is controversial whether only some risk groups should be investigated instead of screening the entire aged population. OBJECTIVES: to describe the prevalence of vitamin B12 deficiency in the Finnish aged, and to find out if the subjects especially prone to vitamin B12 deficiency could be identified by the risk factors or clinical correlates. DESIGN: a cross-sectional, population-based study of 1048 aged subjects (age 65-100 years) was carried out. Data on lifestyle factors and clinical conditions were collected, physical examinations were conducted and laboratory variables related to vitamin B12 were measured. RESULTS: vitamin B12 deficiency had been previously diagnosed in 27 (2.6%) subjects, and a laboratory diagnosis (total vitamin B12 <150 pmol/l, or total vitamin B12 150-250 pmol/l and holotranscobalamin < or =37 pmol/l and homocysteine > or =15 micromol/l) was made for 97 (9.5%) subjects. Low serum total vitamin B12 (<150 pmol/l) was observed in 6.1% and borderline total vitamin B12 (150-250 pmol/l) in 32% of the subjects. Male gender (OR 1.9, 95% CI 1.2-2.9), age > or =75 (OR 2.2, 95% CI 1.4-3.4) and refraining from milk products (OR 2.3, 95% CI 1.2-4.4) increased the probability for vitamin B12 deficiency. Anaemia (OR 1.3, 95% CI 0.7-2.3) or macrocytosis (OR 1.2, 95% CI 0.6-2.7) did not predict vitamin B12 deficiency. CONCLUSION: undiagnosed vitamin B12 deficiency is remarkably common in the aged, but no specific risk group for screening can be identified. Thus, biochemical screening of unselected aged population is justified. General practitioners play a key role in diagnosing early vitamin B12 deficiency.

Age Ageing. 2007 Mar;36(2):177-83

Prevalence of and risk factors for vitamin B(12) deficiency in patients with Crohn’s disease.

BACKGROUND: Crohn’s disease (CD) can commonly involve the terminal ileum, which is the site of B(12) absorption. The aim of this study was to define the prevalence of vitamin B(12) abnormalities in a population with CD and to identify risk factors associated with B(12) abnormalities in CD. METHODS: The medical records of 201 patients with CD evaluated at a tertiary care center were retrospectively reviewed to determine the prevalence of B(12) deficiency and to evaluate factors associated with B(12) deficiency. The prevalence of B(12) deficiency in a control population of 40 patients with ulcerative colitis was also assessed. RESULTS: The prevalence of an abnormal serum B(12) concentration in patients with CD was 18.4% (95% confidence interval [CI] 13.1-23.8%) compared with 5% (95% CI, 0-11.8%) (P = 0.035) in ulcerative colitis controls. Risk factors for B(12) deficiency in patients with CD included prior ileal (odds ratio [OR], 7.22; 95% CI, 1.97-26.51) or ileocolonic (OR, 5.81; 95% CI, 2.09-16.12) resection and the need for ongoing medical therapy (OR, 2.59; 95% CI, 1.03-6.47). Neither disease location nor duration was independently associated with the risk of B(12) deficiency. CONCLUSIONS: Vitamin B(12) abnormalities are common in patients with CD and patients with a prior ileal or ileocolonic resection are at particular risk. Routine screening for B(12) deficiency in patients with CD is warranted.

Inflamm Bowel Dis. 2008 Feb;14(2):217-23

Fruit and vegetable consumption and risk factors for cardiovascular disease.

