Benign prostatic hyperplasia(BPH) in Foods' Points of View

Benign prostatic hyperplasia(BPH) is defined as a condition of increased in the number of cells of prostate gland, causing partial, or sometimes virtually complete obstruction of the urinary tract. According to statistic, BPH commonly starts at age of 30 and symptoms usually can not be realized until age of 50. More than half of men between age of 60-70 are experience symptoms of BPH and only 10% are required treatment. Suggestion of BPH is associated to nutritional status and eating habits, according to the study, 30 male patients with clinically confirmed and treated disease of the prostatic gland, including 15 men (aged 51-75 years) with BPH and 15 men (aged 51-73 years) with PC, indicated improper nutritional status lead of incorrect nutritional habits which fail to improve their health status, may be the cause of  the development of some diet-dependent diseases, such as BPH and prostate cancer(a). A proper diet with vegetable, fruit containing zinc may reduce the risk of the disease from starting(b)(c).
  Epidemiological studies, indicated intake of vegetables and fruits accompanied with healthy life style may be associated in prevented risk and treatment of enlarged prostate(d)(e)(f), it may due to enhancement of antioxidants effect on over production of prostate cells(g)(h).

A. Types of vegetables in reduced risk of BPH
1. Tomato
Tomato is a red, edible fruit, genus Solanum, belonging to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose and often in green house. According to the study by Institute of Biological Chemistry and Nutrition, lycopene found in tomato inhibited the progression and reduced symptoms of BPH.(1) But, intake of lycopene in the study at Universität Bonn, showed no protection from the development of PCA, but in consumption of tomato products, lycopene ingestion might also be effective in PCA therapy(2). Profluss®), composition of Serenoa repens, selenium and lycopene, showed to exhibit its antiinflammatry activities in reduced risk of BPH by significant reductions of extension and grading of flogosis(3) and relieve the BHP symptoms(4). Lycopene, a major antioxidant found in tomato, according to the reviews of Monash University, in the assessment of its effect on BPH and prostate cancer found an inclusive result in supporting the reduced risk of lycopene of the diseases(5).

2. Onion
The onion is a plants in the genus Allium, belonging to the family Alliaceae, a close relation of garlic. It is often called the "king of vegetables" because of its pungent taste and found in a large number of recipes and preparations spanning almost the totality of the world's cultures. Depending on the variety, an onion can be sharp, spicy, tangy, pungent, mild or sweet. Suggestion of rich sources of flavonoids may be effective in treating benign prostatic hyperplasia (BPH)(6). According to the Istituto di Ricerche Farmacologiche Mario Negri, Intake of onion showed an inverse association of BPH(7).

3. Whole grain
Wholegrain is cereal grains containing cereal germ, endosperm, and bran. The study by Beijing Medical University, conducted in 1993-1995 in Beijing of BPH in 413 rural and 419 urban male over 40 years of age, showed an increased BPH incidence with daily intake of total calories, fat and animal protein, and the decreased daily intake of vegetables and whole grain, the sources of phytoestrogens(8). The study of the University of Illinois in Chicago, indicated an inverse associations with dietary intake of plant foods, including whole grain cereals(9). Other researchers suggested that BPH is associated with elevations in plasma estradiol/testosterone ratio, insulin, and insulin-like growth factor-I and daily aerobic exercise can reduce all of these plasma factors, particularly when combined with a low-fat, high-fiber diet consisting of whole grains, fruits, and vegetables(10).

4. Organic soybean
Soybean is genus Glycine, the family Fabaceae, one of the legumes that contains twice as much protein per acre as any other major vegetable or grain crop, native to Southeast Asia. Now, it is grown worldwide with suitable climate for commercial profit and a healthy foods. In a  rat model of benign prostatic hyperplasia (BPH), Anthocyanin, a major chemical constituent  in the pigment and potent antioxidant of black soy bean, showed to inhibit the volume and suppress the proliferation of the prostate(11) and The study Central South University, also indicated that soybean isoflavone inhibits prostate hyperplasia through increased expressions of nitric oxide and nitric oxide synthase in rats(12). The soybean Isoflavone also found to reduced the risk of prostate hyperplasia through increased acid phosphatase and PAP in a dose-dependent manner in rats, according to the Central South University, in Shanghai(13).

5. Cruciferous vegetables
Cruciferous vegetables are the group of  vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc.
Sulforaphane (SFN) an isothiocyanate derived from cruciferous vegetables in the study of its effect in normal (PrEC), benign hyperplasia (BPH1) and cancerous (LnCap and PC3) prostate epithelial cells showed an induced cell cycle arrest and apoptosis in BPH1, through its activities in effects on cell proliferation, HDAC activity and downstream targets in normal and cancer cells(14). Ethyl isothiocyanate (PEITC), found in cruciferous vegetables, in the testing on androgen-influenced growth of the prostate such as benign hyperplasia, showed to regulate the hormone-dependent growth of the prostate, through negated the testosterone-mediated enhancement of the androgen receptor (AR), via down-regulating transcription factor Sp1 expression and Sp1 binding complex formation(15).

6. Squash
Squash is the genus Cucurbita, belongs to family Cucurbitaceae and native to Mexico and Central America. In North America, squash is divided into summer squash or winter squash, depending on the maturity of squash when harvested, immature fruit called summer squash and mature fruit called winter squash.
ProstateEZE Max, a herbal formula containing Cucurbita pepo, Epilobium parviflorum, lycopene, Pygeum africanum and Serenoa repens in the study of its effects in benign prostate hypertrophy (BPH) indicated a positive effect on physical symptoms of BPH when taken over 3 months(16). The ¹Minneapolis VA Center for Chronic Diseases Outcomes Research in the reviews of 6 phytotherapeutic agents (Serenoa repens, Hypoxis rooperi, Secale cereale, Pygeum africanum, Urtica dioica, Curcubita pepo)from 44 studies, showed no convincing evidence supporting the use of Curcubita pepo alone for treatment of BPH but insisting further studies may be necessary(17).

7. Spinach
Spinach is an edible flowering plant in the genus Spinacia, belongs to the family of Amaranthaceae and native to central and southwestern Asia. It is considered as a healthy plant containing vary vitamins and minerals.
The study of the effect of 3 anti-oxidants [a water-soluble natural anti-oxidant. NAO (200 mg/kg). found in spinach leaves; epigallocatechin-3 gallate, EGCG (200 mg/kg), a major green tea polyphenol; and N-acetylcysteine, NAC (125 mg/kg)] plus vehicle in slowing spontaneous tumorigenic progression in TRAMP and wild-type male mice showed a positive effects of NAO inreduced hyperplasia at weeks 9 and 13(18). In a case-control study of prostatic cancer which consisted of 100 patients with prostatic cancer, matched for hospital, age (+/- 3 yr) and hospital admission date (+/- 3 months) to patients with benign prostatic hyperplasia (BPH) and hospital controls, conducted by the Kyoto University, indicated that frequent intake of spinach (RR = 1.96: 1.01-7.73), a typical green and yellow vegetable, was associated to risk BPH and prostate cancer(19).

