The Stages of Endometriosis

By Kyle J. Norton

During the last stage of the menstrual cycle, normally a layer of endometriosis lining on the inside of the uterus is expelled, known as menstruation blood which instead some of the endometriosis tissues grows somewhere in the body causing endometriosis. They also react to hormone signals of the monthly menstrual cycle, builds up tissue, breaks it and eliminates it through menstrual period.
Endometriosis affects
a) About 20% of reproductive age women with endometriosis present but without symptoms.
b) About 55% of women who have developed the new onset of severe menstrual cramps
c) About 25% of women with sub-fertility (less fertile than a normal couple), depending to the stages of endometriosis, according to the Clinical Center of Niš, the decreased fertilization rate in Stage I/II endometriosis might be a cause of subfertility in women, as a result of a hostile environment caused by the disease.
Since they grow in somewhere other than in the uterus, when they break there is no way for the period blood to exit causing blood attaching to the organs or lining of the abdomen resulting in scars or adheresion as well as weakening the normal function of organs.
Most of the time, the endometriosis tissues do not travel far. It is commonly found within the pelvic region, on the lining of peritoneum, in the ovaries, and on the surface of the uterus’s outside wall, but they can be anywhere in the body such as well as fallopian tubes, the cervix, the vagina, and even the vulva.
Endometriosis can vary in appearance. It may be clear or white, reddish, brown or blue black, and cysts. They can be classified according to stage of severity(1):
a) Minimal stage:
Top surface, few in number. Commonly they are found in the inside wall of uterus, ligaments and ovary, causing a significant reduction in both progesterone and its ratio with 17 beta-oestradiol and luteal dysfunction and abnormal secretory patterns(3), in women with minimal stage endometriosis, of that may leads to unexplained causes of infertility(2).

b) Mild stage:
Deeper implants, greater numbers are presented. Commonly found in the same area as minimal stage, causing worsening of oocyte quality of women with mild stage of endometriosis of that may lead to infertility(4).

c) Moderate stage:
Many implants, endometrial cysts present, affecting ovary function, causing scar tissues and adhesion is also present.
d) Severe stage:
Intensive peritoneal implants, large endometromas present and dense adhesion.
Each women experiences differently to endometriosis. Some women may have extensive endometrial tissues in their body but feel little or no pain at all, while other women may only be in the early stage of endometriosis but have excessive pain, according to the 1I Katedra i Klinika Ginekologii Onkologicznej i Ginekologii Uniwersytetu Medycznego w Lublinie, in the advanced stage of endometriosis, Increased peritoneal fluid ox-LDL levels observed in women with advanced-stage endometriosis suggest the important role of oxidative stress in the pathogenesis of the disease(5). The University of California-San Francisco (UCSF), suggested that genetic microRNA 21 (MIR21) and DICER1 transcripts may play important roles for microRNAs (miRNAs) in the pathogenesis of severe versus mild endometriosis, potentially through regulation of gene silencing and epigenetic mechanisms(6).

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(1) Stages of endometriosis: Does it affect in vitro fertilization outcome by Pop-Trajkovic S1, Popović J2, Antić V2, Radović D2, Stavanovic M2, Vukomanović P2.(PubMed)
(2) Mid to late luteal phase steroids in minimal stage endometriosis and unexplained infertility.
Barry-Kinsella C1, Sharma SC, Cottell E, Harrison RF(PubMed)
(3) Cyclical gonadotrophin and progesterone secretion in women with minimal endometriosis by Williams CA, Oak MK, Elstein M.(PubMed)
(4) Follicular fluid from infertile women with mild endometriosis may compromise the meiotic spindles of bovine metaphase II oocytes by Da Broi MG1, Malvezzi H, Paz CC, Ferriani RA, Navarro PA(PubMed)
(5) [Increased oxidized LDL cholesterol levels in peritoneal fluid of women with advanced-stage endometriosis] [Article in Polish] by Polak G1, Mazurek D, Rogala E, Nowicka A, Derewianka-Polak M, Kotarski J(PubMed)
(6) Molecular evidence for differences in endometrium in severe versus mild endometriosis by Aghajanova L1, Giudice LC(PubMed)

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The health effects of Vitamin A in Endometriosis

Endometriosis growing somewhere else other than the endometrium also reacts to hormonal signals of the monthly menstrual cycle by building up tissue, breaking it, and eliminating it through the menstrual period. As we know, nutritional supplements play a very important role in treating endometriosis. In this article, we will discuss how vitamins help to treat endometriosis.
A. Vitamin A
I. Definition
Vitamin A is a bi-polar molecule formed by bonds between carbon and hydrogen. It is a fat soluble vitamin. This means it can not be stored in the liver but it can be converted from beta-carotene, a powerful antioxidant. Besides helping in treating endometriosis, it is also known to have strong effects in improving vision and enhancing bone growth.
II. The health effects
1. Vitamin A is a very powerful antioxidant that not only helps to strengthen the immune system, but also protects against the growth of endometriosis, according to the University of California, The combination of Simvastatin and Retinoic acid (RA), showed that Simvastatin potentiated an inhibitory effect of RA on growth of human endometrial stromal (HES) cells(1), probably through suppressing interleukin-6 production in human endometrial cells(5).

2. Vitamin A helps in regulating the gene expression by fighting against the forming of free radicals and protecting the body organs from abnormal growth of endometrial implants and adhesion, according to the Feinberg School of Medicine at Northwestern, endometriotic stromal cells, cause decreased expression of these genes of that leads to decreased retinol uptake and dominant FABP5-mediated prosurvival activity(2).

3. Vitamin A working together with other antioxidants as well as functioning of protein synthesis and fatty acid metabolism reduced oxidative stress which is a component of the inflammatory reaction associated with endometriosis(4), according to Université Catholique de Louvain(3).

4. Iron is necessary for production of red blood cells that carry oxygen in the blood stream for the body’s cells(7). Women who have endometriosis with heavy blood loss during menstruation normally have iron deficiency because of loss of iron which is far greater than what the body can produce leading to anemia(8) as S-ferritin levels were inversely correlated with the duration of menstrual bleeding. Intake of vitamin A and iron will increase the production of red blood cells far better than taking iron supplements alone(9).
Remember, overloading on zinc or iron is toxic to our body and may induce endometriosis(6). Please make sure to talk to your doctor for the correct amount.