The international guidelines issued by the World Health Organization recommend reduction in dietary saturated fat and cholesterol intakes as means to prevent hypercholesterolemia and cardiovascular disease (CVD); however, only limited data are available on the benefits of fruit and vegetable consumption on CVD risk factors in a community-based population. The aim of this study was to examine whether, and to what extent, intake of fruits and vegetables is inversely associated with CVD risk factors in adults. In this population-based cross-sectional study, a representative sample of 840 Tehranian adults (male and female) aged 18 to 74 years was randomly selected in 1998. Multivariate logistic regression adjusted for lifestyle and nutritional confounders was used in 2 models. After adjusting for confounders, dietary fruit and vegetable were found to be significantly and inversely associated with CVD risk factors. Adjusted odds ratio for high low-density lipoprotein concentrations were 1.00, 0.88, 0.81, and 0.75 (P for trend < .01) in the first model, which was adjusted for age, sex, keys score, body mass index, energy intake, smoking status, dietary cholesterol, and history of diabetes mellitus and coronary artery disease, a trend which was not appreciably altered by additional adjustment for education, physical activity, and saturated, polyunsaturated, and total fat intakes. This association was observed across categories of smoking status, physical activity, and tertiles of the Keys score. Exclusion of subjects with prevalent diabetes mellitus or coronary artery disease did not alter these results significantly. Consumption of fruits and vegetables is associated with lower concentrations of total and low-density lipoprotein cholesterol and with the risk of CVD per se in a dose-response manner.

Metabolism. 2009 Apr;58(4):460-8

Supplementation of conventional therapy with the novel grain Salba (Salvia hispanica L.) improves major and emerging cardiovascular risk factors in type 2 diabetes: results of a randomized controlled trial.

OBJECTIVE: To determine whether addition of Salba (Salvia hispanica L.), a novel whole grain that is rich in fiber, alpha-linolenic acid (ALA), and minerals to conventional treatment is associated with improvement in major and emerging cardiovascular risk factors in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using a single-blind cross-over design, subjects were randomly assigned to receive either 37 +/- 4 g/day of Salba or wheat bran for 12 weeks while maintaining their conventional diabetes therapies. Twenty well-controlled subjects with type 2 diabetes (11 men and 9 women, aged 64 +/- 8 years, BMI 28 +/- 4 kg/m2, and A1C 6.8 +/- 0.9%) completed the study. This study was set in the outpatient clinic of the Risk Factor Modification Center, St. Michael’s Hospital, Toronto, Canada. RESULTS: Compared with the control treatment, Salba reduced systolic blood pressure (SBP) by 6.3 +/- 4 mmHg (P < 0.001), high-sensitivity C-reactive protein (hs-CRP) (mg/l) by 40 +/- 1.6% (P = 0.04), and vonWillebrand factor (vWF) by 21 +/- 0.3% (P = 0.03), with significant decreases in A1C and fibrinogen in relation to the Salba baseline but not with the control treatment. There were no changes in safety parameters including liver, kidney and hemostatic function, or body weight. Both plasma ALA and eicosapentaenoic polyunsaturated fatty acid levels were increased twofold (P < 0.05) while consuming Salba. CONCLUSIONS: Long-term supplementation with Salba attenuated a major cardiovascular risk factor (SBP) and emerging factors (hs-CRP and vWF) safely beyond conventional therapy, while maintaining good glycemic and lipid control in people with well-controlled type 2 diabetes.

Diabetes Care. 2007 Nov;30(11):2804-10

Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat.

