Sunday 16 March 2014

Alzheimer's disease in Foods, Herbs and Vitamins Points of View

By Kyle J. Norton

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas, named after German physician Alois Alzheimer. Alzheimer's destroys 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. It may be a result of  cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions and psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity)(1) Strong evidences emerged in epidemiological studies suggested that certain foods(2) may have potential in reduced risk and treatments of Alzheimer's disease.


I. Types of Foods Reduced risk of Alzheimer's disease

1. Cruciferous vegetables
Cruciferous vegetables are the group of vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc..
Epidemiological studies has demonstrated reduced risk of Alzheimer's disease in cruciferous consumption. The study of 2148 community-based elderly subjects (aged > or = 65 years) without dementia in New York, after 3.9 years,  253 subjects developed AD during a follow-up. Dietary pattern (DP) analysis of food combination indicated that higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter are associated to reduced risk of  AD.(1)

2. Tomatos
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.
Lycopene and alpha carotene found in tometos inhibited symptoms of AD through inhibition of amyloid beta (Aβ) formation, deposition and fibril formation either by reducing the levels of p35 or inhibiting corresponding enzymes(2). In the study of Antioxidants, such as tocopherols and carotenoids,  implicated in the prevention of degenerative diseases showed that aging population exhibit a age related decline of levels retinol, total tocopherols, total xanthophylls and total carotenoids(3).

3. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties.
 S-allyl-L-cysteine (SAC), an active chemical constituents of garlic, showed to inhibit several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. through up and down regulations(4) with intervention to prevent free radicals causes of deterioration of cognitive functions and neurobehavioral activities(5). The Central Food Technological Research Institute supported the binding ability of SAC to Abeta, inducing a partially folded conformation in Abeta.(6) and suggested that consumption of garlic may reduced risk of AD, due to inhibition of Abeta aggregation in human brain(7).

4. 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.
In the Alzheimer disease (AD) rat model, ginger root extract (GRE) administered intra-gastrically to rats after 35 days, exhibited the protective effect against AD through reversed behavioral dysfunction and prevented AD-like symptoms(8).  [6]-gingerol, a pungent ingredient of ginger, pretreatment protected against Aβ(25-35)-induced cytotoxicity and apoptotic cell death such as DNA fragmentation, disruption of mitochondrial membrane potential, elevated Bax/Bcl-2 ratio, and activation of caspase-3 via augmentation of antioxidant capacity(9) and inhibition of acetylcholinesterase activities and prevention of lipid peroxidation in the brain(10).

5. Turmeric
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 traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc. 
Evidences of epidemiological studies suggestion of curcumin in reduced risk of Ad progression. Suggestion of curcumin in treating Alzheimer's disease (AD) depended on the ability to penetrate the blood-brain barrier(11) and on inhibited progression of deposit of  beta-amyloid aggregation.(12).
A novel polymeric nanoparticle (PEG-PLGA) encapsulated curcumin, induced adult neurogenesis through activation of the canonical Wnt/β-catenin pathway(secreted signalling proteins  released by one cell population will trigger concentration-dependent responses in other cells located some distance away)(13) and brain self-repair mechanis(14).  Unfortunately, a 24-week randomized, double blind, placebo-controlled study conducted by the David Geffen School of Medicine at UCLA, oral administration showed no biochemical evidence of efficacy of Curcumin C3 Complex® in AD(15).

6. Cinnamon
Cinnamon is a spice derived from the inner bark of tree, native to South East Asia, of over 300 species of the genus Cinnamomum, belonging to the family Lauraceae.. The herb has been use in herbal and traditional medicine as anti-fungal and bacteria level to improve reproductive organ, prevent flatulence and intestinal cramping, treat indigestion, diarrhea, bad breath, headache, migraine, etc.
Aqueous extract of cinnamon showed to inhibit tau aggregation in vitro and can even induce dissociation of tangles isolated from AD brain and cinnamaldehyde (CA). The organic compound of cinnamon
protected tau from oxidation caused by the reactive oxygen species, H2O2, and prevented subsequent formation of high molecular weight species that are considered to stimulate tangle formation(16) and inhibited tau aggregation associated with Alzheimer's disease in vitro(17). Other study insisted that cinnamon extract (CEppt), markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells and oral administration in AD patients, showed to reduce longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in the brain(18).

7. Black pepper
Black pepper is a  is a flowering vine in the genus Pipper, belonging to the family Piperaceae. It has been used in folk medicine in treating constipation, diarrhea, earache, gangrene, heart disease, hernia, hoarseness, indigestion, insect bites, insomnia, joint pain, etc.
Piperine, a main active alkaloid in black pepper exhibited significantly improved memory impairment and neurodegeneration in hippocampus associated with the decrease lipid peroxidation and acetylcholinesterase enzyme(19). In the evaluation the Piperine therapeutic effects in Alzheimer's Disease, at 2 mg/kg dose, reduced the SOD values, immobility and has shown superior results than Donepezil (5 mg/kg), AD drug and increased the acetylcholenesterase values(20).

8. 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.
Green tea polyphenols (GTPs) may be a next potential agent in protection of neurodegenerative diseases such as Alzheimer's disease (AD). GTPs have found to inhibit amyloid fibril formation and protect neurons from toxicity induced by β-amyloid and OA-induced neurotoxicity by enhancing the amelioration of learning and memory impairments and also reduction of tau hyperphosphorylation(21). Epigallocatechin gallate polyphenols, isolated from green tea, a selective inhibitor of PKC., combination of EGCG and resveratrol protected against GF 109203X-induced cell death and cytoskeleton degeneration, with a maximal effect at 1 and 3 μM, respectively and cells treated increased PKC gamma (γ) activation and promoted neuronal interconnections(22). (-)-epigallocatechin-3 gallate (EGCG) alone also showed to reduce amyloid-β (Aβ) production in both neuronal and mouse Alzheimer's disease (AD) models(23).