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(1) Effects of simvastatin on retinoic acid system in primary human endometrial stromal cells and in a chimeric model of human endometriosis by Sokalska A1, Anderson M, Villanueva J, Ortega I, Bruner-Tran KL, Osteen KG, Duleba AJ.(PubMed)
(2) Altered retinoid uptake and action contributes to cell survival in endometriosis by Pavone ME1, Reierstad S, Sun H, Milad M, Bulun SE, Cheng YH.(PubMed)
(3) Oxidative stress and peritoneal endometriosis by Van Langendonckt A1, Casanas-Roux F, Donnez J.(PubMed)
(4) Women with endometriosis improved their peripheral antioxidant markers after the application of a high antioxidant diet by Mier-Cabrera J1, Aburto-Soto T, Burrola-Méndez S, Jiménez-Zamudio L, Tolentino MC, Casanueva E, Hernández-Guerrero C.(PubMed)
(5) Retinoic acid suppresses interleukin-6 production in human endometrial cells by Sawatsri S1, Desai N, Rock JA, Sidell N.(PubMed)
(6) The role of iron in the pathogenesis of endometriosis by Kobayashi H1, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sakata M, Sado T, Oi H.(PubMed)
(7) Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis by Defrère S1, González-Ramos R, Lousse JC, Colette S, Donnez O, Donnez J, Van Langendonckt A.(PubMed)
(8) Iron status in 268 Danish women aged 18-30 years: influence of menstruation, contraceptive method, and iron supplementation by bMilman N1, Clausen J, Byg KE.(PubMed|)
(9) Iron deficiency and anemia are associated with low retinol levels in children aged 1 to 5 years by Saraiva BC1, Soares MC1, Santos LC1, Pereira SC1, Horta PM2.(PubMed)

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Food therapy – Banana

By Kyle J. Norton

Banana Banana is the common name of a genus of tropical herbaceous plants. It can grow from 3 to 9 m and belongs to the family of the lily and the orchid.

1. Vitamin B6
2. Vitamin C
3. Fiber
4. Potassium
5. Magnesium
6. Iron7. Etc.

Chemical constituents
1. Sterols
2. 3-Methyl butyl butanoate ester
3. steryl esters
4. Diacylglycerols,
5. SAteryl glucosides,
6. Long chain fatty alcohols
7. Aromatic compounds
8. Linoleic acid
9. Linolenic acid
10. Oleic acids
11. Lectin
12. Fructooligosaccharides

Health benefits
1. Banana and constipation
Constipation is a condition of frequent and hard to pass in bowel movement. According to right diagnosis, approximately 30 percent of US population are experience of gastrointestinal complaint every year. chronic constipation (CC) study in adult Moscow population in a 1189 randomly selected subjects, showed statistical significant of 34.3% subjects affected by the disease, 16.5% had CC according to Rome III criteria. Female have significantly higher rate of 2 symptoms of constipation(1). Fructooligosaccharides, a chemical compound found abundantly in banana, in a study by University of Murcia, showed to increase fecal bolus and the frequency of depositions, with a dose of 4-15 g/day given to healthy subjects will reduce constipation(2). Unfortunately, its seeds may induce constipation,(3) especially when they are consume in empty stomach, according to 1SFE Medical Project, Luang Namtha(4).

(1) [Prevalence and risk factors of constipation in the adult population of Moscow (according to population-based study MUSA)].[Article in Russian] by Lazebnik LB, Prilepskaia SI, Baryshnikov EN, Parfenov AI, Kosacheva TN.(PubMed)
(2) Dietary fructooligosaccharides and potential benefits on health by Sabater-Molina M1, Larqué E, Torrella F, Zamora S.(PubMed)
(3) Intestinal obstruction due to phytobezoars of banana seeds: a case report by choeffl V1, Varatorn R, Blinnikov O, Vidamaly V.(PubMed)
(4) Bowel obstruction from wild bananas: a neglected health problem in Laos by Slesak G1, Mounlaphome K, Inthalad S, Phoutsavath O, Mayxay M, Newton PN.(PubMed)

2. Banana and bacterial activity
The immune system is the set of cells and their activity against antigens or infectious agents that comprises of the body’s defense system against diseases. The immune system does a great job of keeping people healthy and preventing infections. Beside foods and nutritional supplements, herbs also play a important role in helping the immune system defend against viruses and bacteria attacks.

According to the National Pingtung University of Science and Technology, Taiwan, hot water banana peel extract may be effective as bacteriostat, and immunostimulant and physiological regulator, through injection administration to enhance immunity, physiological responses, and resistance against L. garvieae in prawns study(1). The combination of saba (Banana)starch with L. plantarum CIF17AN2 showed a statistically significant in inhibition against Sal. Typhimurium SA2093 in the simulated colon model(2). The study of banana peel efficacy in biosurfactant-producing bacteria, showed the peel may be used to obtain crude biosurfactant fora broad spectrum of antimicrobial activity(3).

(1) Effects of hot-water extract of banana (Musa acuminata) fruit’s peel on the antibacterial activity, and anti-hypothermal stress, immune responses and disease resistance of the giant freshwater prawn, Macrobrachium rosenbegii by Rattanavichai W1, Cheng W. (PubMed)
(2) Antagonistic mechanisms of synbiosis between Lactobacillus plantarum CIF17AN2 and green banana starch in the proximal colon model challenged with Salmonella Typhimurium by Uraipan S1, Brigidi P2, Hongpattarakere T3.(PubMed)
(3) Utilization of banana peel as a novel substrate for biosurfactant production by Halobacteriaceae archaeon AS65 by Chooklin CS1, Maneerat S, Saimmai A.(PubMed)

3. Banana and Diabetes
Diabetes is defined as a condition caused by insufficient insulin entering the bloodstream to regulate the glucose. It is either caused by cells in pancreas dying off or receptor sites clogged up by fat and cholesterol. In some cases, diabetes is also caused by allergic reactions of cells in the immune system.
According to the University College of Medical Sciences, India, Musa sapientum Linn (banana), has been used in India for the treatment of gastric ulcer, hypertension, diarrhea, dysentery, and diabetes. In rat study, the stem of lyophilized stem juice of M. sapientum Linn., showed to exhibits antidiabetic and antihyperlipidemic effects.(1). In support of the aboce, the Sri Jayachamarajendra College of Engineering study, suggested that ethanol extract of banana pseudostem (EE) exert an anti-diabetic effect by inhibition of α-glucosidases from the intestine, in turn suppressing the carbohydrate absorption into the bloodstream(2). According to the Central Food Technological Research Institute, banana (Musa sp. var. elakki bale) flower and pseudostem showed to induce symptoms of hyperglycemia, polyuria, polyphagia, polydipsia, urine sugar, and body weight in banana flower- and pseudostem-treated rats(3).

(1) Antidiabetic and antihyperlipidemic effects of the stem of Musa sapientum Linn. in streptozotocin-induced diabetic rats by Dikshit P1, Shukla K, Tyagi MK, Garg P, Gambhir JK, Shukla R.(PubMed)
(2) Investigation of antihyperglycaemic activity of banana (Musa sp. var. Nanjangud rasa bale) pseudostem in normal and diabetic rats by Ramu R1, Shirahatti PS, Zameer F, Nagendra Prasad MN.(PubMed).
(3) Beneficial effects of banana (Musa sp. var. elakki bale) flower and pseudostem on hyperglycemia and advanced glycation end-products (AGEs) in streptozotocin-induced diabetic rats by Bhaskar JJ1,

Shobha MS, Sambaiah K, Salimath PV.(PubMed)

4. Banana and antihyperlipidemic effects
Cholesterol is needed for our body to build cell walls, make hormones and vitamin D, and create bile salts that help you digest fat. However too much of it can be dangerous because cholesterol cannot dissolve in your blood. The special particle called lipoprotein moves this waxy, soft substance from place to place. If you have too much low density lipoprotein LDL that is known as bad cholesterol, overtime cholesterol can build up in your arterial walls causing blockage and leading to heart attack and stroke.
The pulp of banana fruit (Musa sapientum L. var. Cavendishii) , including soluble and insoluble components of dietary fibre showed to exhibit anti hypocholesterolaemic effect with no affect the concentration of serum cholesterol(1). In support of the above, the University of Auckland study showed that resistant starch in Micronesian banana cultivars showed to have beneficial effects in disease prevention including modulation of glycaemic index diabetes, cholesterol lowering capability and weight management(2). Ethanol extract of mature green fruits of Musa AAA (Chenkadali) (bananas and plantains), according to Faculty of Veterinary and Animal Sciences, Mannuthy contained ntioxidant and hypolipidaemic properties and may be used for treating diabetes mellitus(3).