Chemoprevention by chlorophyll (Chl) was investigated in a rat multi-organ carcinogenesis model. Twenty-one male F344 rats in three gavage groups (N = 7 rats each) received five daily doses of 250 microg/kg [(3)H]-aflatoxin B(1) ([(3)H]-AFB(1)) alone, or with 250 mg/kg chlorophyllin (CHL), or an equimolar amount (300 mg/kg) of Chl. CHL and Chl reduced hepatic DNA adduction by 42% (P = 0.031) and 55% (P = 0.008), respectively, AFB(1)-albumin adducts by 65% (P < 0.001) and 71% (P < 0.001), respectively, and the major AFB-N(7)-guanine urinary adduct by 90% (P = 0.0047) and 92% (P = 0.0029), respectively. To explore mechanisms, fluorescence quenching experiments established formation of a non-covalent complex in vitro between AFB(1) and Chl (K(d) = 1.22 +/- 0.05 microM, stoichiometry = 1Chl:1AFB(1)) as well as CHL (K(d) = 3.05 +/- 0.04 microM; stoichiometry = 1CHL:1AFB(1)). The feces of CHL and Chl co-gavaged rats contained 137% (P = 0.0003) and 412% (P = 0.0048) more AFB(1) equivalents, respectively, than control feces, indicating CHL and Chl inhibited AFB(1) uptake. However, CHL or Chl treatment in vivo did not induce hepatic quinone reductase (NAD(P)H:quinone oxidoreductase) or glutathione S-transferase (GST) above control levels. These results are consistent with a mechanism involving complex-mediated reduction of carcinogen uptake, and do not support a role for phase II enzyme induction in vivo under these conditions. In a second study, 30 rats in three experimental groups were dosed as in study 1, but for 10 days. At 18 weeks, CHL and Chl had reduced the volume percent of liver occupied by GST placental form-positive foci by 74% (P < 0.001) and 77% (P < 0.001), respectively compared with control livers. CHL and Chl reduced the mean number of aberrant crypt foci per colon by 63% (P = 0.0026) and 75% (P = 0.0004), respectively. These results show Chl and CHL provide potent chemoprotection against early biochemical and late pathophysiological biomarkers of AFB(1) carcinogenesis in the rat liver and colon.

Carcinogenesis. 2007 Jun;28(6):1294-302

The effects of spirulina on allergic rhinitis.

The prevalence of allergic rhinitis is increasing globally due to various causes. It affects the quality life of a large group of people in all around the world. Allergic rhinitis still remains inadequately controlled with present medical means. The need of continuous medical therapy makes individuals anxious about the side effects of the drugs. So there is a need for an alternative strategy. Effects of spirulina, tinospora cordifolia and butterbur were investigated recently on allergic rhinitis in just very few investigations. Spirulina represents a blue-green alga that is produced and commercialized as a dietary supplement for modulating immune functions, as well as ameliorating a variety of diseases. This double blind, placebo controlled study, evaluated the effectiveness and tolerability of spirulina for treating patients with allergic rhinitis. Spirulina consumption significantly improved the symptoms and physical findings compared with placebo (P < 0.001***) including nasal discharge, sneezing, nasal congestion and itching. Spirulina is clinically effective on allergic rhinitis when compared with placebo. Further studies should be performed in order to clarify the mechanism of this effect.

Eur Arch Otorhinolaryngol. 2008 Oct;265(10):1219-23

Wholegrain foods made from a novel high-amylose barley variety (Himalaya 292) improve indices of bowel health in human subjects.

Himalaya 292 (Hordeum vulgare var. Himalaya 292) is a novel hull-less barley variety lacking activity of a key enzyme of starch synthesis giving a grain containing less total starch, more amylose and higher total dietary fibre. Animal trials have shown that Himalaya 292 contains more resistant starch and has greater positive impact on biomarkers of large-bowel health than comparable wholegrain cereal products. The present study compared the effects of foods made from wholegrain Himalaya 292 with those made from wholegrain wheat on faecal biomarkers of bowel health in human subjects. Seventeen male and female volunteers aged 31-66 years consumed similar quantities of Himalaya 292, whole-wheat or refined cereal foods daily for 4 weeks in a randomised cross-over design. Total dietary fibre intakes from weighed food records were 45, 32, and 21 g/d for the Himalaya 292, whole-wheat and refined cereal periods, respectively. Compared with the refined cereal foods, consumption of Himalaya 292 foods resulted in 33% higher faecal weight, a lowering of faecal pH from 7.24 to 6.98, a 42% higher faecal concentration and a 91% higher excretion of butyrate, a 57% higher faecal total SCFA excretion and a 33% lower faecal p-cresol concentration. pH and butyrate concentration and excretion were also significantly different compared with wholemeal wheat. It is concluded that consumption of a diet that included foods made from Himalaya 292 supplied more fibre and improved indices of bowel health compared with refined cereal foods and, for some indices, similar wholemeal wheat foods at equivalent levels of intake.