8. Mushrooms
Mushroom is a standard name of white button mushroom, the fleshy, spore-bearing fruiting body of a fungus produced above ground on soil or on its food source, It is a genus A. Muscaria and belong to the family Amanitaceae and has been cultivation in many cultures all over the world for foods and health benefits. In the examination of methanol extracts of 19 edible and medicinal mushrooms on 5alpha-reductase activity indicated an inhibited effects of the testosterone-induced growth of the ventral prostate in castrated rats(20). But the study conducted by Gunma University Graduate School of Medicine, Maebashi, indicated that oral administration of extract of mushroom Phellinus linteus induced prostate enlargement(21). Therefore using mushroom in treating BPH should be taken with care only with the approval of specialist.

B. Types of fruit in reduced risk BPH
1. Orange
Orange is a species of Citrus Sinensis, belong to the family Rutaceae and native to the Southeast Asia. Orange is round citrus fruits with finely-textured skins, orange in color and one of most popular fruits in the world. The extract of red orange juice (ROE)  showed to inhibit proliferation of fibroblast and epithelial prostate cells, and may be a potential usefulness in the management of benign prostatic hyperplasia, according to University of Rome(22).

2. Water melon and strawberry
Lycopene, a member of the carotenoid family, found abundantly in Water melon, strawberry, exerted its antioxidants effect as preventive agent for prostate disease(23). The study of Profluss® on prostatic chronic inflammation (PCI) in 168 subjects, the compositions included serenoa repens+Selenium+Lycopene exhibited its anti-inflammatory activity for treatment of PCI in BPH and/or PIN/ASAP patients(24). The study by University of Messina, found that Serenoa repens, lycopene and selenium is superior than Serenoa repens alone in reducing benign prostatic hyperplasia, through reduction of  prostate weight and hyperplasia and cell proliferation and growth factor expression augmentation of apoptosis(25).

3. Cranberry
Cranberry is a species of Vaccinium oxycoccos, belong to the family Ericaceae. It is low, creeping shrubs or vines up to 2 m long and 5 to 20 cm in height and found in the cooler part of Northern America. In the study to evaluate the efficacy and tolerability of cranberry (Vaccinium macrocarpon) powder in men at risk of prostate disease with LUTS, showed a positive effects with lower total PSA level on day 180 of the study(26) and lower urinary tract symptoms of benign prostatic hyperplasia(27), In a total of 370 consecutive patients study, cranberry found to reduced urinary tract symptoms (dysuria, nocturia, urinary frequency, urgency) of that may be  in reduced risk of BPH(28).

C. Others
1. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
The levels or activity of androgen hormones are associated to the risk of BPH, green tea catechin, (-)epigallocatechin-3-gallate, exhibited its modulation of androgenic activity that may be useful for the treatment of various hormone-related abnormalities, such as benign prostatic hyperplasia(29). 5 alpha-reductase activity may be involved in the development of benign prostatic hyperplasia, according to the
The Ben May Institute for Cancer Research, and The Tang Center for Herbal Medicine Research, green tea catechin (-)-epigallocatechin gallate (EGCG). EGCG showed potent inhibition in cell-free and in replacement of the gallate ester in EGCG with long-chain fatty acids produced potent 5 alpha-reductase inhibitors(30). The study by the Oregon State University, also showed that in the study of male noble rats implanted with estradiol and testosterone divided into 4 dietary groups: control, soy, tea, or soy+tea, the combinartion of  soy and tea attenuated prostate malignancy by decreasing prostate hyperplasia(31). Also, green tea catechin, (-)epigallocatechin-3-gallate, according to Dr. Liao S., may be useful for the treatment of various hormone-related abnormalities, such as benign prostatic hyperplasia, due to its modulation of androgenic activity(32).

2. Coffee
Coffee made from the roasted seeds of the genus Coffee, belonging to the family Rubiaceae native to southern Arabia.
Coffee intake has been found to be effective in reduced risk of prostate cancer, as we mentioned in the prostate cancer article. According to Dr. Morrison AS. Coffee drinking was inversely but only weakly related to prostatic hypertrophy(BPH) in 910 residents of Rhode Island who had a partial or total prostatectomy that was not related to cancer in the years 1985-1987(33). But the study of a total of 1369 patients younger than 75 years old surgically treated for BPH and 1451 controls younger than 75 years of age, showed no association of coffee intake in risk of BPH.(34)(35). and  according to the study by the Univ Estadual Paulista (UNESP) in the rat prostate gland, chronic caffeine intake from puberty may increase androgenic signalling and cell proliferation  and can be related to the development of benign prostatic hyperplasia(36).

3. Pumpkin seeds
Pumpkin seed or pepita is an edible seed of a pumpkin with flat, dark green color. Pumpkin is the genus Cucurbita and belong the family Cucurbitaceae. The origin of pumpkins is unknown, although many people believe that they have originated in North America.
Pumpkins seed has been known to consist certain chemical constituents in reduced risk and management of benign prostatic hyperplasia (BPH). Pumpkin seed, in the study of 20 male Wistar rats, conducted by the Michael Okpara University of Agriculture, inhibited the induction of BPH  and through increasing the testosterone:estradiol ratio(37). A randomized, double-blind, placebo-controlled trial in over 12 months on 47 benign prostatic hyperplasia patients with average age of 53.3 years and international prostate symptom score over 8, showed a positive effect of pumpkin seeds as complementary and alternative medicine treatments for benign prostatic hyperplasia(38). Other study also showed that oral administration of pumpkin seed oil inhibited testosterone-induced hyperplasia of the prostate(39).

4. Coconut oil
Coconut palm tree is a genus cocos, belonging to the family Arecaceae, native to the tropic and subtropic area. It is said that coconut oil may reduce total cholesterol, triglycerides, phospholipids, LDL, and VLDL cholesterol levels and increased HDL cholesterol in serum, etc.(40). Coconut oil, in the study of the effect on BPH, showed to  reduce the increase of both prostate weight (PW) and  PW:body weight (BW) ratio, markers of testosterone-induced PH in rats(41).

5. Fish oil
Fish oil, rich in long-chain polyunsaturated essential fatty acids of the omega-3 group may be used to reduced BPH risk. According to the study by the University of California at Davis, gamma-linolenic acid (GLA) from fish oil inhibited 80% of gamDHT-enhanced activity of 5 alpha-reductase with their precursor fatty acids, respectively, exerted moderate inhibition(42). Other in the study of the serum samples of 24 BPH and 19 PC patients, and from 21 age-matched normal male subjects, found that the omega-3 PUFAs level was significantly decreased in patient with BPH(43). Unluckily, the comparison of the levels of n-3 polyunsaturated fatty acids (PUFAs) in leukocytes and prostate tissue in men with prostate cancer or benign prostatic hyperplasia (BPH), indicated no association in correlation of long-chain polyunsaturated essential fatty acids  intake in reduced risk of BPH(44).

Taking altogether, with out going into reviews, certain foods have been found effectively in reduced risk and treatments of Benign prostatic hyperplasia(BPH). But large sample and multi centers studies are necessary to validate their effectiveness. As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.