(1) Hypocholesterolaemic effect of banana (Musa sapientum L. var. Cavendishii) pulp in the rat fed on a cholesterol-containing diet by Horigome T1, Sakaguchi E, Kishimoto C.(PubMed)
(2) Resistant starch in Micronesian banana cultivars offers health benefits by Thakorlal J1, Perera CO, Smith B, Englberger L, Lorens A.(PubMed)
(3) Hypolipidaemic and antioxidant effects of fruits of Musa AAA (Chenkadali) in alloxan induced diabetic rats by Kaimal S1, Sujatha KS, George S.(PubMed)

5. Banana and gastric ulcer
Gastric ulcer, a type of peptic ulcer is defined as a condition of a localized tissue erosion in the lining the stomach.
Extract of Musa sapientum fruit (MSE) exhibit antidiabetic and better ulcer healing effects ) in diabetic rat and could be more effective in diabetes with concurrent gastric ulcer, according to the Banaras Hindu University(1). The study of Methanolic extract of Musa sapientum var. Paradisiaca (MSE, 100 mg/kg), showed to exert its ulcer protective through its predominant effect on mucosal glycoprotein, cell proliferation, free radicals and antioxidant systems(2). In Peptic ulcer disease (PUD), encompassing gastric and duodenal ulcers, active compound of Musa sapientum, a monomeric flavonoid (leucocyanidin) showed to promote anti-ulcerogenic activity(3).

(1) Healing effects of Musa sapientum var. paradisiaca in diabetic rats with co-occurring gastric ulcer: cytokines and growth factor by PCR amplification by Kumar M, Gautam MK, Singh A, Goel RK1.(PubMed)
(2) Effect of plantain banana on gastric ulceration in NIDDM rats: role of gastric mucosal glycoproteins, cell proliferation, antioxidants and free radicals by Mohan Kumar M1, Joshi MC, Prabha T, Dorababu M, Goel RK.(PubMed)
(3) Indigenous anti-ulcer activity of Musa sapientum on peptic ulcer. by Prabha P1, Karpagam T, Varalakshmi B, Packiavathy AS.(PubMed)

6. Banana and hypertension
Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. High blood pressure means raising pressure in your heart.If it stays high over time it can damage the body in many ways.
Blood pressure medications have undoubtedly prevented many deaths from heart disease in the past 30 years, but they have many side effects such as damaging the kidney
Corosolic acid (CRA), a constituent of banaba leaves, according to the Mukogawa Women’s University, showed to ameliorate hypertension, abnormal lipid metabolism, and oxidative stress as well as the inflammatory state in a 14 weeks rat study(1). In healthy volunteers study, banana showed no significant changes in heart rate and peak expiratory flow rate but only significant decrease in plasma ACE activity. Banana treatment decreased the rise of systolic blood pressure and diastolic blood pressure in healthy volunteers subjected to cold stress test without much effect on heart rate and peak expiratory flow rate(2)

(1) Corosolic acid prevents oxidative stress, inflammation and hypertension in SHR/NDmcr-cp rats, a model of metabolic syndrome by Yamaguchi Y1, Yamada K, Yoshikawa N, Nakamura K, Haginaka J, Kunitomo M.(PubMed)
(2) Effect of banana on cold stress test & peak expiratory flow rate in healthy volunteers by Sarkar C1, Bairy KL, Rao NM, Udupa EG.(PubMed)

7. Banana and diarrhea
Diarrhea is a condition of frequent bowel movements with three loose or liquid each day. prolong period of diarrhea may result in dehydration due to fluid loss.
Banana flakes, according to the 1Pennsylvania Hospital, can be used as a safe, cost-effective treatment for diarrhea in critically ill tube-fed patients. Banana flakes can be given concurrently with a workup for C. difficile colitis, thereby expediting treatment of diarrhea.(1). Green banana or its chemical compound pectin in the study of Bangladeshi children showed to benefit in management of persistent diarrhea in hospitalized children and may also be useful to treat children at home(2). In support to the above, the Hospital Universitario de Maracaibo, insisted that green plantain showed to be effective in dietary management of persistent diarrhea, in a prospective, in-hospital controlled trial, two different treatments were administered to a sample of 80 children of both sexes, with ages ranging from 1 to 28 months(3).

(1) Banana flakes control diarrhea in enterally fed patients by Emery EA1, Ahmad S, Koethe JD, Skipper A, Perlmutter S, Paskin DL.(PubMed)
(2) Clinical studies in persistent diarrhea: dietary management with green banana or pectin in Bangladeshi children by Rabbani GH1, Teka T, Zaman B, Majid N, Khatun M, Fuchs GJ.(PubMed)
(3) Beneficial role of green plantain [Musa paradisiaca] in the management of persistent diarrhea: a prospective randomized trial by Alvarez-Acosta T1, León C, Acosta-González S, Parra-Soto H, Cluet-Rodriguez I, Rossell MR, Colina-Chourio JA.(PubMed)

8. Banana as antioxidants
BHT and water extracts of banana showed to exhibit its natural antioxidants in preservation of raw poultry meat and meat products, according to Central Institute of Post Harvest Engineering and Technology(1). In the comparison of 4 different Musa sp. leave extracts of hexane, ethyl acetate and methanol antioxidant effect, researchers at the King Saud University, suggested that Antioxidant activity of Musa acuminate exhibited maximum activity among other three Musa species(2).

(1) Comparative antioxidant effect of BHT and water extracts of banana and sapodilla peels in raw poultry meat by Devatkal SK, Kumboj R, Paul D.(PubMed)
(2) Antibacterial and antioxidant activities of Musa sp. leaf extracts against multidrug resistant clinical pathogens causing nosocomial infection by Karuppiah P1, Mustaffa M.(PubMed)

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Chaste tree berry (Vitex agnus-castus)

By Kyle J. Norton

Chaste tree berry is a species of Vitex agnus-castus, genus Vitex, belonging to the family Lamiaceae, native to the Mediterranean region. It has been used in herbal medicine for thousands of year as anaphrodisiac herb and is considered as Queen herb in treating menstrual problems and discomforts by taking it in a prolonged period of time. There was report that reports chaste tree berry stems and leaves used by women as bedding “to cool the heat of lust” during the time of the Thesmophoria,

Chemical constituents
1. β-citronellol
2. Labdane-type diterpenoids,
3. Halimane-type diterpenoid,
4. Oleanane-type triterpenoids,
5. Ursane-type triterpenoids,
6. Sesquiterpenoid,
7. Flavonoid
8. Viteagnusins C, D, E, F, G, and H
9. Abietane-type diterpenoids