9. Coffee
Coffee made from the roasted seeds of the genus Coffee, belonging to the family Rubiaceae native to southern Arabia. Coffee may consist certain substances, effecting the risk of Alzheimers' disease. AD mice given caffeine in their drinking water from young adulthood into older age showed to inhibit memory and cognitive impairment and lower brain levels of amyloid-beta; Abeta)(24)(25). In mice with Alzheimers' disease caused by dysregulated endoplasmic reticulum (ER) calcium (Ca 2+), induced deletion of RyanR3, showed the enhancement of coffee in activation of RyanRs which protected AD neurons from synaptic and network dysfunction(26). Intake of 5 cups of coffee per day(moderate caffeine intake) found to protect against the development of certain cognitive impairment and decreased hippocampal amyloid-beta (Abeta) levels through suppression of both beta-secretase (BACE1), a beta-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 (PS1)/gamma-secretase expression(mutations in the presenilin proteins)(27)(28).

10. Red wine
Red wine made from made  dark-coloured (black) grape varieties as a result of anthocyan pigments  present in the skin of the grape.
Red wine may be a therapeutic potential  for treating AD patients through reduction of forming of beta-amyloid peptid. In human umbilical vein endothelial cells (HUVECs), black grape skin extract inhibited the ROS production, protected the cellular membrane from oxidative damage, and consequently prevented DNA fragmentation(29).  Red wine extract resveratrol, in another study inhibited the expression of soluble oligomers of the amyloid-β (Aβ) peptide cause of neurotoxicity, synaptic dysfunction, and memory impairments(30). Polyphenols derived from red wine, according to Mount Sinai School of Medicine, New York, may protect against cognitive deterioration of Alzheimer's disease, thriugh generation and assembly of β-amyloid peptides into neurotoxic oligomeric aggregated species(31).

10. Olive oil
Olive is belongs to the 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.
Oleuropein aglycone, the main polyphenol derived from extra virgin olive oil, in the study of the double transgenic TgCRND8 mice, showed to improve the cognitive performance and reduce ß-amyloid levels and plaque deposits, through  increase of autophagic markers expression and of lysosomal (break down waste materials and cellular debris)activity(32), induction of the Aβ transgene expression(33) and enhancement of Aβ clearance from the brain(34). The study by VA Medical Center, also found that EVOO inhibited learning and memory deficits found in aging and diseases, due to overproduction of amyloid-β protein, and reversed oxidative damage in the brain(35).

11. Fish oil
Fish oil derived from the tissues of oily fish, contains high amount of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), etc.
Epidemiological studies suggested that higher dietary intake of ω-3 PUFA reduced risk of incident AD and slower cognitive decline(36) through reduction of plasma levels of Aβ42(37) and may be through induced the PTEN expression(ova tumor suppressor gene) by activation of peroxisome proliferator-activated receptor(regulating the expression of genes)(38). Genetically, defection of the ε4 allele of the APOE gene (APOE4), according to the Central Michigan University, in the mu-p75 saporin (SAP)-induced mouse model of AD, daily treatments of Cerise(®) Total-Body-Rhythm™ (TBR; containing tart cherry extract, Nordic fish oil, and refined emu oil), reduced the severity of cognitive deficits in disorders involving cholinergic deficits(39). 