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References
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(c) Associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms by Raheem OA¹, Parsons JK.(PubMed)
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(g) Evaluation of oxidative stress and DNA damage in benign prostatic hyperplasia patients and comparison with controls by Ahmad M¹, Suhail N, Mansoor T, Banu N, Ahmad S(PubMed).
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[Article in German] by Ellinger S¹, Ellinger J, Müller SC, Stehle P.(PubMed)

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(8) Changes in the prevalence of benign prostatic hyperplasia in China by Gu F.(PubMed)
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(10) Benign prostatic hyperplasia: does lifestyle play a role by Barnard RJ¹, Aronson WJ.(PubMed)
(11) Anthocyanin extracted from black soybean reduces prostate weight and promotes apoptosis in the prostatic hyperplasia-induced rat model by Jang H¹, Ha US, Kim SJ, Yoon BI, Han DS, Yuk SM, Kim SW.(PubMed)
(12) [Effects of soy bean isoflavone on inhibition of benign prostatic hyperplasia and the expressions of NO and NOS of rats].[Article in Chinese] by Yang A¹, Ren G, Tang L, Jiang W.(PubMed)
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(14) Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells by Clarke JD¹, Hsu A, Yu Z, Dashwood RH, Ho E.(PubMed)
(15) Modulating testosterone stimulated prostate growth by phenethyl isothiocyanate via Sp1 and androgen receptor down-regulation by Beklemisheva AA¹, Feng J, Yeh YA, Wang LG, Chiao JW.(PubMed)
(16) A phase II randomised double-blind placebo-controlled clinical trial investigating the efficacy and safety of ProstateEZE Max: a herbal medicine preparation for the management of symptoms of benign prostatic hypertrophy by Coulson S¹, Rao A, Beck SL, Steels E, Gramotnev H, Vitetta L.(PubMed)
(17) Phytotherapy for benign prostatic hyperplasia by Wilt TJ¹, Ishani A, Rutks I, MacDonald R.(PubMed)
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(19) A case-control study of prostatic cancer with reference to dietary habits by Oishi K¹, Okada K, Yoshida O, Yamabe H, Ohno Y, Hayes RB, Schroeder FH.(PubMed)
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(21) Administration of extract of mushroom Phellinus linteus induces prostate enlargement with increase in stromal component in experimentally developed rat model of benign prostatic hyperplasia by Shibata Y¹, Kashiwagi B, Arai S, Fukabori Y, Suzuki K.(PubMed)
(22) Effect of a standardized extract of red orange juice on proliferation of human prostate cells in vitro by Vitali F¹, Pennisi C, Tomaino A, Bonina F, De Pasquale A, Saija A, Tita B.(PubMed)
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(25) [The association of Serenoa repens, lycopene and selenium is superior to Serenoa repens alone in reducing benign prostatic hyperplasia].[Article in Italian] by Squadrito F¹, Morgia G.(PubMed)
(26) The effectiveness of dried cranberries ( Vaccinium macrocarpon) in men with lower urinary tract symptoms by Vidlar A¹, Vostalova J, Ulrichova J, Student V, Stejskal D, Reichenbach R, Vrbkova J, Ruzicka F, Simanek V.(PubMed)
(27) Risk factors for lower urinary tract symptoms suggestive of benign prostatic hyperplasia in a community based population of healthy aging men: the Krimpen Study by Kok ET¹, Schouten BW, Bohnen AM, Groeneveld FP, Thomas S, Bosch JL.(PubMed)
(28) Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma by Bonetta A¹, Di Pierro F.(PubMed)
(29) The medicinal action of androgens and green tea epigallocatechin gallate by Liao S.(PubMed)
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(31) Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFκB pathway in the Noble rat model by Hsu A¹, Bruno RS, Löhr CV, Taylor AW, Dashwood RH, Bray TM, Ho E.(PubMed)
(32) The medicinal action of androgens and green tea epigallocatechin gallate by Liao S.(PubMed)
(33) Risk factors for surgery for prostatic hypertrophy by Morrison AS.(PubMed)
(34) Food groups and risk of benign prostatic hyperplasia. by Bravi F¹, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C.(PubMed)
(35) Benign prostatic hyperplasia: the opposite effects of alcohol and coffee intake by Gass R.(PubMed)
(36) Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate by Sarobo C¹, Lacorte LM, Martins M, Rinaldi JC, Moroz A, Scarano WR, Delella FK, Felisbino SL.(PubMed)
(37) Inhibition of the experimental induction of benign prostatic hyperplasia: a possible role for fluted pumpkin (Telfairia occidentalis Hook f.) seeds by Ejike CE¹, Ezeanyika LU.(PubMed)
(38) Effects of pumpkin seed oil and saw palmetto oil in Korean men with symptomatic benign prostatic hyperplasia by Hong H¹, Kim CS, Maeng S.(PubMed)
(39) Inhibition of testosterone-induced hyperplasia of the prostate of sprague-dawley rats by pumpkin seed oil by Gossell-Williams M¹, Davis A, O'Connor N.(PubMed)
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(41) Effects of coconut oil on testosterone-induced prostatic hyperplasia in Sprague-Dawley rats. by de Lourdes Arruzazabala M¹, Molina V, Más R, Carbajal D, Marrero D, González V, Rodríguez E.(PubMed)
(42) 5 alpha-reductase-catalyzed conversion of testosterone to dihydrotestosterone is increased in prostatic adenocarcinoma cells: suppression by 15-lipoxygenase metabolites of gamma-linolenic and eicosapentaenoic acids by Pham H¹, Ziboh VA.(PubMed)
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Ovarian Cancer in Foods' Points of View

Kyle J. Norton

Ovarian cancer is defined as a condition of  abnormal ovarian cells growth of ovaries.  It is one of most common cancer in US, according to the statistics adapted from the American Cancer Society's publication, Cancer Facts & Figures 2010, an estimated 21,880 women in the United States will be diagnosed with ovarian cancer, causing 3,850 deaths.
Depending to the stage and grade of the cancer, chemotherapy such as cisplatin, carboplatin, paclitaxel, liposomal doxorubicin may be necessary to prevent the spread and recurrence of the cancer. Epidemiological studies focusing in vegetables and fruits in reduced risk and treatment of ovarian cancer have not been conclusive(a)(b)(c)(d), some foods have showed to inhibit the progression of cancer with little or no side effects.

1. Cruciferous vegetables
Cruciferous vegetables are the group of  vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc. A meta-analysis of observational studies in reviews of a total of 4,306 cases in 375,562 controls in 11 independent studies indicated a positive effect of consumption of Cruciferous vegetables in a reduced risk of ovarian cancer(1). Isothiocyanates, antioxidants and chemical constituent in cruciferous vegetable, inhibited the cell viability of human ovarian cancer cells, through improved antioxidant status(2). Sulforaphane, SFN the active compound in  Isothiocyanates, inhibited the human ovarian cancer cell lines through down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types and up- regulate the cleaved poly(ADP-ribose) polymerase (PARP) after 6 days of treatment(3). In  cell lines MDAH 2774 and SkOV-3, SFN exhibited the suppression of growth in a dose-dependent manner by reduced cell migration and increased apoptotic cell death(4).

2. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties. Allium vegetables have been found in many studies to have an inverse association between the frequency of use of and the risk of several common cancers(5). In Human epithelial ovarian cancer cell line A2780, S-allylcysteine (SAC), , an antioxidant and chemical compound extracted from garlic, induced apoptosis through G1/S phase arrest by decreased the proliferative expression and increased expression of active of pro apoptosis(6). In human ovarian cancer cell lines, SAC and SAMC induced apoptosis through activation of E-cadherin(7).

3. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc. 6-shogaol, a chmeical constituent isolated from ginger showed to inhibited cell growth and modulated secretion of angiogenic factors in ovarian cancer cells, through activation of NF-kappaB and and production of VEGF(stimulation of vasculogenesis and angiogenesis) and IL-8(Interleukin 8, a chemokine of the immune system)(8). In human A549, SK-OV-3, SK-MEL-2, HCT15 tumor cells and the transgenic mouse ovarian cancer cell lines, 6-shogaol exhibited the most potent cytotoxicity against cell proliferation(9).

4. Curcumin
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in trditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
Curcumin, a major chemical compound found in turmeric, inhibited the proliferation of both cisplatin-resistant (CR) and sensitive (CS) human ovarian cancer cells through cell cycle arrest, by enhancing the p53 phosphorylation and apoptosis through the activation of caspase-3 followed by PARP degradation(10). E24, a novel curcumin analog, in platinum-sensitive (IGROV1) and platinum-resistant (SK-OV-3) human ovarian cancer cells, in  time- and dose-dependently suppressed the growth of both cell lines and synergized with cisplatin to induce apoptosis(11). The Dalhousie University study also showed a positive effect of curcumin in inhibition of ovarian cancer cell lines independently to p53 but involves p38 MAPK activation, ablation of prosurvival Akt signaling(role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration), and reduced expression of the antiapoptotic proteins Bcl-2 and surviving((baculoviral inhibitor)(12).

5. Tomatos Tomato is a red, edible fruit, genus Solanum, belonging to the family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose and often in green house.
In the study conduced by Brigham and Women's Hospital, lycopene found abundantly in tomato, was inversely associated to risk of ovarian cancer, predominantly in premenopausal women(13). and the Loma Linda University study also showed a significantly reduced risk of all ovarian cancer with higher tomato consumption in comparing intakes > or = five times/week versus never to < 1 time/week(14). But the reviews from FDA's  of the scientific data for tomato and/or lycopene intake with respect to risk reduction for certain forms of cancer, found very limited evidence to support an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers(15).

6. Red wine
Red wine made from anthocyan pigments of the skin of the grape
Resveratrol (trans-3,4',5-trihydroxystilbene; RES), a phytoestrogen, existed in grape skin and red wine showed to inhibited on estrogen-dependent ovarian cancer cells  proliferation, through cell cycle arrest at the G1 phase and increased the expression of p21(16). Other researchers suggested that a diet mixed with a dose of 100 mg resveratrol/kg body weight/day for 28 days exhibited effectively in suppressing the in vitro cellular invasion of NuTu-19 ovarian cancer cells(17). The University of Michigan study indicated the effectiveness of  Resveratrol (3,5,4-trihydroxystilbene) in inhibited growth and induced death in a panel of five human ovarian carcinoma cell lines, through association with mitochondrial release of cytochrome c, formation of the apoptosome complex, and caspase activation(18).

7. Organic soybean
Soybean is genus Glycine, the family Fabaceae, one of the legumes that contains twice as much protein per acre as any other major vegetable or grain crop, native to Southeast Asia. Now, it is grown worldwide with suitable climate for commercial profit and a healthy foods.
Genistein(7-difluoromethoxyl-5,4'-di-n-octyl ), as a major isoflavonoid isolated from dietary soybean, inhibited ovarian cancer cell growth and migration, through down-regulated miR-27a expression and significantly increased expression of Sprouty2, a putative miR-27a target gene(19) and on bisphenol A (BPA) or 17β-estradiol (E2)-induced cell growth and gene alterations of BG-1 ovarian cancer cells expressing estrogen receptors (ERs), GEN(Glycine) effectively suppressed BG-1 cell proliferation promoted by E2 or BPA throuh inhibiting cell cycle progression and decreased the expression of cyclin D1, a factor responsible for the G1/S cell cycle transition(20). According to the First Affiliated Hospital of Guangzhou Medical college, the derivative 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), a novel synthetic genistein, was more potent by exerting strongest activity against CoC1 and SKOV3 cells through cell cycle arrest in the G2/M phase and exhibited apoptotic cell death with concomitant attenuation of Forkhead box protein M1 (FoxM1)(a transcriptional activator involved in cell proliferation.)(21).

8. Olive oil
Olive is belongs to the family Oleaceae, native to the coastal areas of the eastern Mediterranean Basin and south end of the Caspian Sea. Its fruit, is also called the olive and the source of olive oil.
Accumulations of evidence suggested that Olive oil, an integral ingredient of the "Mediterranean diet" may play an important role  in lowering the risk of several types of cancer, including ovarian cancer, through suppressesion of HER2 at the transcriptional level by up-regulating the expression of the Ets protein PEA3 -a DNA-binding protein that specifically blocks HER2 promoter activity- in ovarian cancer cell lines(22). Data from a multicentre case-control study conducted between 1992 and 1999 in Italy, indicated a protective effect of olive oil against ovarian cancer in Italian population(23). Oleic acid, the main olive oil's monounsaturated fatty acid, showed to suppress the overexpression of HER2 (erbB-2), a well know nutation gene in expression of invasive progression and metastasis in several human cancers, including ovarian cancer(24). 

9. Green Tea 
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world. Recent study conducted in China also reported that green tea consumption reduced risk of ovarian cancer and increased survival post diagnosis(26).
"Green tea consumption suggested to enhance the survival of epithelial ovarian cancer", the cohort comprised 254 patients recruited during 1999-2000 with histopathologically confirmed epithelial ovarian cancer and followed up for a minimum of 3 years said, out of 254, 81 (77.9%) of 104 tea-drinkers who survived to the time of interview, compared to only 67 women (47.9%) still alive among the 140 non-drinkers(27). Epigallocatechin‑3‑gallate, phytochemical found in green tea EGCG significantly inhibited the proliferation of OVCAR‑3 cells in a time‑ and concentration‑dependent manner, through increased expression of the activity of p38/MAPK( control of stemness of glioma-initiating cells) and downregulation of the protein expression of MMP2(usually seen in invasive and highly tumorigenic cancers)(28). The study of combination of Epigallocatechin gallate and sulforaphane against paclitaxel-resistant ovarian cancer cells, showed to induced apoptosis of paclitaxel-resistant ovarian cancer cell lines through down-regulating of hTERT(Telomerase reverse transcriptase allows senescent cells that would otherwise become postmitotic and undergo apoptosis) and Bcl-2 and promote DNA damage response(29).


10. Rice bran
Rice bran contains layer between the inner white rice grain and the outer hull. Phytic acid (PA) isolated from rice bran induced marked growth inhibition in ovary, with 50% growth inhibition concentration (IC50)(30). In methanolic extracts from Njavara rice bran, showed to exhibit its anti-proliferative property in C6 glioma cells, possibly through superior antioxidant activity as evidenced by scavenging of free radicals including DPPH and NO(31).

12. Avocado
Avocados are a commercially valuable fruit and are cultivated in tropical climates throughout the world, it is a green-skinned, pear-shaped fruit that ripens after harvesting and native to the Caribbean, Mexico, South America and Central America, belonging to the flowering plant family Lauraceae.
Omega-6 polyunsaturated (n-6) fatty acids found in avocado inhibited the proliferation of ovarian cancer cell(32).

13. Fatty Fish
Fatty fish containing a large amounts of omega-3 fatty acids may be associated to reduced risk of ovarian cancer. High fish intake may be associated with a significantly reduced risk in the 2 case-control studies(33). The Southern Illinois University Carbondale, in hen study indicated that 175 and 700 mg/kg fish oil reduced proliferation and 700 mg/kg increased apoptosis in hen ovaries. may be an effective approach in preventing ovarian carcinogenesis(34).   

