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).
 Epedemiological studies, indicated that intake of vegetable and fruit accompanied with healthy life may be associated in prevented risk 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 in the dieases(5).

2. Onion
The onion is a plants in the genus Allium, belongs to the family Alliaceae, a close relation of garlic. It 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 tin treating benign prostatic hyperplasia (BPH)(6). According to the Istituto di Ricerche Farmacologiche Mario Negri, Intake of onion showed an inverse association between allium vegetable consumption and BPH(7).

3. Whole grain
Wholegrain is cereal grains containing cereal germ, endosperm, and bran. Diet may be associated to increased risk of BPH. 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 reduyced 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 cCruciferous 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 six six 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 ne 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, Infrequent 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 to 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). Certain lower urinary tract symptoms may be suggestive of benign prostatic hyperplasia(27), in a total of 370 consecutive patients included in the 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 n, noble rats implanted with estradiol and testosterone were 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. Dr. Morrison AS. showed that 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, showed that chronical 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 the certain chemical constuents  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 plam 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 richs in long-chain polyunsaturated essential fatty acids of the omega-3 group may be used in reduced risk of BPH. 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 as well(42). Other inthe 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 effectivelt in reduced risk and treatments of Benign prostatic hyperplasia(BPH). But large sample and multi centers studies are necessary to vadilate 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






 



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)

Alzheimer's disease in Vitamin D Points of view

 Kyle J. Norton(Draft Article)

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
Vitamin 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, plays 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 association 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 ijn 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 patient than health individuals with the same genotype, of that may be an indication of "Aa" genotype may be 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 researcher 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 at the 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, modulating angiogenin, and advanced glycation end products, etc.(1i). The combination of memantine with vitamin D, a neurosteroid hormone, in the joint study, showed an evidence lesser cortical axons degeneration after exposure to amyloid-beta peptide or glutamate in microfluidic neuronal cultures.(12). Unfortunately, regardless to the effectiveness of vitamin D in reduced risk of cognitive impairment or Aβ, many researchers still believed that there is no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment(13).

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

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Back to Researched articles - Points of view of Vitamins, Foods and Herbs
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Back to Kyle J. Norton Home page http://kylejnorton.blogspot.ca References
(1) A novel perspective for Alzheimer's disease: vitamin D receptor suppression by amyloid-β and preventing the amyloid-β induced alterations by vitamin D in cortical neurons by Dursun E¹, Gezen-Ak D, Yilmazer S.(PubMed)
(2) Vitamin D receptor gene haplotype is associated with late-onset Alzheimer's disease.

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

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

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

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

Alzheimer's disease in Vitamin C Points of view

 Kyle J. Norton(Draft Article)

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

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

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

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References
(1) Dietary fat and antioxidant vitamin intake in patients of neurodegenerative disease in a rural region of Jalisco, Mexico by Navarro-Meza M, Gabriel-Ortiz G, Pacheco-Moisés FP, Cruz-Ramos JA, López-Espinoza A.(PubMed) 
(2) A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease by Harrison FE.(PubMed)
(3) Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis by Li FJ¹, Shen L, Ji HF.(PubMed)
(4) Ascorbic acid, alpha-tocopherol, and beta-carotene reduce oxidative stress and proinflammatory cytokines in mononuclear cells of Alzheimer's disease patients by de Oliveira BF, Veloso CA, Nogueira-Machado JA, de Moraes EN, Santos RR, Cintra MT, Chaves MM.(PubMed)
(5) Formation of the 42-mer Amyloid β Radical and the Therapeutic Role of Superoxide Dismutase in Alzheimer's Disease by Murakami K¹, Shimizu T, Irie K.(PubMed)
(6) Vitamin C transport and its role in the central nervous system by May JM.(PubMed)



(7)Vitamin C and vitamin E for Alzheimer's disease by Boothby LA¹, Doering PL.(PubMed) 
(8) Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer's disease by Arlt S¹, Müller-Thomsen T, Beisiegel U, Kontush A.(PubMed)
(9) Nutrient intake and plasma β-amyloid by Gu Y¹, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N.(PubMed)

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

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

Alzheimer's disease in Vitamin A Points of view

 Kyle J. Norton(Draft Article)

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.

Vitamin 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 was found to be sgnificantly lower of that may suggested the vascular comorbidities of patients with AD may be 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, there was an association between higher carotenoids levels and DHA and higher MMSE (tests that screen for Alzheimer's,)scores, supports a protective role of both types of nutrients in AD(9)(10). In a in the 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) with 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 which may be beneficiary with the intake of vitamin A, 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)

Alzheimer's disease In Herbs' Points of View

Alzheimer's disease is a brain disorder correlated with major reductions in the addition of new neurons to the respective target areas and 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 diseas. It may be results of  cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity)(1) 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 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 efficacies 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 in these mice 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 bythe 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, and specifically 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 moderate 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 calms 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 M₃ receptor expression or AChE activity(47). 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, tthe 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