Taking altogether, without going into reviews, The list of foods above may be effective in reduced risk and treatment of Alzheimers' disease through improvement of cognitive function, via reduced plasma levels of Aβ42 and ß-amyloid and plaque deposits. Some researchers suggested that larger sample and multi centers studies are necessary to identify the principle ingredients for validation of 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
(1) Food combination and Alzheimer disease risk: a protective diet by Gu Y1, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N.(PubMed)
(2) Carotenoids and Alzheimer's disease: an insight into therapeutic role of retinoids in animal models by Obulesu M1, Dowlathabad MR, Bramhachari PV.(PubMed)
(3) Carotenoid, tocopherol, and retinol concentrations in elderly human brain by Craft NE1, Haitema TB, Garnett KM, Fitch KA, Dorey CK.(PubMed)
(4) The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD) by Ray B1, Chauhan NB, Lahiri DK.(PubMed)
(5) S-allyl cysteine attenuates oxidative stress associated cognitive impairment and neurodegeneration in mouse model of streptozotocin-induced experimental dementia of Alzheimer's type by Javed H1, Khan MM, Khan A, Vaibhav K, Ahmad A, Khuwaja G, Ahmed ME, Raza SS, Ashafaq M, Tabassum R, Siddiqui MS, El-Agnaf OM, Safhi MM, Islam F.(PubMed)
(6) Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer's beta-amyloid fibrils in vitro by Gupta VB1, Rao KS.(PubMed)
(7) Garlic extract exhibits antiamyloidogenic activity on amyloid-beta fibrillogenesis: relevance to Alzheimer's disease by Gupta VB1, Indi SS, Rao KS(PubMed)
(8) Protective effects of ginger root extract on Alzheimer disease-induced behavioral dysfunction in rats by Zeng GF1, Zhang ZY, Lu L, Xiao DQ, Zong SH, He JM.(PubMed)
(9) [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system by Lee C1, Park GH, Kim CY, Jang JH.(PubMed)
(10) Inhibition of acetylcholinesterase activities and some pro-oxidant induced lipid peroxidation in rat brain by two varieties of ginger (Zingiber officinale) by Oboh G1, Ademiluyi AO, Akinyemi AJ.(PubMed)
(11) Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer's disease Tg2576 mice by Cheng KK1, Yeung CF, Ho SW, Chow SF, Chow AH, Baum L.(PubMed)
(12) Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study by Ringman JM1, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM.(PubMed)
(13) Curcumin-Loaded Nanoparticles Potently Induce Adult Neurogenesis and Reverse Cognitive Deficits in Alzheimer's Disease Model via Canonical Wnt/β-Catenin Pathway by Tiwari SK1, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK, Gupta KC.(PubMed)
(14) Curcumin-Loaded Nanoparticles Potently Induce Adult Neurogenesis and Reverse Cognitive Deficits in Alzheimer's Disease Model via Canonical Wnt/β-Catenin Pathway by Tiwari SK1, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK, Gupta KC.(PubMed)
(15) Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study by Ringman JM1, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM.(PubMed)
(16) Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis by George RC1, Lew J, Graves DJ.(PubMed)
(17) Cinnamon extract inhibits tau aggregation associated with Alzheimer's disease in vitro by Peterson DW1, George RC, Scaramozzino F, LaPointe NE, Anderson RA, Graves DJ, Lew J.(PubMed)
(18) Orally administrated cinnamon extract reduces β-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models by Frydman-Marom A1, Levin A, Farfara D, Benromano T, Scherzer-Attali R, Peled S, Vassar R, Segal D, Gazit E, Frenkel D, Ovadia M(PubMed)
(19) Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease. by Chonpathompikunlert P1, Wattanathorn J, Muchimapura S.(PubMed)
(20) Preparation, characterization, in vivo and biochemical evaluation of brain targeted Piperine solid lipid nanoparticles in an experimentally induced Alzheimer's disease model by Yusuf M1, Khan M, Khan RA, Ahmed B.(PubMed)
(21) Green tea polyphenols protect against okadaic acid-induced acute learning and memory impairments in rats by Li H1, Wu X1, Wu Q1, Gong D1, Shi M1, Guan L1, Zhang J1, Liu J1, Yuan B1, Han G2, Zou Y3(PubMed)
(22) Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma. Menard C1, Bastianetto S2, Quirion R3(PubMed)
(23) Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation by Zhang SQ1, Sawmiller D, Li S, Rezai-Zadeh K, Hou H, Zhou S, Shytle D, Giunta B, Fernandez F, Mori T, Tan J.(PubMed)
(24) Caffeine and coffee as therapeutics against Alzheimer's disease by Arendash GW1, Cao C.(PubMed)
(25) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice by Arendash GW1, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, Echeverria V, Potter H.(PubMed)
(26) The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease by Liu J1, Supnet C2, Sun S1, Zhang H1, Good L3, Popugaeva E4, Bezprozvanny I5.(PubMed)
(27) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice by Arendash GW1, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, Echeverria V, Potter H.(PubMed)
(28) Caffeine and coffee as therapeutics against Alzheimer's disease by Arendash GW1, Cao C.
(PubMed)
(29) Red wine micronutrients as protective agents in Alzheimer-like induced insult by Russo A1, Palumbo M, Aliano C, Lempereur L, Scoto G, Renis M.(PubMed)
(30) rion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1 by Rushworth JV1, Griffiths HH, Watt NT, Hooper NM(PubMed)
(31) Novel role of red wine-derived polyphenols in the prevention of Alzheimer's disease dementia and brain pathology: experimental approaches and clinical implications by Pasinetti GM.(PubMed)
(32) The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology by Grossi C1, Rigacci S, Ambrosini S, Dami TE, Luccarini I, Traini C, Failli P, Berti A, Casamenti F, Stefani M(PubMed)
(33) Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit by Diomede L1, Rigacci S, Romeo M, Stefani M, Salmona M(PubMed)
(34) Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against Alzheimer's disease: in vitro and in vivo studies by Abuznait AH1, Qosa H, Busnena BA, El Sayed KA, Kaddoumi A(PubMed).
(35) Extra virgin olive oil improves learning and memory in SAMP8 mice by Farr SA1, Price TO, Dominguez LJ, Motisi A, Saiano F, Niehoff ML, Morley JE, Banks WA, Ercal N, Barbagallo M.(PubMed)
(36) Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease by Dacks PA1, Shineman DW, Fillit HM.(PubMed)
(37) Nutrient intake and plasma β-amyloid by Gu Y1, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N.(PubMed)
(38) Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury by Kitagishi Y1, Matsuda S.(PubMed)
(39) Combinatorial treatment of tart cherry extract and essential fatty acids reduces cognitive impairments and inflammation in the mu-p75 saporin-induced mouse model of Alzheimer's disease.
Matchynski JJ1, Lowrance SA, Pappas C, Rossignol J, Puckett N, Sandstrom M, Dunbar GL.(PubMed)

II. Types of Herbs Reduced risk of Alzheimer's disease

Strong evidences emerged in epidemiological studies suggested that certain herbs(2) may have potential in reduced risk and treatments of Alzheimer's disease but geographic source of the plant material, climatation, and time of harvest may effect their effectiveness. It is understandable that commercially available herbal medicinal products with the same herbal ingredients vary in their content and concentration of chemical constituents when compared between manufacturers.

1. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
 Extracts of the leaves of the maidenhair tree, Ginkgo biloba, in identified trails on 26 June 2002 through a search of the CDCIG Specialized Register which contains records from all main medical databases, showed a positive effect of Ginkgo biloba in improvement of cognition and function(3). Study from Hospital St. Naum, Sofia, in enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, showed no significance effect in either EGb 761(R)(Ginkgo biloba extract) and donepezil, but the result of the combination of 2 both substances are efficacy in treatment in patients with AD and neuropsychiatric features(4). But in the study of the same extract, Maria-Hilf Hospital Krefeld, Krefeld indicated that EGb 761® improved cognitive functioning, neuropsychiatric symptoms and functional abilities in both types of dementia namely Alzheimer's disease and vascular dementia(5)(6).

2. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root).
In an open-label study, conducted by Seoul National University Hospital, Ginseng improved ADAS and MMSE scores declined and may be considered as clinically effective in the cognitive performance of AD patients(7). Other study also showed the effect of KRG on cognitive functions which was sustained for 2 yr follow-up and may be an indication of  a feasible efficacy of long-term follow-up for Alzheimer's disease(9). Korean red ginseng (KRG) in high doses, significant improved on the ADAS and CDR after 12 weeks(8). Unfortunately, Study by the Korea Institute of Oriental Medicine, on Mini-Mental Status and the Alzheimer's Disease Assessment Scale (ADAS)-cognitive, showed inconclusive in the result of the efficacy of Ginseng(10).