14. Flaxseed
Flax seed is native to the region of the eastern Mediterranean to India and also known as common flax or linseed. Flax is an erect annual plant, it can grow to 1.2 m tall. The leaves are 20–40 mm long and 3 mm broad. Omega-3 fatty acids (OM-3FAs) found in flaxseed, showed statistically significant inhibitory effect under the influence of OM-3FAs detected in all four cell lines, (SKOV-3 [p53 null], TOV-21G [wt p53] and OVCAR-3 [mutant p53]) and one immortalized ovarian surface epithelial cell line (IOSE-29)(35). In hens study, flaxseed mediated reduction in the severity of ovarian cancer, correlated to the reduction in PGE2 in the ovaries of flaxseed-fed hens(36). The Southern Illinois University study also indicated the effective of long term flaxseed enriched diet in decreased ovarian cancer incidence and prostaglandin E₂in hens(37).

Taking altogether, without going into reviews, the list above has found effectively in reduced risk and treatment of ovarian cancer, but further studies with large example size and multi centers are necessary to identify the principle ingredients to validate the their effectiveness. As always, All articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.


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References
(a) Fruit and vegetable consumption and risk of epithelial ovarian cancer: the European Prospective Investigation into Cancer and Nutrition by Schulz M¹, Lahmann PH, Boeing H, Hoffmann K, Allen N, Key TJ, Bingham S, Wirfält E, Berglund G, Lundin E, Hallmans G, Lukanova A, Martínez Garcia C, González CA, Tormo MJ, Quirós JR, Ardanaz E, Larrañaga N, Lund E, Gram IT, Skeie G, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, Büchner FL, Pasanisi P, Galasso R, Palli D, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Chang-Claude J, Linseisen J, Boutron-Ruault MC, Touillaud M, Clavel-Chapelon F, Olsen A, Tjønneland A, Overvad K, Tetsche M, Jenab M, Norat T, Kaaks R, Riboli E.(PubMed)
(b) Fruits and vegetables and ovarian cancer risk in a pooled analysis of 12 cohort studies by Koushik A¹, Hunter DJ, Spiegelman D, Anderson KE, Arslan AA, Beeson WL, van den Brandt PA, Buring JE, Cerhan JR, Colditz GA, Fraser GE, Freudenheim JL, Genkinger JM, Goldbohm RA, Hankinson SE, Koenig KL, Larsson SC, Leitzmann M, McCullough ML, Miller AB, Patel A, Rohan TE, Schatzkin A, Smit E, Willett WC, Wolk A, Zhang SM, Smith-Warner SA(PubMed).
(c) Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk by Riboli E¹, Norat T.(PubMed)
(d) Risk of ovarian carcinoma and consumption of vitamins A, C, and E and specific carotenoids: a prospective analysis by Fairfield KM¹, Hankinson SE, Rosner BA, Hunter DJ, Colditz GA, Willett WC.(PubMed)
(1) Cruciferous vegetables consumption and the risk of ovarian cancer: a meta-analysis of observational studies by Han B, Li X, Yu T(PubMed)
(2) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM¹, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)
(3) Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation by Chen H¹, Landen CN, Li Y, Alvarez RD, Tollefsbol TO(PubMed)
(4) Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells by Bryant CS¹, Kumar S, Chamala S, Shah J, Pal J, Haider M, Seward S, Qazi AM, Morris R, Semaan A, Shammas MA, Steffes C, Potti RB, Prasad M, Weaver DW, Batchu RB(PubMed).
(5) Onion and garlic use and human cancer by Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, Giacosa A, La Vecchia C.(PubMed)
(6) S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro by Xu YS¹, Feng JG², Zhang D³, Zhang B⁴, Luo M³, Su D⁵, Lin NM(PubMed)
(7) A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression by Chu Q¹, Ling MT, Feng H, Cheung HW, Tsao SW, Wang X, Wong YC.(PubMed)
(8) Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe by Kim JS¹, Lee SI, Park HW, Yang JH, Shin TY, Kim YC, Baek NI, Kim SH, Choi SU, Kwon BM, Leem KH, Jung MY, Kim DK.(PubMed)
(9) Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe by Kim JS¹, Lee SI, Park HW, Yang JH, Shin TY, Kim YC, Baek NI, Kim SH, Choi SU, Kwon BM, Leem KH, Jung MY, Kim DK.(PubMed)
(10) Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK by Weir NM¹, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridandapani S, Anant S, Kuppusamy P.(PubMed)
(11) Multiple anticancer activities of EF24, a novel curcumin analog, on human ovarian carcinoma cells by Tan X¹, Sidell N, Mancini A, Huang RP, Shenming Wang, Horowitz IR, Liotta DC, Taylor RN, Wieser F.(PubMed)
(12) Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling by Watson JL¹, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA, Hoskin DW.(PubMed)
(13) Carotenoids, antioxidants and ovarian cancer risk in pre- and postmenopausal women by Cramer DW¹, Kuper H, Harlow BL, Titus-Ernstoff L.(PubMed)
(14) Dietary risk factors for ovarian cancer: the Adventist Health Study (United States) by Kiani F¹, Knutsen S, Singh P, Ursin G, Fraser G.(PubMed)
(15) The U.S. Food and Drug Administration's evidence-based review for qualified health claims: tomatoes, lycopene, and cancer by Kavanaugh CJ¹, Trumbo PR, Ellwood KC(PubMed)
(16) Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression by Kang NH¹, Hwang KA, Kim TH, Hyun SH, Jeung EB, Choi KC.(PubMed)
(17) Resveratrol exerts differential effects in vitro and in vivo against ovarian cancer cells by Stakleff KS¹, Sloan T, Blanco D, Marcanthony S, Booth TD, Bishayee A.(PubMed)
(18) Resveratrol-induced autophagocytosis in ovarian cancer cells by Opipari AW Jr¹, Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR.(PubMed)
(19) Oncogenic MicroRNA-27a is a target for genistein in ovarian cancer cells by Xu L¹, Xiang J, Shen J, Zou X, Zhai S, Yin Y, Li P, Wang X, Sun Q.(PubMed)
(20) Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression by Hwang KA¹, Kang NH, Yi BR, Lee HR, Park MA, Choi KC.(PubMed)
(21) Apoptosis induced by 7-difluoromethoxyl-5,4'-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells by Ning Y¹, Li Q, Xiang H, Liu F, Cao J.(PubMed)
(22) Mediterranean diet, olive oil and cancer by Colomer R¹, Menéndez JA.(PubMed)
(23) Olive oil, seed oils and other added fats in relation to ovarian cancer (Italy) by Bosetti C¹, Negri E, Franceschi S, Talamini R, Montella M, Conti E, Lagiou P, Parazzini F, La Vecchia C.(PubMed)
(24) Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9) by Menendez JA¹, Lupu R.(PubMed).
(25) Green tea consumption enhances survival of epithelial ovarian cancer by Zhang M¹, Lee AH, Binns CW, Xie X.(PubMed)
(26) Possible role for green tea in ovarian cancer prevention by Lee AH¹, Fraser ML, Binns CW.(PubMed)
(27) Epigallocatechin‑3‑gallate inhibits the proliferation and migration of human ovarian carcinoma cells by modulating p38 kinase and matrix metalloproteinase‑2 by Wang F, Chang Z, Fan Q, Wang L.(PubMed)
(28) Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation by Chen H¹, Landen CN, Li Y, Alvarez RD, Tollefsbol TO.(PubMed)
(29) Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation by Chen H¹, Landen CN, Li Y, Alvarez RD, Tollefsbol TO.(PubMed)
(30) Antioxidant and cytotoxicity effect of rice bran phytic acid as an anticancer agent on ovarian, breast and liver cancer cell lines by Norhaizan ME¹, Ng SK, Norashareena MS, Abdah MA.(PubMed)
(31) The antioxidant and antiproliferative activities of methanolic extracts from Njavara rice bran by Rao AS¹, Reddy SG, Babu PP, Reddy AR.(PubMed)
(32) Intake of omega-3 and omega-6 fatty acids and risk of ovarian cancer by Ibiebele TI¹, Nagle CM, Bain CJ, Webb PM.(PubMed)
 (33) Meat, fish, and ovarian cancer risk: Results from 2 Australian case-control studies, a systematic review, and meta-analysis by Kolahdooz F¹, van der Pols JC, Bain CJ, Marks GC, Hughes MC, Whiteman DC, Webb PM; Australian Cancer Study (Ovarian Cancer) and the Australian Ovarian Cancer Study Group.(PubMed)
(34) Anti-inflammatory effects of fish oil in ovaries of laying hens target prostaglandin pathways by Eilati E, Small CC, McGee SR, Kurrey NK, Hales DB¹(PubMed)