Br J Nutr. 2008 May;99(5):1032-40

Wheat grass juice may improve hematological toxicity related to chemotherapy in breast cancer patients: a pilot study.

Myelotoxicity induced by chemotherapy may become life-threatening. Neutropenia may be prevented by granulocyte colony-stimulating factors (GCSF), and epoetin may prevent anemia, but both cause substantial side effects and increased costs. According to non-established data, wheat grass juice (WGJ) may prevent myelotoxicity when applied with chemotherapy. In this prospective matched control study, 60 patients with breast carcinoma on chemotherapy were enrolled and assigned to an intervention or control arm. Those in the intervention arm (A) were given 60 cc of WGJ orally daily during the first three cycles of chemotherapy, while those in the control arm (B) received only regular supportive therapy. Premature termination of treatment, dose reduction, and starting GCSF or epoetin were considered as “censoring events.” Response rate to chemotherapy was calculated in patients with evaluable disease. Analysis of the results showed that five censoring events occurred in Arm A and 15 in Arm B (P = 0.01). Of the 15 events in Arm B, 11 were related to hematological events. No reduction in response rate was observed in patients who could be assessed for response. Side effects related to WGJ were minimal, including worsening of nausea in six patients, causing cessation of WGJ intake. In conclusion, it was found that WGJ taken during FAC chemotherapy may reduce myelotoxicity, dose reductions, and need for GCSF support, without diminishing efficacy of chemotherapy. These preliminary results need confirmation in a phase III study.

Nutr Cancer. 2007;58(1):43-8

Supplementation with active hexose correlated compound increases the innate immune response of young mice to primary influenza infection.

The emergence of H5N1 avian influenza and the threat of new or adapted viruses in bioterrorism have created an urgent interest in identifying agents to enhance the immune response to primary virus infection. Active hexose correlated compound (AHCC) is a natural mushroom extract reported to increase natural killer (NK) cell activity, survival, and bacterial clearance in young mice. However, the effects of AHCC on the response to viral infections have not been studied. In this study, young C57BL/6 mice were supplemented with 1 g AHCC/(kg body weight x d) for 1 wk prior to and throughout infection with influenza A (H1N1, PR8). Supplementation increased survival, decreased the severity of infection, and shortened recovery time following intranasal infection with flu, as determined by the recovery of body weight and epithelial integrity in the lungs. AHCC increased NK activity in lungs at d 1 (P < 0.05) and d 4 (P < 0.01) and in the spleen at d 2 postinfection (P < 0.01). Supplementation increased the percentage (P < 0.05) and number (P < 0.01) of NK1.1+ cells in the lung and reduced the infiltration of lymphocytes and macrophages compared with controls (P < 0.01). These data suggest that AHCC supplementation boosts NK activity, improves survival, and reduces the severity of influenza infection in young mice. Bolstering innate immunity with dietary bioactives may be one avenue for improving the immune response to primary flu infection.

J Nutr. 2006 Nov;136(11):2868-73

Cordysinocan, a polysaccharide isolated from cultured Cordyceps, activates immune responses in cultured T-lymphocytes and macrophages: signaling cascade and induction of cytokines.

Cordyceps sinensis, a well-known traditional Chinese medicine, possesses activities in anti-tumor, anti-oxidation and stimulating the immune response; however, the identity of active component(s) is not determined. A strain of Cordyceps sinensis, namely UST 2000, has been isolated. By using activity-guided purification, a novel polysaccharide of molecular weight approximately 82 kDa was isolated from the conditioned medium of cultured Cordyceps. The isolated exo-polysaccharide, namely cordysinocan, contains glucose, mannose, galactose in a ratio of 2.4:2:1. In cultured T-lymphocytes, application of cordysinocan induced the cell proliferation and the secretion of interleukin-2, interleukin-6 and interleukin-8. In addition, the phosphorylation of extracellular signal-regulated kinases (ERK) was induced transiently by the treatment of cordysinocan. Moreover, application of cordysinocan in cultured macrophages increased the phagocytosis activity and the enzymatic activity of acid phosphatase. These results therefore verify the important role of Cordyceps polysaccharide in triggering such immune responses.