Health Benefits
1. Chaste tree berry and premenstrual syndrome (PMS)
Premenstrual syndrome effects over 70% to 90% of women in the US and less for women in Southeast Asia because of their difference in living style and social structure. It is defined as faulty function of the ovaries related to the women’s menstrual cycle, it effects a women’s physical and emotional state, and sometimes interferes with daily activities as a result of hormone fluctuation. The syndrome occurs one to two weeks before menstruation and then declines when the period starts.
A double-blind, randomized, placebo-controlled parallel trial was conducted over 16 weeks on menopause-related symptoms with combination of Hypericum perforatum (St. John’s wort) and Vitex agnus-castus (chaste tree/berry), showed a superior effect of the combination when compare to placebo in total PMS-like scores (p = 0.02), PMS-D (p = 0.006), and PMS-C clusters (p = 0.027). significant reductions in the anxiety (p = 0.003) and hydration (p = 0.002) clusters and suggested that the combination may be a potentially significant clinical application for this phytotherapeutic combination in PMS-like symptoms among perimenopausal women(1). The preliminary data of Technion-Israel Institute of Technology also support the efficacy of Chaste tree fruit (Vitex agnus) in the treatment of PMS(2). In a 1634 patients suffering from premenstrual syndrome (PMS), to test fpr the effects of Vitex on psychic and somatic complaints, on the four characteristic PMS symptom complexes depression, anxiety, craving, and hyperhydration (DACH), and on single groups of symptoms, indicated that Vitex treatment period of three menstrual cycles 93% of patients reported a decrease in the number of symptoms or even cessation of PMS complaints(3).
(1) Effects of a combination of Hypericum perforatum and Vitex agnus-castus on PMS-like symptoms in late-perimenopausal women: findings from a subpopulation analysis by van Die MD1, Bone KM, Burger HG, Reece JE, Teede HJ.(PubMed)
(2) [Herbal medicine in womens' life cycle].[Article in Hebrew] by Ben-Arye E1, Oren A, Ben-Arie A.(PubMed)
(3) Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus by Loch EG1, Selle H, Boblitz N.(PubMed)

2. Chaste tree berry (Vitex agnus-castus) and leukaemia
Leukemia is defined as condition of abnormal increase of white blood cells produced by the bone marrow and/or the lymphatic system. Depending to the malignant granulocytes or lymphocytes, leukemia is classified into myelogenous or lymphoblastic leukemia.
Bone marrow is soft tissue inside the hollow center of major bone. including spine, pelvis, under arm, leg. etc.
Chaste tree berry may process an anti leukaemia effect. According to the Tokyo University of Pharmacy and Life Sciences, Chaste tree berry extract inhibited HL60 liver cancer cell line through Vitex induced a dose- and time-dependent decrease in cell viability associated with induction of apoptosis and G2/M cell cycle arrest in a a dose- and time-dependent manner(1). Also on leukemia cell lines, HL-60 and U-937, extract from the ripe fruit of Vitex agnus-castus (Vitex), inhibited both cell lines through its cytotoxicity activity in dose depend manner(2).

(1) Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract by chi H1, Yuan B1, Yuhara E1, Imai M1, Furutani R1, Fukushima S1, Hazama S1, Hirobe C2, Ohyama K1, Takagi N3, Toyoda H1.(PubMed)
(2) Cytotoxicity of Vitex agnus-castus fruit extract and its major component, casticin, correlates with differentiation status in leukemia cell lines by chi H1, Yuan B, Nishimura Y, Imai M, Furutani R, Kamoi S, Seno M, Fukushima S, Hazama S, Hirobe C, Ohyama K, Hu XM, Takagi N, Hirano T, Toyoda H.(PubMed)

3. Chaste tree berry (Vitex agnus-castus) and anticancer effects
Cancer is a class of diseases in which a group of cells growing and multiplying disordered and uncontrollable way in our body, have become progressively worse and damaged other healthy tissues, sometimes spreads to other organs in the body via lymph or blood and results may be in death.

In human uterine cervical canal fibroblast (HCF), human embryo fibroblast (HE-21), ovarian cancer (MCF-7), cervical carcinoma (SKG-3a), breast carcinoma (SKOV-3), gastric signet ring carcinoma (KATO-III), colon carcinoma (COLO 201), and small cell lung carcinoma (Lu-134-A-H) cells, crude extract prepared with ethanol from dried ripened Vitex agnus-castus fruits, inhibited SKOV-3, KATO-III, COLO 201, and Lu-134-A-H cell lines through its cytotoxic activity and apoptosis(1).
In a human gastric signet ring carcinoma cell line, KATO-III, according to Tokyo University of Pharmacy and Life Science, ethanol extract of the dried ripe fruit of Vitex agnus-castus (Vitex) also displayed cytotoxic activity through intracellular oxidative stress and mitochondrial membrane damage(2). In prostate epithelial cell lines (BPH-1, LNCaP, PC-3), the Extracts of Vitex agnus-castus fruits (VACF), inhibited proliferation and induced apoptosis in a concentration-dependent manner(3).

(1) Cytotoxicity and apoptotic inducibility of Vitex agnus-castus fruit extract in cultured human normal and cancer cells and effect on growth by Ohyama K1, Akaike T, Hirobe C, Yamakawa T.(PubMed)
(2) Human gastric signet ring carcinoma (KATO-III) cell apoptosis induced by Vitex agnus-castus fruit extract through intracellular oxidative stress by Ohyama K1, Akaike T, Imai M, Toyoda H, Hirobe C, Bessho T.(PubMed)
(3) A Vitex agnus-castus extract inhibits cell growth and induces apoptosis in prostate epithelial cell lines by Weisskopf M1, Schaffner W, Jundt G, Sulser T, Wyler S, Tullberg-Reinert H.(PubMed)

4. Chaste tree berry (Vitex agnus-castus) and Menopausal symptoms
Menopause is the defined as a condition in which a woman is in the transition stage of permanent cessation of the ovaries functions in egg production because of less production of estrogen and progesterone, signalling the end of the reproductive phrase a woman’s life. In menopause, menstruation has become irregular and slowly stop overtime, but in some women, menstrual flow comes to a sudden halt.

In a self-administered questionnaire, containing 15 questions, sent to all gynecologists in private practice in Germany to evaluate the complementary and alternative medicine (CAM) in the treatment of climacteric disorders, 98% of the returnees are experience with therapies of black cohosh (Cimicifuga racemosa), chaste tree (Vitex agnus castus) and St. John’s wort(1). According to the 1Royal Melbourne Institute of Technology (RMIT) University, Bundoora, although evidence from rigorous randomized controlled trials is lacking for the individual herb emerging pharmacological evidence supports a role for V. agnus-castus in the alleviation of menopausal symptoms(2). Dr. Chopin Lucks B. in the trial of two essential oils (derived separately from leaf and fruit) of Vitex agnus castus indicated that both essential oil shows a strong symptomatic relief of common menopausal symptoms(3).
Unfortunately, according to the University Hospital Hamburg-Eppendorf, Agnus castus showed no significant difference in the treatment of climacteric complaints(4) with a combination of Hypericum perforatum (St. John’s wort) and Vitex agnus-castus (Chaste tree/berry) also showed the same(5).