3. Gotu Kola
Gotu Kola also known as centella, is a annual plant of the genus, belonging to the family Mackinlayaceae, native to India, Sri Lanka, northern Australia, Indonesia, Iran, Malaysia, Melanesia, Papua New Guinea. The herb has been used in traditional medicine to treat nervous disorders, epilepsy, senility, premature aging, etc.
Centella asiatica (CA), commonly named gotu kola water extract of CA (GKW), in the Tg2576 mouse, a murine model of AD with high β-amyloid burden, showed to attenuated β-amyloid-associated behavioral abnormalities and protected SH-SY5Y cells and MC65 human neuroblastoma cells from toxicity(11) through the impact of the amyloid cascade altering amyloid beta pathology(12) and colchicine-induced memory impairment and oxidative damage(13).

4. Lemon Balm
Lemon Balm is is a perennial plant in the genus Melissa, belonging to the family Lamiaceae, native to southern Europe and the Mediterranean region. The herb has been used in traditional medicine to treat nervous complaints, lower abdominal disorders and as anti-inflammatory, antivirus, antibacterial agent.
 Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy(14). In a study of 20 healthy, young participants received single doses of 600, 1000, and 1600 mg of encapsulated dried leaf at 7-day intervals, indicated that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood(15). Other study of a standardized M. officinalis extract (300 mg, 600 mg), indicated a significantly increased self-ratings of calmness and reduced self-ratings of alertness and negated the negative mood effects of the DISS(16)(17).

5. Rosemary
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing. Rosnary has been used in traditional medicine as an antiseptic, antioxidant, and antispasmodic agent to treat circulatory problem, eczema, rheumatism, muscle pain, etc.
Carnosic acid (CA), a chemical compound found in rosemary and sage, reduces Aβ production, at least partially, by activating TACE in human astroglial cells(18) and  the University of Tlemcen, also indicated that CA may be potential against Acetylcholinesterase (AChE) which gradual and irreversible declines in cognitive functions in AD patients(19). In an aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening, showed that the combination may have some potential for improving cognitive function, especially in AD patients(20).

6. Chinese Cat's claw 
Chinese Cat's claw also known as Gou Teng, Uncaria rhynchophylla, a genus of Uncaria, belonging to the family Rubiaceae, native to China. The herb is said to consist neuroprotective, anticonvulsive, sedative and antipsychotic effect.
Mice given a subcutaneous injection of D-gal (50 mg/kg) and orally administered  Uncaria rhynchophylla (EUR) (100, 200, or 400 mg/kg) daily for 8 weeks, significantly increased exploratory behavior (assessed by an open-field test) and improved spatial learning and memory function (assessed by the Morris water maze test) as well as increasing the levels of acetylcholine and glutathione and decreasing the activity of acetylcholinesterase and the level of malondialdehyde in the brains through enhancement of the antioxidant status of brain tissue(21. Center for Asian Traditional Medicine Research, Tohoku University also indicated that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils(22), a significant step in the pathogenesis of Alzheimer's disease. 

7. Polygala tenuifolia
 Polygala tenuifolia also known as Yuan Zhi is a genus Polygala, belonging to family Polygalaceae, native to China. The herb has been used in TCM to insomnia, forgetfulness, emotional and disorientation with abundance of phlegm, seizures, anxiety, listlessness, boils, abscesses, sores,etc.
Extract of dried root of Polygala tenuifolia Willdenow was found to provide some protective effects against neuronal death and cognitive impairments in Alzheimer's disease (AD), in the study by the Seoul National University(23). Tenuigenin, a crude extract of Polygala tenuifolia Willd. significantly decreased Abeta secretion from COS-7 cells without altering the ratio of Abeta1-40 and Abeta-42 (in differentiation of change in Abeta metabolism) probably through inhibition of the deposit of beta-site APP cleaving enzyme(causing increased levels of amyloid beta (Abeta) peptide, an early and critical feature of Alzheimer's disease)(24) or inhibited the secretion of A beta in SH-SY5Y APP 695 cells (amyloid precursor protein (APP)) via BACE1 inhibition(reduced risk of the build up of beta-amyloid and slow or stop Alzheimers disease)(25). Ninjin-yoei-to (NYT; Ren-shen-yang-rong-tang in Chinese formula, among 14 kinds of component herbs in NYT, the roots of Polygala tenuifolia  extracts increased nerve growth factor NGF levels from the astrocytes(star shaped glial cells with function of support to neurons and clean up debris within the brain)(26).

8. Salvia officinalis (Sage)
Sage is a ornamental plant of the genus Salvia, belonging to family Lamiaceae, native to the Central and South America, Central, Eastern Asia and Mediterranean. The herb has been used in traditional medicine as carminative, antiperspirant, antispasmodic, astringent, antiseptic, and antibiotic agent and to calm the central nervous system, treat spasms in smooth and skeletal muscles, relieve digestive problems, regulate menstruation, etc.
According to the Northumbria University, extracts Salvia officinalis exerted its anti-oxidant, estrogenic, anti-inflammatory properties, to inhibited butyryl- and acetyl-cholinesterase (to prevent impeded neurotransmission)(27). Rosmarinic acid from Sage, in mild to moderate Alzheimer's disease (AD), enhanced the neuroprotective effect of sage against Abeta-induced toxicity, through inhibition of reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation(cell apoptosis), and tau protein hyperphosphorylation(neurofibrillary degeneration)(28)

9. Papaver somniferum (Opium poppy)
Papaver somniferum is a genus of Papaver, belonging to the family Papaveraceae, native to the Mediterranean Basin, Southeastern Europe, and Western Asia. The herb has been used in folk medicine for treating asthma, stomach illnesses, and bad eyesight.
Opium poppy exerted it neuroprotective effect through interaction of alkaloid opioids of herb with endogenous opiate receptors in the brain, according to Medical Research Council, Newcastle General Hospital(29). Some alkaloids isolated from plants, or are derived from templates of compounds from plant sources have been in clinical use for treatment of cognitive disorders(30).