(35) The effects of Omega-3 fatty acids on growth regulation of epithelial ovarian cancer cell lines by Sharma A¹, Belna J, Logan J, Espat J, Hurteau JA(PubMed)
(36) Flaxseed enriched diet-mediated reduction in ovarian cancer severity is correlated to the reduction of prostaglandin E(2) in laying hen ovaries by Eilati E¹, Hales K, Zhuge Y, Ansenberger Fricano K, Yu R, van Breemen RB, Hales DB(PubMed)
(37) Long term consumption of flaxseed enriched diet decreased ovarian cancer incidence and prostaglandin E₂in hens by Eilati E¹, Bahr JM, Hales DB.(PubMed)

Alzheimer's disease in B Vitamins Points of view

Kyle J. Norton

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal. According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
The B Vitamin are a group of water-soluble vitamins found abundantly in whole grains, potatoes, bananas, lentils, chili peppers, tempeh, beans, nutritional yeast, brewer's yeast,  molasses, etc. The vitamins are essential for normal cellular growth and function and best known for converting energy from protein, fat, and carbohydrates during metabolism.

1. B vitamins and elevated plasma homocysteine
Hyperhomocysteinemia is one of the risk factors of AD.(1). B vitamins showed to slow the atrophy of specific brain regions which contribute to cognitive decline and influenced the progression of Alzheimer's' disease, through lowering elevated plasma homocysteine, according to the University of Oxford(2). A ingle-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B(6) and B(12) in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment confirmed that the homocysteine-lowering by B vitamins through inhibition of accelerated brain atrophy in prevention of mild cognitive impairment conversion to Alzheimer's disease.(3)(4). Raising plasma total homocysteine may be a strong prognostic marker of future cognitive decline, by targeting the low-normal concentrations of the B vitamins in lowering the levels of elevated of homocysteine concentrations, but large-scale randomized trials of homocysteine-lowering vitamins are necessary to validate these effectiveness(5).

2. The conflict results
Epidemiological studies, linking dietary supplementation of B vitamin in reduced risk of Alzheimers' diseases have been inconclusive. According to the study at the School of Medicine, Qingdao University, dietary supplementation of antioxidants, including B vitamins, are beneficial to AD(6). Other study suggest that a formula of shilajit with B complex vitamins, may emerge as novel nutraceutical with potential uses against this brain disorder(7). Some researchers suggested that nutritional compositions, including B vitamins to stimulate synapse formation (between neurons in the nervous system) effectively reduce Alzheimer Disease neuropathology. These preclinical models provides a solid basis to predict potential to modify the disease process, especially during the early phases of Alzheimer Disease(8).
 On the other hand, the study by University of California in a multicenter, randomized, double-blind controlled clinical trial, indicated that high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD and In 89 patients (45 men, 44 women; all Taiwanese; mean [SD] age, 75 [7.3] years) randomized study, no statistically significant beneficial effects on cognition or change in performance of activities of daily living (ADLs) function between multivitamin and placebo at 26 weeks(8).

Taking altogether, B vitamins may be effective in reduced levels of Hyperhomocysteinemia of which indicated an early onset of Alzheimers' disease. Combination use of B vitamins and other micronutrients and antioxidants may be associated in reduced risk and treatment of the disease. As always, All articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.



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References
(1) [The clinical studies of hyperhomocysteinemia and Alzheimer's disease].[Article in Chinese]by Li YL¹, Hou Y, Niu C, Yu LX, Cheng YY, Hong Y.(PubMed)
(2) Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment by Douaud G¹, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD(PubMed)
(3) Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial by Smith AD¹, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H(PubMed)
(4) Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment by Douaud G¹, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD.(PubMed)
(5) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? by Smith AD.(PubMed)
(6) Nutrition and the risk of Alzheimer's disease by Hu N¹, Yu JT, Tan L, Wang YL, Sun L, Tan L.(PubMed)
(7) Can nutraceuticals prevent Alzheimer's disease? Potential therapeutic role of a formulation containing shilajit and complex B vitamins by Carrasco-Gallardo C¹, Farías GA, Fuentes P, Crespo F, Maccioni RB.(PubMed)
(8) The potential role of nutritional components in the management of Alzheimer's Disease by van der Beek EM¹, Kamphuis PJ.(PubMed)
(9) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial by Aisen PS¹, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study(PubMed)
(10) Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients by Sun Y¹, Lu CJ, Chien KL, Chen ST, Chen RC.(PubMed)

Alzheimer's disease in Vitamin E Points of view

Alzheimer's disease is a brain disorder correlated with major reduction of neurons to the respective target  areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
Vitamin E,  a fat soluble vitamin, consisting eight different variants (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) with varying levels of biological activity(2), found abundantly in corn oil, soybean oil, margarine, wheat germ oil, sunflower,safflower oils, etc. plays an important role in neurological functions and inhibition of platelet aggregation, regulation of enzymatic activity, free radical scavenger, etc..

1. The serum of vitamin E
Epidemiological studies, in determination of the forms of vitamin E in reduced risk of Alzheimers disease have been inclusive. According to the joint study by the University and University of Perugia,  elevated levels of tocopherol and tocotrienol forms are associated with reduced risk of cognitive impairment in older adults(1). In other study of vitamin E and risk if AD in advanced age, high plasma levels of beta-tocopherol was associated to reduced risk of developing AD but levels of alpha-tocopherol, alpha- tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model(2). The differentiation of vitamin E marker in mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects, suggested nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of the onset of AD(3). Other researchers suggest that various tocopherol forms rather than alpha- tocopherol alone may be important in the vitamin E protective association with Alzheimer disease(4) and low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD(5)(6).