(1) The value of complementary and alternative medicine in the treatment of climacteric symptoms: results of a survey among German gynecologists by von Studnitz FS1, Eulenburg C, Mueck AO, Buhling KJ.(PubMed)
(2) Vitex agnus-castus (Chaste-Tree/Berry) in the treatment of menopause-related complaints by van Die MD1, Burger HG, Teede HJ, Bone KM.(PubMed)
(3) Vitex agnus castus essential oil and menopausal balance: a research update [Complementary Therapies in Nursing and Midwifery 8 (2003) 148-154] by Chopin Lucks B.(PubMed)
(4) Efficacy of Cimicifuga racemosa, Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: a systematic review by Laakmann E1, Grajecki D, Doege K, zu Eulenburg C, Buhling KJ.(PubMed)
(5) Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: a randomized, controlled trial by van Die MD1, Burger HG, Bone KM, Cohen MM, Teede HJ.(PubMed)

5. Chaste tree berry (Vitex agnus-castus) and Hyperprolactinaemia
Hyperproclinaemia is a condition with levels of prolactin in the blood that may disrupt the normal menstrual period in women.
Vitex agnus-castus L. (chaste tree; chasteberry) has long been sued in herbal medicine for treatment, predominantly in wide range of female reproductive conditions. According to the 1Royal Melbourne Institute of Technology-University, Bundoora, there are some reports of the herb in reducing TRH-stimulated prolactin secretion, normalising a shortened luteal phase, increasing mid-luteal progesterone and 17β-oestradiol levels of which comparable to bromocriptine for reducing serum prolactin levels and ameliorating cyclic mastalgia(1). The study in monitoring the prolactin release 15 and 30 min after i.v. injection of 200 micrograms TRH. 37 complete case reports (placebo: n = 20, verum: n = 17) after 3 month of therapy, indicated that the herb did not change with the exception of 17 beta-estradiol which rouse up in the luteal phase in patients receiving verum with no adverse effect(2).

(1) Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials by van Die MD1, Burger HG, Teede HJ, Bone KM.(PubMed)
(2) [Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study].[Article in German] by Milewicz A1, Gejdel E, Sworen H, Sienkiewicz K, Jedrzejak J, Teucher T, Schmitz H.(PubMed)

6. Chaste tree berry (Vitex agnus-castus) and Mastalgia
Mastalgia is a condition of breast tenderness and pain come and gone with monthly periods.
Vitex agnus castus (VACS) extract in treatment phase lasted 3 consequent menstrual cycles (2 x 30 drops/day = 1.8 ml of VASC) or placebo in a double-blind, placebo controlled in two parallel groups (each 50 patients), showed to inbibit cyclical breast pain in women(1). In support to the view, the study of Gynecology: select topics, indicated that chaste tree may attenuate the symptoms of mastalgia(2) such as premenstrual mastodynia(Breast pain)(3).

(1) [Treatment of cyclical mastodynia using an extract of Vitex agnus castus: results of a double-blind comparison with a placebo].[Article in Czech by Halaska M1, Raus K, Bĕles P, Martan A, Paithner KG.(PubMed)
(2) Gynecology: select topics by Sidani M1, Campbell J.(PubMed)
(3) Chaste tree (Vitex agnus-castus)--pharmacology and clinical indications by Wuttke W1, Jarry H, Christoffel V, Spengler B, Seidlová-Wuttke D.(PubMed)

7. Chaste tree berry (Vitex agnus-castus) and Propionibacterium acnes
Propionibacterium acnes is a type of acne dur to infection of aerotolerant anaerobic, Gram-positive bacterium (rod) or as a result of chronic blepharitis and endophthalmitis.
Vitex agnus-castus has long been used for treatment of hormonally induced acne in herbal medicine(1) with mild or no adverse side effect(2). Vitex negundo, a five-leaved chaste tree extract, according to the study by the The Institute of Science, India, showed a significant inhibition of lipase activity and number of P. acnes(1).

(1) The genus Vitex: A review by Rani A1, Sharma A2.(PubMed)
(2) Vitex agnus castus: a systematic review of adverse events by Daniele C1, Thompson Coon J, Pittler MH, Ernst E.(PubMed)
(3) Inhibition of Propionibacterium acnes lipase by extracts of Indian medicinal plants by Patil V1, Bandivadekar A, Debjani D.(PubMed)

8. Chaste tree berry (Vitex agnus-castus) and oligomenorrhea and Amenorrhea
Oligomenorrhea is an irregular menstruation and defined as a condition of infrequent period or a woman menstrual period does not occur at a interval of greater than 35 days.
Amenorrhea is defined as a health condition of absence of period.
In a study of 37 women with oligomenorrhea and 30 women with amenorrhea received 50 drops of Phyto Hypophyson , a an Agnus castus-containing homeopathic preparation, or placebo 3 times a day over 3 months or 3 cycles, conducted by Universitäts-Frauenklinik, suggested that women with sterility and oligomenorrhea, a treatment with Phyto Hypophyson L can be recommended over a period of 3-6 months(1). Dr. Veal L. suggested that Vitex agnus-castus, or a blend of essential oils designed to treat amenorrhoea or scanty/irregular periods(2).
(1) [The efficacy of the complex medication Phyto-Hypophyson L in female, hormone-related sterility. A randomized, placebo-controlled clinical double-blind study].[Article in German] by Bergmann J1, Luft B, Boehmann S, Runnebaum B, Gerhard I.(PubMed)
(2) Complementary therapy and infertility: an Icelandic perspective by Veal L.(PubMed)

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Dehydroascorbic acid (DHA)(*) 12% concentration regained the youthfulness of Forearm between the Wrist and Elbow in stimulated reproduction of Collagen against Sagging skin

Kyle J. Norton

I have truly believed that scientists have found a natural ingredient for define-aging, but it was shelved as it offers no commercial value. If one is published with effectiveness more superior than the currently sold products, it may be a death spell to many companies which rely totally in selling cosmetic products.
Anti-aging and maintaining our youthful appearance has been researched throughout human civilization. Today, these researchers have become more aggressive as finding a workable agent may produce billions of dollars of profits to the found company. According to statistics, Global Anti-Aging Products Market will reach $291.9 Billion by 2015.

Dehydroascorbic acid (DHA)(*) 12% concentration may be a potent solution in regained the youthfulness of forearm between the wrist and elbow in stimulated reproduction of collagen against Skin sagging due to aging progression.

Skin aging is one of the most visible ageing processes that occur constantly in our skin organ. Many ingredients from synthetic and natural sources have been proven in studies to have certain effects on skin aging. In our previous study, Dehydroascorbic acid (DHA) at 4% showed a significant improvement in smoothing of the skin, skin elasticity, firming, disappearance of black and white heads, liver spots, pigmentation, and healing acne and acne scars. In this study, Dehydroascorbic acid (DHA) at 12% is tested for its effectiveness in stimulated reproduction of collagen in the forearm between the wrist and elbow.

Method of Experimentation
10 Patients at age 59 -60 (5 females and 5 males; 5 Caucasians, 3 Asians and 2 Africans) were recruited to test for aging process due to loss of collagen causes of skin sagging in the forearm (left or right) between the wrist and elbow.