10. saffron (Crocus sativus) 
Saffron is a spice derived from the flower of Crocus sativus which is a genus Crocus, belonging to the family Iridaceae, native to Southeast Asia.
Saffron extract, showed moderated AChE inhibitory activity, verified by in silico docking studies(31) and some promising effects in clinical studies with dementia patients(32). In a double-blind, placebo-controlled Tehran University of Medical Science study, suggested a positive mild to moderate Alzheimer's disease effect through inhibition of the aggregation and deposition of amyloid β in the human brain(33). Crocin isolated from Saffron, in Alzheimer's disease induced by intracerebroventricular (icv) streptozocin (STZ) in male rats, significantly attenuated learning and memory impairment(34).

11. Bacopa  monnieri
Bacopa  monnieri  is a genus Bacopa, belonging to family Plantaginaceae, native to the wetlands of southern India and Australia. The herb has been used in Indian traditional medicine as a neurological tonic and cognitive enhancer.
In intracerebroventricular administration of colchicine induced cognitive impairment in rats, Bacopa  monnieri decreased in activity of antioxidant enzyme, reversed memory impairment and altered activity of membrane bound enzymes(35). Other study of Bacopa monnieri extract indicated an improvement of   the escape latency time (p<.01) in Morris water maze test with reduction of neurons and cholinergic neuron densities were also mitigated(36). Researchers at the suggested that Bacopa monnieri may be effective in improving memory performance and exerted protective effects against AD by increasing expression or activity of Na, K-ATPase.Na-K-ATPase which plays an important role in AD, and may be a potent neuroprotective modulator against AD(37).

12. Alpinia galanga
Alpinia galanga is the genus Alpinia, belonging to the family Zingiberaceae, native to Indonesia and South Asia. The herb has been used in folk medicine in treating arthritis and rheumatoid arthritis, relieving discomfort caused due to inflammation of the abdomen and ulcers, etc.
On oxidative stress induced Alzheimer's type amnesia in mice, Alphinia galanga attenuated the elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mic(38) and acted as Acetylcholinesterase (AChE) inhibitors which are widely used for the treatment of Alzheimer's disease (AD)(39). The Lalitha College of Pharmacy study suggested that Alpinia galanga fractions increases habituation memory and decreased escape latency in Alzheimer's type of amnesia in mice induced by Aβ((25-35), through increment in Na(+)/K(+)-ATPase and antioxidant activity depicts brain membrane integrity improvement and free radical scavenging property(40).

13. Calabar bean
 Calabar bean is the seed of climbing perennial plant, a genus Physostigma, belonging to the family Fabaceae, native to the tropical Africa. The herb has been used in folk medicine in contract the pupil, manage ocular pressure in glaucoma, etc.
Physostigmine, a major alkaloids from Physostigma venenosum exhibited its neuroprotective affect in Alzheimers' disease through inhibition of acetyl- and butyrylcholinesterase (BChE) activities(41) and alleviated of AD pathology and associated symptoms, for cognitive and for behavioural and psychological symptoms of dementia (BPSD)(42). The University of Massachusetts study showed that Calabar bean in dose-response relationships, enhances memory, and improves drug discovery activities(42).

14. The Compositions
14.1. Yi-Gan San
Yi-Gan San also known as Yokukansanin Japan, is a Bupleurum Formula consisting Chai Hu,  Fu Ling,  Chuan Xiong, Gan Cao, Dang Gui, Gou Teng and Cang Zhu. The composition has been used in traditional Chinese medicine for treatment of calm impatience, difficulty falling asleep or staying asleep.
Yi-Gan San exhibited a clinically significant decrease in terms of hallucinations, agitation, anxiety, irritability or abnormal behavior(44)(45) and improved behavioral and psychological symptoms of dementia (BPSD) and activities of daily living (ADL)(46). In olfactory bulbectomized (OBX) mice, The composition reversed spatial working memory and non-spatial working memory impairments, through reversed OBX-induced down-regulation of choline acetyltransferase and muscarinic muscarinic M1 receptor expression without affecting muscarinic M receptor expression or AChE activity(47). But the Kanto Central Hospital study reported a case of 81 years of age patient with symptoms of metabolic alkalosis with hypokalemia, due to intake of Yokukansan for 6 months(48).

14.2.  Ba Wei Di Huang Wan (BDW)
Ba Wei Di Huang Wan (BDW) is also known as Rehmannia Eight Formula, cosisting, Chinese herbs Fu Zi, Rou Gui, Shu Di Huang, Shan Yao, Shan Zhu Yu, Mu Dan Bi, Fu Ling and Ze Xie. The formula has been used in traditional Chniese medicine in tonifying Kidney and enhancing kidney Qi.
In the search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy, the composition found to be effective in treating cognitive impairment of AD(49). The Tohoku University suggested that Ba Wei Di Huang Wan (BDW) improved Cognitive function and activities of daily living (ADLs)(50).