2. The conflict results
A Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD, combination of 2000 IU/d of alpha tocopherol and memantine, exhibited the slower functional decline in mild to moderate AD(7). A placebo-controlled, clinical trial of vitamin E in patients with moderately advanced Alzheimer disease treatment with with 2000 IU (1342 alpha-tocopherol equivalents) vitamin E/d. may slow functional deterioration and prevent a clinical diagnosis of Alzheimer disease in elderly persons with mild cognitive impairment(8).  In the testing of the hypothesis of oxygen free radicals are probably involved in the deterioration of cognitive function, showed a positive effect of  alpha-tocopherol in reduced risk of the cognitive impairment but inconsistent for women taking vitamin E alone, with no evidence of higher scores with longer durations of use(9). The double-blind, randomized trials in which treatment with vitamin E at any dose was compared with placebo for patients with mild cognitive impairment (MCI) and Alzheimer's dementia (AD) showed a positive effects of vitamin E in  treatment of AD or MCI, but future trials assessing vitamin E treatment in AD should not be restricted to alpha-tocopherol(10). Unfortunately, there is no evidence of vitamin E in the prevention or treatment of people with AD or MCI, according to the study by the Milton Court Resourse Centre(11) and The Maudsley Hospital(12).

Taking altogether, without going into reviews, serum of vitamin E and vitamin E may be used as an indicator for the early onset and in reduced risk and treatment of Alzheimers' disease respectivelt. Over doses of vitamin E supplement can cause symptoms of blurred vision, weakness, dizziness, nausea, diarrhea, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.



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References
(1) Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults by Mangialasche F¹, Solomon A, Kåreholt I, Hooshmand B, Cecchetti R, Fratiglioni L, Soininen H, Laatikainen T, Mecocci P, Kivipelto M.(PubMed)
(2) High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in advanced age by Mangialasche F¹, Kivipelto M, Mecocci P, Rizzuto D, Palmer K, Winblad B, Fratiglioni L.(PubMed)
(3) Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol by Mangialasche F¹, Westman E, Kivipelto M, Muehlboeck JS, Cecchetti R, Baglioni M, Tarducci R, Gobbi G, Floridi P, Soininen H, Kłoszewska I, Tsolaki M, Vellas B, Spenger C, Lovestone S, Wahlund LO, Simmons A, Mecocci P; AddNeuroMed consortium.(PubMed)
(4) Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change by Morris MC¹, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, Scherr PA(PubMed)

(5) Tocopherols and tocotrienols plasma levels are associated with cognitive impairment by Mangialasche F¹, Xu W, Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, Cecchetti R, Baglioni M, Simmons A, Soininen H, Tsolaki M, Kloszewska I, Vellas B, Lovestone S, Mecocci P; AddNeuroMed Consortium.(PubMed)
(6) Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults by Mangialasche F¹, Solomon A, Kåreholt I, Hooshmand B, Cecchetti R, Fratiglioni L, Soininen H, Laatikainen T, Mecocci P, Kivipelto M.(PubMed)

(7) Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial by Dysken MW¹, Sano M², Asthana S³, Vertrees JE⁴, Pallaki M⁵, Llorente M⁶, Love S¹, Schellenberg GD⁷, McCarten JR¹, Malphurs J⁸, Prieto S⁸, Chen P⁵, Loreck DJ⁹, Trapp G¹⁰, Bakshi RS¹⁰, Mintzer JE¹¹, Heidebrink JL¹², Vidal-Cardona A¹³, Arroyo LM¹³, Cruz AR¹⁴, Zachariah S¹⁴, Kowall NW¹⁵, Chopra MP¹⁵, Craft S¹⁶, Thielke S¹⁶, Turvey CL¹⁷, Woodman C¹⁷, Monnell KA¹⁸, Gordon K¹⁸, Tomaska J¹, Segal Y¹, Peduzzi PN¹⁹, Guarino PD.(PubMed)
(8) Vitamin E and Alzheimer disease: the basis for additional clinical trials by Grundman M.(PubMed)
(9) High-dose antioxidant supplements and cognitive function in community-dwelling elderly women by Grodstein F¹, Chen J, Willett WC.(PubMed)
(10) Vitamin E for Alzheimer's dementia and mild cognitive impairment by Farina N¹, Isaac MG, Clark AR, Rusted J, Tabet N.(PubMed|)
(11) Vitamin E for Alzheimer's disease and mild cognitive impairment by Isaac MG¹, Quinn R, Tabet N.(PubMed)
(12) Vitamin E for Alzheimer's disease by Tabet N¹, Birks J, Grimley Evans J.(PubMed)

Alzheimer's disease in Vitamin D Points of view

 Kyle J. Norton

Alzheimer's disease is a brain disorder correlated with major reduction of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
Vitamin D is a fat-soluble secosteroids found in small amount in few foods, including salmon, mackerel, sardines and tuna. The vitamin plays an important role in modulation of cellular proliferation, apoptosis induction, tumor growth suppression and promotion in absorption of minerals, including calcium, iron, magnesium, phosphate and zinc.

1. Vitamin D receptors(VDR)
Vitamin D receptors, also known as NR1I1 (nuclear receptor subfamily 1, group I, member 1), with functions of regulation in many metabolic pathways, including cancers, play an important role in risk of Alzheimers' disease. Polymorphisms in the vitamin D receptor (VDR), and insufficient serum 25 hydroxyvitamin D₃ levels patients have been found to associate with age- dependent cognitive decline(1). The study of Vitamin D(3), a neurosteroid that mediates its effects via the vitamin D receptor (VDR) also indicated  a possible link between AD and certain VDR polymorphisms in early onset of  AD(2) through suppression of VDR by Aβ(3). Treatment of Vitamin D was found effectively in inhibition of Aβ induced alterations in primary cortical neurons(4). The Istanbul University in study of the association of between VDR gene and late-onset Alzheimer's disease (AD) with 104 cases of dementia of Alzheimer type and 109 age-matched controls, showed an significant increased Aa genotype in AD patients than health individuals with the same genotype, of that may be an indication of "Aa" genotype associated to increased risk of developing AD. In the comparison of "AA" genotype, risk of AD in men with Aa genotyes  are 2.3 times higher(5).

2, Plasma of vitamin D
Suggestion of serum levels of vitamin D used as diagnosis for indication of early onset of Alzheimer's' diseases may be controversial. Some researchers suggested that lower plasma nutrient levels  only a indication for impaired systemic availability of several nutrients in AD(6). The Kingston University study showed level of 25hydroxyvitamin D (25OHD) was found to be lower in patients with the disease, arising from extremely low levels of 25OHD2 along with low levels of 25OHD3.(7). In the study of the correlation of Alzheimer's disease and osteoporosis, the Heinrich-Heine-University showed that 25 (OH) vitamin D plasma levels were low normal and of equal amount in all groups except for the osteoporosis group(8).

The benefits
Epidemiological studies, focusing vitamin D and its derivative in reduced risk of Alzheimer's diseases have not been consistent. Researchers indicated that Gene polymorphisms alternation of vitamin D metabolism are also associated with a higher incidence or a worse disease prognosis, and despite the links between vitamin D deficiency and the risks of developing neurological disorders, there is, to date, no proof that supplementation could alter the course of these diseases(9). Study of the effects of vitamin D showed an indication of prevention of neurons cytotoxicity and apoptosis through downregulating  LVSCC A1C(L-type voltage-sensitive calcium channel with function of gene expression, synaptic efficacy, and cell survival) and upregulating VDR and balancing nerve growth factor (NGF) expressions(10). Researchers at the ¹Vietnamese American Medical Research Foundation, suggested that vitamin D supplements appeared beneficial to patients of AD through many mechanisms including regulating micro-RNA, enhancing toll-like receptors, modulating vascular endothelial factor expression, angiogenin, and advanced glycation end products, etc.(11). The combination of memantine with vitamin D, a neurosteroid hormone, in the joint study, showed an evidence lesser cortical axons degeneration after exposure to amyloid-beta peptide or glutamate in microfluidic neuronal cultures.(12). Unfortunately, regardless to the effectiveness of vitamin D in reduced risk of cognitive impairment or Aβ, many researchers still believed that there is no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment(13).