Patients must also agree during the study that they will not to use any other topical products (such as including moisturizers, sunscreens, and fragrances, make-up and any facial procedures such as peels, facials, microdermabrasion, and injection of botulinum toxin type A or dermal fillers) but the testing solution. The study also examines the patient with any cosmetic surgery and/or medication use of which may interfere with the study, as well as history of facial skin diseases. All patients are also required to sign an informed consent. Solutions of Dehydroascorbic acid (DHA)(*)were remixed every 3 days in order to maintain their refreshness and concentration levels.
Patients were instructed to stir the solution well with wooden chopstick or ice cream stick and wear glove when apply the solution to prevent oxidation causes of brownness in the palm and figure nails due to high concentration of the solution, as well as to cover the applied areas before going out to extreme sunlight.
Patients were also instructed to apply the provided solution on their forearm between the wrist and elbow for a duration of 12 weeks. Forearm up to the wrist examinations were conducted and recorded every 4 weeks.

All patients completed the trial. Topical administration of Dehydroascorbic acid (DHA)(*) 12% showed to stimulate the reproduction of collagen in enhancing the youthfulness of the applied area up to 95% in 4 patients

Treatment of concentrations of Dehydroascorbic acid (DHA)(*) at 12 % exhibited a significant efficacy in rejuvenation of the youthfulness of forearm between the wrist and elbow through reproduction of collagen skin smoothing, elasticity, firming, probably through anti-inflammatory and skin absorption pathways, in doses, skin aging progression and durative depending manner. It may be used to rejuvenate the skin in other parts of the body. Since the experimental group is small in nature, further studies with a larger sample size are necessary to improve the ingredient’s validation.

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Skin aging is one of the most visible aging processes that occur constantly in our skin. According to the Clinical Centre of Nis, certain plant extracts may have the ability to scavenge free radicals to protect the skin matrix through the inhibition of enzymatic degradation, or to promote collagen synthesis in the skin, and affect skin elasticity and tightness (a). Another study suggested that free radicals induced domino effects in production of reactive oxygen species and can react with DNA, proteins, and fatty acids causing oxidative damage and impairment of the antioxidant system, leading to injuries, damage of the regulation pathways of skin causing wrinkles, roughness, appearance of fine lines, lack of elasticity, and de-pigmentation or hyperpigmentation marks (b).
Walking through the drug and commercial cosmetic stores, one can see hundreds of anti-aging creams and products displayed. Many of them have also gone through certain studies for its efficacy with advertisement through media and celebrities. In fact, according to statistics, Global Anti-Aging Products Market will be worth $291.9 Billion by 2015.
Searching through the key word of Dehydroascorbic Acid (Oxidized Vitamin C, DHAA) and skin has yielded no related studies or clinical trials. It may be the result of the solution having no commercial value as it can be made by any cosmetic purchaser, or the studies indicate that L-ascorbic acid must be formulated at pH levels less than 3.5 to enter the skin with maximal concentration of 20% for optimal percutaneous absorption. But according to Dr. Douglas Q. Kitt, Dehydroascorbic Acid (DHAA) permeates stratum corneum at a rate up to 12 times faster than AA. This supports the concept that lower concentrations of DHAA in topical preparations can enhance skin vitamin C levels with less potential side effects (c).
Ingredient 1: Dehydroascorbic Acid (DHA) (vitamin C supplement oxidized form)
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 scavenging activity and regenerating oxidized vitamin E for immune system support. In skin aging, the vitamin may improve solar radiation protection and epidermal aging (1) through production of collagen due to its antioxidant activity (2)(3).
Epidemiological studies linking vitamin C in prevention of skin damage and aging have produced some certain results (3a)(3b)(3c), but the large sample size and multi-centred studies are necessary to validate its effectiveness. Vitamin C oxidized form or dehydroascorbic acid (DHA) processed antiviral and virucidal effects (23) showed to prevent H2O2-induced cell death by increasing the GSH levels mediated by the GPx and GR activities and PPP (17), and regulated neuronal energy metabolism, through facilitating the utilization of glucose via the PPP for antioxidant purposes (18) by increasing antioxidant potential in the central nervous system (19). Dehydroascorbic acid (DHA) may be a potential anti-cancer agent to treat aggressive cancers (20)(21). Dr. Toohey at the Cytoregulation Research said “rapidly-dividing tumour cells make unusually large amounts of homocysteine thiolactone and that administered dehydroascorbic acid enters the cells and converts the thiolactone to mercaptopropionaldehyde which kills the cancer cells” (22).
1. Plasma levels of vitamin C L-ascorbic acid is known for its effects on skin-whitening and against the anti-oxidation causes of skin aging. During the aging process, levels of vitamin C was found to slowly deplete according to the Tokyo Metropolitan Institute of Gerontology in the measurement of plasma and urine of C57BL/6 male mice during 3 to 30 months of aging(4). Therefore, restoration of physiological levels of vitamin C inside the cells might improve the lysosomal degradation (protection of cell from the degradative enzymes through protection of the cytosol) in the outflow pathway cells and prevent the pathogenesis of glaucomadegrade proteins(5).
Unfortunately, some researchers suggested that higher levels of circulating vitamin C may not provide protection against incident radiographic knee OA, and be associated with an increased risk of knee OA(6) and the 1Panorama Research Institute and Regenerative Sciences Institute, insisted “careful attention to individual and family medical history and personal genomic data may prove essential to make wise dietary and supplement choices to be combined with exercise”(7).