Taking altogether, without going into reviews. the list of herbs above may be effective in alleviating symptoms and treating Alzheimer's disease through inhibition of of acetyl- and butyrylcholinesterase (BChE) activities. Some researchers suggested that the use of herbal medicines in the treatment of AD should be comparable to the pharmacological treatment currently in use, including the identification of the active ingredients in order to improve the validation of the clinical trial with large-scale, multicenter studies(51).
   References
(1) Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. by Qiu C, Kivipelto M, von Strauss E.(PubMed)
(2) The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review by Leopoldo Luiz dos Santos-Neto,1 Maria Alice de Vilhena Toledo,2 Patrícia Medeiros-Souza,3 and Gustavo Almeida de Souza(PubMed)
(3) Ginkgo biloba for cognitive impairment and dementia by Birks J, Grimley EV, Van Dongen M.(PubMed)
(4) Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: a randomised, double-blind, exploratory trial by Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R; GINDON Study Group(PubMed)
(5) Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trial by Ihl R, Tribanek M, Bachinskaya N; GOTADAY Study Group(PubMed)
(6) Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trialby Napryeyenko O, Borzenko I; GINDEM-NP Study Group(PubMed)
(7) Panax ginseng enhances cognitive performance in Alzheimer disease by Lee ST, Chu K, Sim JY, Heo JH, Kim M(PubMed)
(8) An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease by Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.(PubMed)
(9) Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with korean red ginseng by Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M(PubMed)
(10) Ginseng for cognitive function in Alzheimer's disease: a systematic review by Lee MS, Yang EJ, Kim JI, Ernst E(PubMed)
(11) Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer's Disease: Investigation of a Possible Mechanism of Action by Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J, Gold BG, Quinn JF(PubMed)
(12) Neuroprotective Effects of Centella asiatica against Intracerebroventricular Colchicine-Induced Cognitive Impairment and Oxidative Stress by Kumar A, Dogra S, Prakash A(PubMed)
(13) Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model by Dhanasekaran M, Holcomb LA, Hitt AR, Tharakan B, Porter JW, Young KA, Manyam BV(PubMed)
(14) Effect of aromatherapy on patients with Alzheimer's disease by Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K(PubMed)
(15) Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties by Kennedy DO, Wake G, Savelev S, Tildesley NT, Perry EK, Wesnes KA, Scholey AB.(PubMed)
(16) Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm) by Kennedy DO, Little W, Scholey AB(PubMed)
(17) Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm) by Kennedy DO, Scholey AB, Tildesley NT, Perry EK, Wesnes KA.(PubMed)
(18) Carnosic acid suppresses the production of amyloid-β 1-42 and 1-43 by inducing an α-secretase TACE/ADAM17 in U373MG human astrocytoma cells by Yoshida H1, Meng P2, Matsumiya T2, Tanji K3, Hayakari R2, Xing F2, Wang L2, Tsuruga K4, Tanaka H5, Mimura J6, Kosaka K7, Itoh K6, Takahashi I8, Imaizumi T(PubMed)2.
(19) Molecular Interaction of Acetylcholinesterase with Carnosic Acid Derivatives: A Neuroinformatics Study by Merad M, Soufi W, Ghalem S, Boukli F, Baig MH, Ahmad K, Kamal MA.(PubMed)
(20) Effect of aromatherapy on patients with Alzheimer's disease by Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K(PubMed)
(21) Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice.
Xian YF, Lin ZX, Zhao M, Mao QQ, Ip SP, Che CT(PubMed)
(22) Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins by Fujiwara H, Iwasaki K, Furukawa K, Seki T, He M, Maruyama M, Tomita N, Kudo Y, Higuchi M, Saido TC, Maeda S, Takashima A, Hara M, Ohizumi Y, Arai H(PubMed)
(23) Novel cognitive improving and neuroprotective activities of Polygala tenuifolia Willdenow extract, BT-11 by Park CH, Choi SH, Koo JW, Seo JH, Kim HS, Jeong SJ, Suh YH.(PubMed)
(24) Tenuifolin, an extract derived from tenuigenin, inhibits amyloid-beta secretion in vitro by Lv J, Jia H, Jiang Y, Ruan Y, Liu Z, Yue W, Beyreuther K, Tu P, Zhang D(PubMed)
(25) Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid beta-protein in cultured cells by Jia H, Jiang Y, Ruan Y, Zhang Y, Ma X, Zhang J, Beyreuther K, Tu P, Zhang D(PubMed)
(26) Induction of NGF synthesis in astrocytes by onjisaponins of Polygala tenuifolia, constituents of kampo (Japanese herbal) medicine, Ninjin-yoei-to by Yabe T, Tuchida H, Kiyohara H, Takeda T, Yamada H.(PubMed)
(27) The psychopharmacology of European herbs with cognition-enhancing properties by Kennedy DO, Scholey AB(PubMed)
(28) The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity by Iuvone T, De Filippis D, Esposito G, D'Amico A, Izzo AA(PubMed)
(29) Medicinal plants and Alzheimer's disease: from ethnobotany to phytotherapy by Perry EK, Pickering AT, Wang WW, Houghton PJ, Perry NS.(PubMed)
(30) Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders by Howes MJ, Perry NS, Houghton PJ(PubMed)
(31) Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies by Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, Sinakos Z.(PubMed)
(32) Ethnobotanical treatment strategies against Alzheimer's disease by Howes MJ, Houghton PJ.(PubMed)
(33) Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial by Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SSh, Yousefi MH, Alimardani R, Jamshidi A, Zare F, Moradi A.(PubMed)
(34) Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer's disease in male rats by Khalili M, Hamzeh F.(PubMed)
(35) Neuroprotective effects of Bacopa monnieri in experimental model of dementia by Saini N, Singh D, Sandhir R.(PubMed)
(36) Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer's disease model by Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K.(PubMed)
(37) Na-K-ATPase, a potent neuroprotective modulator against Alzheimer disease by Zhang LN, Sun YJ, Pan S, Li JX, Qu YE, Li Y, Wang YL, Gao ZB.(PubMed)
(38) Neurotransmitter metabolic enzymes and antioxidant status on Alzheimer's disease induced mice treated with Alpinia galanga (L.) Willd by Hanish Singh JC, Alagarsamy V, Sathesh Kumar S, Narsimha Reddy Y.(PubMed)
(39) Galangin, a flavonol derived from Rhizoma Alpiniae Officinarum, inhibits acetylcholinesterase activity in vitro by Guo AJ, Xie HQ, Choi RC, Zheng KY, Bi CW, Xu SL, Dong TT, Tsim KW.(PubMed)
(40) Neuroprotective effect of Alpinia galanga (L.) fractions on Aβ(25-35) induced amnesia in mice by Hanish Singh JC, Alagarsamy V, Diwan PV, Sathesh Kumar S, Nisha JC, Narsimha Reddy Y.(PubMed)
(41) Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease by Konrath EL, Passos Cdos S, Klein LC Jr, Henriques AT(PubMed)
(42) Ethnobotanical treatment strategies against Alzheimer's disease.
Howes MJ, Houghton PJ(PubMed)
(43) Alzheimer's disease drugs: an application of the hormetic dose-response model by Calabrese EJ.(PubMed)