Taking altogether, without going into reviews, vitamin D may be considered as a therapeutic treatment in reduced risk of Alzheimers' diseases, through many mechanisms, including induction of Aβ, regulation of micro-RNA expression, etc.. Over doses of vitamin D supplement may cause excessive calcium absorption, calcification, Urinary stones etc. please make sure to follow the guideline of the Institute of Medicine of the National Academies.



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References
(1) A novel perspective for Alzheimer's disease: vitamin D receptor suppression by amyloid-β and preventing the amyloid-β induced alterations by vitamin D in cortical neurons by Dursun E¹, Gezen-Ak D, Yilmazer S.(PubMed)
(2) Vitamin D receptor gene haplotype is associated with late-onset Alzheimer's disease.

Gezen-Ak D¹, Dursun E, Bilgiç B, Hanağasi H, Ertan T, Gürvit H, Emre M, Eker E, Ulutin T, Uysal O, Yilmazer S.(PubMed)
(3) A new mechanism for amyloid-β induction of iNOS: vitamin D-VDR pathway disruption by Dursun E¹, Gezen-Ak D, Yilmazer S(PubMed)
(4) A novel perspective for Alzheimer's disease: vitamin D receptor suppression by amyloid-β and preventing the amyloid-β induced alterations by vitamin D in cortical neurons by Dursun E¹, Gezen-Ak D, Yilmazer S(PubMed)

(5) Association between vitamin D receptor gene polymorphism and Alzheimer's disease.

Gezen-Ak D¹, Dursun E, Ertan T, Hanağasi H, Gürvit H, Emre M, Eker E, Oztürk M, Engin F, Yilmazer S.(PubMed)
(6) Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis by Lopes da Silva S¹, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, Sijben J, Groenendijk M, Stijnen T.(PubMed)
(7) Low 25OH vitamin D2 levels found in untreated Alzheimer's patients, compared to acetylcholinesterase-inhibitor treated and controls by Shah I¹, Petroczi A, Tabet N, Klugman A, Isaac M, Naughton DP.(PubMed)
(8) Blood biomarkers of osteoporosis in mild cognitive impairment and Alzheimer's disease by Luckhaus C¹, Mahabadi B, Grass-Kapanke B, Jänner M, Willenberg H, Jäger M, Supprian T, Fehsel K.(PubMed)
(9) [Vitamin D and neurology].[Article in French] by Thouvenot ɹ, Camu W(PubMed)

(10) The Effects of Vitamin D Receptor Silencing on the Expression of LVSCC-A1C and LVSCC-A1D and the Release of NGF in Cortical Neurons by Duygu Gezen-Ak, Erdinç Dursun, and Selma Yilmazer(PubMed)
(11) The role of vitamin D in Alzheimer's disease: possible genetic and cell signaling mechanisms by Lu'o'ng KV¹, Nguyen LT.(PubMed)
(12) Combination of memantine and vitamin D prevents axon degeneration induced by amyloid-beta and glutamate by Annweiler C¹, Brugg B, Peyrin JM, Bartha R, Beauchet O(PubMed)

Alzheimer's disease in Vitamin C Points of view

 Kyle J. Norton

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support.

Epidemiological studies, linking vitamin C in reduced risk of Alzheimers' disease may be inconclusive. 
But some researchers in the survey of Alzheimers' patients found inadequate dietary vitamin C due to low intake of vegetables and fruits(1). The study from Vanderbilt University Medical Center showed a positive effect in maintaining healthy vitamin C levels enhanced  protective function against age-related cognitive decline and Alzheimer's disease, but avoiding vitamin C deficiency would be more beneficiary than taking supplements(2). On the basis of the meta-analysis studies published up to October 2011 between in Medline and Scopus databases, dietary intakes of the three antioxidants (vitamin E, vitamin C, and β-carotene) can lower the risk of AD(3). Vitamin complex included ascorbic acid, alpha-tocopherol, and beta-carotene, showed to reduce oxidative stress in PBMNC of AD patients through lowering ROS (Reactive oxygen species)  production, improved cellular antioxidant capacities and modified cytokine induced inflammation(4). Aβ42 aggregation induced neurotoxicity, causing synaptic dysfunction and  induced tissue oxidation (DNA/RNA, proteins, and lipids), trace metals may be inhibited by antioxidants such as vitamin C through conversion of toxic superoxide radical to less reactive hydrogen peroxide, contributing to protection from AD(5). Other suggested that since intracellular ascorbate serves several functions in the CNS, including antioxidant protection, peptide amidation, myelin formation, synaptic potentiation, and protection against glutamate toxicity, it may protect neurons from the oxidant damage associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's(6). Unfortunately, in Oral supplementation of vitamin C and vitamin E therapy against Alzheimers' disease conducted by Auburn University detected no difference in the incidence of AD during the 4-year follow-up, and suggested vitamin C should not be recommended due to  lack of consistent efficacy data of vitamin C in preventing or treating AD(7)(8) and a cross-sectional study, plasma Aβ40 and Aβ42 and dietary data obtained from 1,219 cognitively healthy elderly with age >65 years, found no association of vitamins complex correlated with plasma Aβ levels(9).

Taking altogether, composition of vitamin complex included vitamin C may be effective in reduced risk of Alzheimers' disease and treatment through protection of neurons from oxidative damage, against glutamate toxicity, etc. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(10)(11).


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References
(1) Dietary fat and antioxidant vitamin intake in patients of neurodegenerative disease in a rural region of Jalisco, Mexico by Navarro-Meza M, Gabriel-Ortiz G, Pacheco-Moisés FP, Cruz-Ramos JA, López-Espinoza A.(PubMed) 
(2) A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease by Harrison FE.(PubMed)
(3) Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis by Li FJ¹, Shen L, Ji HF.(PubMed)
(4) Ascorbic acid, alpha-tocopherol, and beta-carotene reduce oxidative stress and proinflammatory cytokines in mononuclear cells of Alzheimer's disease patients by de Oliveira BF, Veloso CA, Nogueira-Machado JA, de Moraes EN, Santos RR, Cintra MT, Chaves MM.(PubMed)
(5) Formation of the 42-mer Amyloid β Radical and the Therapeutic Role of Superoxide Dismutase in Alzheimer's Disease by Murakami K¹, Shimizu T, Irie K.(PubMed)
(6) Vitamin C transport and its role in the central nervous system by May JM.(PubMed)
(7)Vitamin C and vitamin E for Alzheimer's disease by Boothby LA¹, Doering PL.(PubMed) 
(8) Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer's disease by Arlt S¹, Müller-Thomsen T, Beisiegel U, Kontush A.(PubMed)
(9) Nutrient intake and plasma β-amyloid by Gu Y¹, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N.(PubMed)

(10) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)

(11) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)