2. The effects
According to the Minghsin University of Science and Technology, in doses of a dependent manner, the concentration of L-ascorbic acid induced absorption of the collagen solution in exhibition of smoothing wrinkles and clear up spots(8). Ascorbic acid (AA) is essential in stimulating collagen gene expression. In type 1 and type 4 collagen and SVCT2, the vitamin was found to enhance the expression of type 1 and type 4 collagens and SVCT2 mRNA in cultured human skin fibroblasts at 100 μM AA placed every 24h for 5 days to prevent depletion(9). The Chiang Mai University study also supported the effects of ascorbic acid in the anti-aging process through exhibition pro and active MMP-2 inhibitory(10). Other studies suggested the combined vitamins, including vitamin C in a single formulation had a slightly lower degradation rate and more stable formulations as compared to different preparations containing only one of the vitamins(11)(12). Amazingly, in vivo, application of vitamin C showed a significant reduction of oxidative stress in the skin, an improvement of the epidermal-dermal microstructure and a reduction of fine lines and wrinkles in aged skin within a relatively short period of time of product application(13). The Bruce and Associates study also insisted the effectiveness of vitamin C application over a 12 week period as the vitamin enhanced the overall intensity of pigmentation, fine lines and wrinkles, tactile roughness, and laxity with a 100% satisfaction of overall appearance of the tested subjects’ skin(14).
1. Skin roughness and Scaliness
Skin roughness due to aging is a result of dead skin cells shedding more slowly, and building up in the upper layer of skin causing skin complexion to become rough and dull. According to the University of California at San Francisco, they are the result of aging and anatomic site of which demonstrated a significant influence on skin roughness and scaliness(25). Another study suggested that frictional properties of skin are dependent on more than water content or non-apparent sweating and the role of sebum secretion may be one possible factor(26), or it may be result of depletion of surface lipid content(27).
2. Wrinkles
Wrinkles are also associated with aging, hormonal status, smoking, and intercurrent disease according to the study by the University of California-San Francisco(28). Some researchers suggested that vitamin C may play an important role in collagen production due to its antioxidant properties(28). Another study indicated a positive anti-wrinkle effect through consumption of a mixture of soy isoflavones, lycopene, vitamin C, vitamin E, and fish oil(29).
3. Skin elasticity and firming
Skin sagging is a result of a loss of collagen and elastin of the skin due to aging in combination with the dreaded pull of gravity. The study of a novel dietary supplement (Imedeen Prime Renewal) including soy extract, fish protein polysaccharides, extracts from white tea, grape seed and tomato, vitamins C and E as well as zinc and chamomile extract, showed to inhibit forehead, periocular and perioral wrinkles, mottled pigmentation, laxity, sagging, under eye dark circles, and overall appearance. After 6 months treatment, it was suggested that the formula may provide improved condition, structure and firmness of the skin in post-menopausal women(30). Other studies insisted that since vitamin C (Vit. C) in the form of L-ascorbic acid (Asc) can accelerate wound healing(33)(32) and protect fatty tissues from oxidation damage(33), it may play an integral role in collagen synthesis of reducing wrinkles and skin sagging(34)(35)
5. Liver and aging spots
Liver spot is a condition of brown or black spots appearing on the surface of the skin due to aging and exposure to ultraviolet radiation from the sun. According to skin care guides, high concentration of Vitamin C may improve the skin and lighten the spots(36). Other articles insisted that liver spots may be the result of a deficiency of vitamin C(37). According to the Duke University Medical Center, the application of topical solutions containing vitamins C and E provided protection for human skin against damage caused by ultraviolet radiation(38)(39)(40)(41).
6. Pigmentation
Skin pigmentation disorder is a result of damage most likely caused by UV sunlight, or unhealthy cells due to aging affecting the production of melanin. Vitamin C topical and by iontophoresis are found effectively in aiding post-laser hyperpigmentation or short and long term treatment (42) for melism (43). In an experiment where 29 females with melisma enrolled for iontophoresis, a vitamin C solution was applied to one side of the face, while distilled water was applied to the other side as a control, treatment with colorimeter site showed a significant decrease in the luminance value, (a photometric measure of the luminous intensity per unit area of light) compared to that of the control site (44).
8. Acne and Acne scars
According to Dr. GEORGE E. MORRIS, M.D., in a study of 60 patients with acne being given 8 oz of citrus juice twice daily and vitamin C in 3 gm a day, after 4 months 43 showed improvement, 10 failed to show improvement and 7 did not return for follow up(45). Some articles showed that vitamin C may be effective in the reduction of the formation of acne scars through it’s anti-inflammatory and free radical scavenger activities(46), but no study has been found through searching on PubMed.

9. Back and White heads
Black and white heads are the result of a skin pore becoming clogged with sebum from the body’s natural oil and becoming black heads if oxidized. No study has been found specifically for the key word vitamin C and back and white heads on PubMed.

10. Fine Lines
No study and been found.

A total of 10p atients were recruited with ages ranging from 59 – 60 (5 Caucasians, 3 Asians and 2 Africans, and 5 females and 5 males) to test for the effectiveness in the difference of concentrations of Dehydroascorbic acid (DHA) at 12% ( 24000mg diluted into 100 mL of hot water which is let cool before refrigerating).

Patients are eligible to enter this study
Selection was based on those who had moderate to severe forearm wrinkles. Patients must also agree during the study that they will not to use any other topical products but the testing solution, such as moisturizers, sunscreens, fragrances, make-up, and any facial procedures such as peels, facials, microdermabrasion, and injection of botulinum toxin type A or dermal fillers. The study also examines the patient with any cosmetic surgery and medication use which may interfere with the study, as well as history of facial skin diseases. All patients are also required to sign an informed consent.
Patients were instructed to stir the solution well with wooden chopstick or ice cream stick and wear glove when apply the solution to prevent oxidation causes of brownness in the palm and figure nails due to high concentration of the solution, as well as to cover the applied areas before going out to extreme sunlight.
Patients were also instructed to apply the provided solution on their forearm up to the wrist for a duration of 12 weeks. Facial skin examinations were conducted and recorded every 4 weeks.

Total patients study Genders Ages
Ethnicity 5 Females, 59 – 60
5 Caucasians, 5 Males,
3 Asians,
2 Africans

Initial examination
Based on scale of 0 – 4 (0 – Not applicable, 1 – Minimum, 2 – Mild, 3 – Moderated, 4 – Severe)
6 patients with wrinkle on the forearm between the wrist and elbow range from mild to moderated
4 patients with wrinkle on the forearm up to the wrist range from moderated to severe.

Treatment solution
1. Equipment’s contained a solution provided or mixed by patients as instructed. All solutions were refrigerated to protect its effectiveness.
2. Solution was applied twice per day, once in the morning and once in the evening.
Patients applied the solution first to the affected areas using the sponge path containing Dehydroascorbic acid (DHA)(*) at 12% with little pressure to enhance the absorption for about 1 minute. The sponge path would then be cleared and the solution would be returned to the refrigerator.

Patients were also advised not to let the solution get into their eyes. If this did happen, patients were advised to use cold water to clean them out.

Outcome measure
The results will be measured 3 times:
1. The end of week 4
2. The end of week 8
3. The end of week 12
Patients were measured for the intensity of the applicable areas and to check for efficacy of the solution by comparing to the base line.

Observation report
At the end of weeks 4
Dehydroascorbic acid (DHA)(*) at 12% concentration showed to exhibit the reproduction of collagen as follow
6 Patient with reduction of skin sagging of forearm between the wrist and elbow of 75%
4 Patient with reduction of forearm between the wrist and elbow of 80%

At the end of weeks 4
Dehydroascorbic acid (DHA)(*) at 12% concentration showed to exhibit the reproduction of collagen as follow
6 Patient with reduction of skin sagging of forearm between the wrist and elbow of 85%
4 Patient with reduction of skin sagging of forearm between the wrist and elbow of 90%

At the end of weeks 4
Dehydroascorbic acid (DHA)(*) at 12% concentration showed to exhibit the reproduction of collagen as follow
6 Patient with reduction of skin sagging of forearm between the wrist and elbow of 90%
4 Patient with reduction of skin sagging of forearm between the wrist and elbow of 95%

As the data indicates, patient satisfaction with the solution and the progression of skin sagging reduction.

Through over 12 weeks of application with the designed solution, no adverse effect has been reported in the group.

Dehydroascorbic acid (DHA)(*) showed the most efficacy in enhanced smoothness, firmness, and elasticity of the skin through stimulation the production of collagen on forearm between the wrist and elbow, probably through its antioxidant activities via inflammatory pathways, and skin absorption property. It may be used in other parts of the body including facial skin.
The efficacy of the solutions indicated a logical thinking through maintaining healthy skin by preventing the loss of collagen due to aging is the most effective way to slow down the aging progression. Dehydroascorbic acid (DHA)(*) at 12% concentration may provide us with more insight with this astonished result, but further study is necessary to rule out any adverse effect and improve its validation, due to small sample size.