(44) Treatment of behavioral and psychological symptoms of Alzheimer-type dementia with Yokukansan in clinical practice by Hayashi Y, Ishida Y, Inoue T, Udagawa M, Takeuchi K, Yoshimuta H, Kiue K, Ninomiya Y, Kawano J, Sameshima T, Kawahara T, Goto I, Shudo K, Kurayama S, Nakamura J, Okahara K, Mitsuyama Y.(PubMed)
(45) Effects of Yokukansan on behavioral and psychological symptoms of dementia in regular treatment for Alzheimer's disease by Okahara K, Ishida Y, Hayashi Y, Inoue T, Tsuruta K, Takeuchi K, Yoshimuta H, Kiue K, Ninomiya Y, Kawano J, Yoshida K, Noda S, Tomita S, Fujimoto M, Hosomi J, Mitsuyama Y.(PubMed)
(46) A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients by Iwasaki K, Satoh-Nakagawa T, Maruyama M, Monma Y, Nemoto M, Tomita N, Tanji H, Fujiwara H, Seki T, Fujii M, Arai H, Sasaki H.(PubMed)
(47) Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice by Yamada M, Hayashida M, Zhao Q, Shibahara N, Tanaka K, Miyata T, Matsumoto K.(PubMed)
(48) [A case of severe hypokalemia caused by a Chinese herbal remedy (Yokukansan) in an 81-year-old woman with dementia].[Article in Japanese]by Nishiyama N, Takeshita M, Tanaka K, Miyao M, Mizuno Y.(PubMed)
(49) The use of herbal medicine in Alzheimer's disease-a systematic review by Dos Santos-Neto LL, de Vilhena Toledo MA, Medeiros-Souza P, de Souza GA.(PubMed)
(50) A randomized, double-blind, placebo-controlled clinical trial of the Chinese herbal medicine "ba wei di huang wan" in the treatment of dementia by Iwasaki K, Kobayashi S, Chimura Y, Taguchi M, Inoue K, Cho S, Akiba T, Arai H, Cyong JC, Sasaki H.(PubMed)
(51) The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review by Leopoldo Luiz dos Santos-Neto,1 Maria Alice de Vilhena Toledo,2 Patrícia Medeiros-Souza,3 and Gustavo Almeida de Souza(PubMed)3

III. Types of Vitamins Reduced risk of Alzheimer's disease

1. Vitamin A

Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.
Recommended intakes of vitamin A, according to the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity, causing dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc.

1. Retinols
Retinoids, derived from Vitamin A involve in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. In patients with Alzheimers; disease, plasma levels including retinols were found to be significantly lower of that may suggested the vascular comorbidities of patients with AD possibly as a result of certain degrees of depletion of the antioxidant defense system(1). The study of Kanazawa University Graduate School of Medical Science, indicated that vitamin A (retinol, retinal and retinoic acid) inhibited the formation, extension and destabilizing effects of β-amyloid fibrils and  the oligomerization of Aβ (Aβ40 and Aβ42)(2) and Aβ1-16 and Aβ25-35(3). According to University Hospitals Case Medical Center, Retinoids may influence Amyloid beta processing upregulation of alpha secretase via ADAM10 and inhibit formation of Amyloid fibrils(4) with these properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis.
Retinoic acid receptor (RAR) α systemactivated by both all-trans retinoic acid and 9-cis retinoic acid sginalling is found downreguated by amyloid beta (Aβ) in Alzheimers patients. There fore stimulation of the RARα signalling pathway using a synthetic agonist may be effective reverse the the cognitive impairment caused by amyloid beta (Aβ)(5). In Streptozotocin (STZ) induced mice, all-trans-retinoic acid (ATRA) treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations(6).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, play an important role in prevention and treatment of some diseases through it antioxidant effects.
The study of Plasma Levels of HDL and Carotenoids in Alzheimer's patients indicated the protective effects of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia(7). The study of Rayalaseema University, Kurnool, Andhra Pradesh showed the anti oxidant effects of carotenoids in reduced symptoms of Alzheimer's diseases through inhibition of amyloid beta (Aβ) formation, deposition and fibril(8). Plasma of carotenoids may be used as a marker to determine the severity of AD. According to Oregon Health and Science University, an association between higher carotenoids levels and DHA and higher MMSE (tests that screen for Alzheimer's,)scores, supported a protective role of both types of nutrients in AD(9)(10). In a community-dwelling elderly study indicated that use of supplemental antioxidants (vitamins A, C, or E, plus selenium or zinc) is associated with reduction of cognitive decline(11) and vitamin A is found to be destabilization of beta-amyloid fibrils (fAbeta)(12).

Taking altogether, plasma levels of vitamin A may be an indication of marker in identification of the early onset of Alzheimer's disease. Regardless to its forms, overdoses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.


References
(1) [Influence of vascular comorbidities on the antioxidant defense system in Alzheimer's disease].
[Article in German by Polidori MC1, Stahl W, De Spirt S, Pientka L(PubMed)
(2) Vitamin A and Alzheimer's disease by Ono K1, Yamada M.(PubMed)
(3) Vitamin A has anti-oligomerization effects on amyloid-β in vitro by Takasaki J1, Ono K, Yoshiike Y, Hirohata M, Ikeda T, Morinaga A, Takashima A, Yamada M(PubMed)

(4) Retinoids for treatment of Alzheimer's disease by Lerner AJ1, Gustaw-Rothenberg K, Smyth S, Casadesus G(PubMed)
(5) Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist by Goncalves MB1, Clarke E, Hobbs C, Malmqvist T, Deacon R, Jack J, Corcoran JP(PubMed)
(6) All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of streptozotocin-induced dementia of Alzheimer's type by Sodhi RK1, Singh N.(PubMed)
(7) Plasma Levels of HDL and Carotenoids are Lower in Dementia Patients with Vascular Comorbidities by Dias IH1, Polidori MC2, Li L1, Weber D3, Stahl W4, Nelles G5, Grune T3, Griffiths HR1.(PubMed)
(8) Carotenoids and Alzheimer's disease: an insight into therapeutic role of retinoids in animal models by Obulesu M1, Dowlathabad MR, Bramhachari PV.(PubMed)
(9) Nutritional biomarkers in Alzheimer's disease: the association between carotenoids, n-3 fatty acids, and dementia severity by Wang W1, Shinto L, Connor WE, Quinn JF.(PubMed)
(10) Plasma levels of antioxidants are not associated with Alzheimer's disease or cognitive decline by Engelhart MJ1, Ruitenberg A, Meijer J, Kiliaan A, van Swieten JC, Hofman A, Witteman JC, Breteler MM.(PubMed)
(11) Is antioxidant use protective of cognitive function in the community-dwelling elderly? by Gray SL1, Hanlon JT, Landerman LR, Artz M, Schmader KE, Fillenbaum GG.(PubMed)
(12) Vitamin A exhibits potent antiamyloidogenic and fibril-destabilizing effects in vitro by Ono K1, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M.(PubMed)

B. B Vitamins 

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.