J Ethnopharmacol. 2009 Jul 6;124(1):61-8

Clinical application of Cordyceps sinensis on immunosuppressive therapy in renal transplantation.

OBJECTIVE: We sought to explore the adjunctive effects of Cordyceps sinensis (CS) in clinical renal transplantation. MATERIALS AND METHODS: Patients (n = 202) were divided randomly by lottery into a treatment (n = 93) and a control group (n = 109). Patients in the treatment group were treated with CS 1.0 g 3 times a day in addition to the immunosuppressive regimen given to the control group. We compared patient and graft survivals, incidence, time and severity of acute rejection episodes, chronic allograft nephropathy (CAN), hepatotoxicity and nephrotoxicity, biochemistry parameters including indicators of liver and kidney functions, fats, proteinuria, dosages, and whole blood concentrations of cyclosporine (CsA). RESULTS: Patient and graft survival rates, serum creatinine (SCr), and blood urea nitrogen (BUN) were not significantly different between the 2 groups (P > .05). Serum uric acid (UA) and 24-hour urinary total protein (24-hour UTP) were

significantly lower in the treatment group than in the control group (P < .05). The incidences (11.83% vs 15.60%) and times to acute renal allograft rejection (23.48 +/- 7.22 vs 22.27 +/- 8.03 days posttransplantation) were not significantly different between the treated and control groups (P > .05). Patients receiving thymoglobulin antirejection therapy (3 cases) were fewer in the heated versus control group (13 cases; P = .014). The incidences of hepatotoxicity and nephrotoxicity in the treated group were 12.90% and 19.35%, significantly lower than 24.77% and 33.94% in the control group, respectively (P < .05). At 2 to 6 months posttransplantation, the CsA dosages in the treated group were significantly lower than those in the control group (P < .05). The whole blood trough CsA concentrations in the treated group were significantly lower than those in the control group at 3 to 6 months posttransplantation (P < .05). The decreasing trends of the 2 aforementioned parameters in the treatment group were approximately linear among treated subjects compared with approximately quadratic in the control group (P < .05). The incidence of CAN in the treated group was 7.53%, which was significantly lower than 18.35% in the control group (P = .024). The 24-hour UTP level in CAN patients within the treated group was significantly lower than the control group after transplantation (P = .045). The differences in total bilirubin, SCr, serum UA, and total cholesterol levels among otherwise normal patients in the treated group were significantly lower than those among the control group (P < .05). CONCLUSIONS: The use of CS may allow decreased dosages and concentrations of CsA causing fewer side effects without an increased risk of acute rejection. In addition, CS with reduced dose CsA may decrease proteinuria and retard CAN progression.

Transplant Proc. 2009 Jun;41(5):1565-9

Induction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militaris.

Cordyceps militaris is well known as a traditional medicinal mushroom and is a potentially interesting candidate for use in cancer treatment. In this study, the potential of the water extract of C. militaris (WECM) to induce apoptosis in human lung carcinoma A549 cells and its effects on telomerase activity were investigated. The growth inhibition and apoptosis induction by WECM treatment in A549 cells was associated with the induction of Fas, catalytic activation of caspase-8, and Bid cleavage. Activation of caspases, downregulation of anti-apoptotic Bcl-2 expression, and upregulation of pro-apoptotic Bax protein were also observed in WECM-treated cells. However, the cytotoxic effects and apoptotic characteristics induced by WECM were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 plays in the process. In addition, WECM exerted a dose-dependent inhibition of telomerase activity via downregulation of human telomerase reverse transcriptase (hTERT), c-myc and Sp1 expression. Taken together, the data from this study indicate that WECM induces the apoptosis of A549 cells through a signaling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways. It was also conclude that apoptotic events due to WECM were mediated with diminished telomerase activity through the inhibition of hTERT transcriptional activity.

Food Chem Toxicol. 2009 Jul;47(7):1667-75