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)

C. Vitamin C

Epidemiological studies, linking vitamin C in reduced risk of Alzheimers' disease may be inconclusive. 
But some researchers in the survey of Alzheimers' patients found to be 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 in 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).
 

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)

D. Vitamin D
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.

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 É1, 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)

E. Vitamin E

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.




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)


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Saturday 15 March 2014

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
(a) Nutritional status and nutritional habits of men with benign prostatic hyperplasia or prostate cancer - preliminary investigation by Goluch-Koniuszy Z, Rygielska M, Nowacka I.(PubMed)
(b) Diet and benign prostatic hyperplasia: a study in Greece by Lagiou P1, Wuu J, Trichopoulou A, Hsieh CC, Adami HO, Trichopoulos D.(PubMed)
(c) Associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms by Raheem OA1, Parsons JK.(PubMed)
(d) Nutrition and benign prostatic hyperplasia by Espinosa G.(PubMed)
(e) Dietary patterns and prostatic diseases by Sebastiano C1, Vincenzo F, Tommaso C, Giuseppe S, Marco R, Ivana C, Giorgio R, Massimo M, Giuseppe M.(PubMed)
(f) Fruit and vegetable consumption, intake of micronutrients, and benign prostatic hyperplasia in US men by Rohrmann S1, Giovannucci E, Willett WC, Platz EA.(PubMed)
(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).
(h) Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostatic hyperplasia by Aydin A1, Arsova-Sarafinovska Z, Sayal A, Eken A, Erdem O, Erten K, Ozgök Y, Dimovski A.(PubMed)
(1) Lycopene inhibits disease progression in patients with benign prostate hyperplasia by Schwarz S1, Obermüller-Jevic UC, Hellmis E, Koch W, Jacobi G, Biesalski HK(PubMed).
(2) [Tomatoes and lycopene in prevention and therapy--is there an evidence for prostate diseases?].

[Article in German] by Ellinger S1, Ellinger J, Müller SC, Stehle P.(PubMed)
(3) Effects of Serenoa repens, selenium and lycopene (Profluss®) on chronic inflammation associated with benign prostatic hyperplasia: results of "FLOG" (Flogosis and Profluss in Prostatic and Genital Disease), a multicentre Italian study by Morgia G1, Cimino S, Favilla V, Russo GI, Squadrito F, Mucciardi G, Masieri L, Minutoli L, Grosso G, Castelli T.(PubMed)
(4) Treatment of chronic prostatitis/chronic pelvic pain syndrome category IIIA with Serenoa repens plus selenium and lycopene (Profluss) versus S. repens alone: an Italian randomized multicenter-controlled study by Morgia G1, Mucciardi G, Galì A, Madonia M, Marchese F, Di Benedetto A, Romano G, Bonvissuto G, Castelli T, Macchione L, Magno C.(PubMed)
(5) Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: a systematic review by Ilic D1, Misso M(PubMed).

(8) Changes in the prevalence of benign prostatic hyperplasia in China by Gu F.(PubMed)
(9) Correlations of dietary patterns with prostate health by Stacewicz-Sapuntzakis M1, Borthakur G, Burns JL, Bowen PE.(PubMed)
(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)
(13) [Inhibitive effect of soybean isoflavone on prostate hyperplasia in rats].[Article in Chinese] by Ren GF1, Huang YM.(PubMed)
(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)
(18) Slowing tumorigenic progression in TRAMP mice and prostatic carcinoma cell lines using natural anti-oxidant from spinach, NAO--a comparative study of three anti-oxidants by Nyska A1, Suttie A, Bakshi S, Lomnitski L, Grossman S, Bergman M, Ben-Shaul V, Crocket P, Haseman JK, Moser G, Goldsworthy TL, Maronpot RR.(PubMed)
(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)
(20) Anti-androgenic activities of Ganoderma lucidum by Fujita R1, Liu J, Shimizu K, Konishi F, Noda K, Kumamoto S, Ueda C, Tajiri H, Kaneko S, Suimi Y, Kondo R.(PubMed)
(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)
(23) Lycopene for the prevention and treatment of prostate disease by Ilic D.(PubMed)
(24) Effects of Serenoa repens, selenium and lycopene (Profluss®) on chronic inflammation associated with benign prostatic hyperplasia: results of "FLOG" (Flogosis and Profluss in Prostatic and Genital Disease), a multicentre Italian study by Morgia G1, Cimino S, Favilla V, Russo GI, Squadrito F, Mucciardi G, Masieri L, Minutoli L, Grosso G, Castelli T.(PubMed)
(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)
(30) Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols by Hiipakka RA1, Zhang HZ, Dai W, Dai Q, Liao S.(PubMed)
(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)
(40) Beneficial effects of virgin coconut oil on lipid parameters and in vitro LDL oxidation. Nevin KG. Rajamohan T. Clinical Biochemistry. 37(9):830-5, 2004 Sep. [Comparative Study. Journal Article] UI: 15329324 Authors Full Name Nevin, K G. Rajamohan, T.
(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)
(43) Comparison of fatty acid profiles in the serum of patients with prostate cancer and benign prostatic hyperplasia by Yang YJ1, Lee SH, Hong SJ, Chung BC.(PubMed)
(44) Prostate tissue and leukocyte levels of n-3 polyunsaturated fatty acids in men with benign prostate hyperplasia or prostate cancer by Christensen JH1, Fabrin K, Borup K, Barber N, Poulsen J.(PubMed)

Friday 14 March 2014

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)