Please make sure that you discuss the use of any topical solution in the study with your doctor or related field specialist before applying. Please Donate for funding the larger sample size study to improve the validation of this discovery.

(*) (The oxidation of ascorbic acid and its reduction in vitro and vivo)
(a) Skin ageing: natural weapons and strategies by Binic I1, Lazarevic V, Ljubenovic M, Mojsa J, Sokolovic D.(PubMed)
(b) Phytoconstituents as photoprotective novel cosmetic formulations by Saraf S1, Kaur CD.(PubMed)
(c) Topical Dehydroascorbic Acid (Oxidized Vitamin C) Permeates Stratum Corneum More Rapidly Than Ascorbic Acid by Douglas Q Kitt
(1) Active ingredients against human epidermal aging by Lorencini M1, Brohem CA2, Dieamant GC2, Zanchin NI3, Maibach HI(PubMed)
(2) CAM use in dermatology. Is there a potential role for honey, green tea, and vitamin C? by Barbosa NS1, Kalaaji AN2.(PubMed)
(3) The science behind vitamins by Linder J.(PubMed)
(3a) Split-face study of topical 23.8% L-ascorbic acid serum in treating photo-aged skin by Xu TH1, Chen JZ, Li YH, Wu Y, Luo YJ, Gao XH, Chen HD(PubMed)
(3b) Use of topical ascorbic acid and its effects on photodamaged skin topography by Traikovich SS.(PubMed)
(3c) Formulation and in-vivo evaluation of a cosmetic multiple emulsion containing vitamin C and wheat protein by Akhtar N1, Yazan Y(PubMed)
(4) Ascorbic acid levels in various tissues, plasma and urine of mice during aging by Iwama M1, Amano A, Shimokado K, Maruyama N, Ishigami A.(PubMed)
(5) Ascorbic Acid Modulation of Iron Homeostasis and Lysosomal Function in Trabecular Meshwork Cells by Xu P1, Lin Y, Porter K, Liton PB(PubMed)
(6) High plasma levels of vitamin C and E are associated with incident radiographic knee osteoarthritis by Chaganti RK1, Tolstykh I2, Javaid MK3, Neogi T4, Torner J5, Curtis J6, Jacques P7, Felson D4, Lane NE8, Nevitt MC9; Multicenter Osteoarthritis Study Group (MOST)(PubMed)
(7) Trade-offs between anti-aging dietary supplementation and exercise by Mendelsohn AR1, Larrick JW(PubMed)
(8) [The study of absorption efficiency and restoring effects of collagen and ascorbic acid on aged skin by fluorescence and reflection spectroscopy].[Article in Chinese] by Yang BW1, Lin YM, Wang SY, Yeh DC.(PubMed)
(9) Ascorbic acid enhances the expression of type 1 and type 4 collagen and SVCT2 in cultured human skin fibroblasts by Kishimoto Y1, Saito N, Kurita K, Shimokado K, Maruyama N, Ishigami A.(PubMed)
(10) Nanoscale gelatinase A (MMP-2) inhibition on human skin fibroblasts of Longkong (Lansium domesticum Correa) leaf extracts for anti-aging by Manosroi A1, Kumguan K, Chankhampan C, Manosroi W, Manosroi J.(PubMed)
(11) Benefits of combinations of vitamin A, C and E derivatives in the stability of cosmetic formulations by Gianeti MD1, Gaspar LR, Camargo FB Jr, Campos PM.(PubMed)
(12) Stability of vitamin C derivatives in topical formulations containing lipoic acid, vitamins A and E. by Segall AI1, Moyano MA.(PubMed)
(13) Topical activity of ascorbic acid: from in vitro optimization to in vivo efficacy by Raschke T1, Koop U, Düsing HJ, Filbry A, Sauermann K, Jaspers S, Wenck H, Wittern KP.(PubMed)
(14) Evaluation of a prescription strength 4% hydroquinone/10% L-ascorbic acid treatment system for normal to oily skin by Bruce S1, Watson J(PubMed)
(15) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)
(16) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)
(17) Dehydroascorbic acid prevents oxidative cell death through a glutathione pathway in primary astrocytes by Kim EJ1, Park YG, Baik EJ, Jung SJ, Won R, Nahm TS, Lee BH.(PubMed)
(18) The oxidized form of vitamin C, dehydroascorbic acid, regulates neuronal energy metabolism by Cisternas P1, Silva-Alvarez C, Martínez F, Fernandez E, Ferrada L, Oyarce K, Salazar K, Bolaños JP, Nualart F.(PubMed)
(19) Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters by Agus DB1, Gambhir SS, Pardridge WM, Spielholz C, Baselga J, Vera JC, Golde DW.(PubMed)
(20) Expression and/or activity of the SVCT2 ascorbate transporter may be decreased in many aggressive cancers, suggesting potential utility for sodium bicarbonate and dehydroascorbic acid in cancer therapy by McCarty MF.(PubMed)
(21) Gelatin crosslinked with dehydroascorbic acid as a novel scaffold for tissue regeneration with simultaneous antitumor activity by Falconi M1, Salvatore V, Teti G, Focaroli S, Durante S, Nicolini B, Mazzotti A, Orienti I.(PubMed)
(22) Dehydroascorbic acid as an anti-cancer agent by Toohey JI.(PubMed)
(23) Antiviral and virucidal activities of natural products by Arakawa T1, Yamasaki H, Ikeda K, Ejima D, Naito T, Koyama AH.(PubMed)
(24) Topical L-ascorbic acid: percutaneous absorption studies, by Pinnell SR1, Yang H, Omar M, Monteiro-Riviere N, DeBuys HV, Walker LC, Wang Y, Levine M.(PubMed)
(25) Use of topical ascorbic acid and its effects on photodamaged skin topography by Traikovich SS.(PubMed)
(26) Frictional properties of human skin: relation to age, sex and anatomical region, stratum corneum hydration and transepidermal water loss by Cua AB1, Wilhelm KP, Maibach HI.(PubMed)
(27) Skin surface lipid and skin friction: relation to age, sex and anatomical region by Cua AB1, Wilhelm KP, Maibach HI.(PubMed)
(28) Skin aging. Effect on transepidermal water loss, stratum corneum hydration, skin surface pH, and casual sebum content by Wilhelm KP1, Cua AB, Maibach HI.(PubMed)
(29) Wrinkle reduction in post-menopausal women consuming a novel oral supplement: a double-blind placebo-controlled randomized study by Jenkins G1, Wainwright LJ, Holland R, Barrett KE, Casey J.(PubMed)
(30) Effect of a novel dietary supplement on skin aging in post-menopausal women by Skovgaard GR1, Jensen AS, Sigler ML.(PubMed)
(31) Vitamin C: a wound healing perspective, by Moores J.(PubMed)
(32) Nutrition 411: revisiting vitamin C and wound healing by Collins N.(PubMed)
(33) Ef[The study of absorption efficiency and restoring effects of collagen and ascorbic acid on aged skin by fluorescence and reflection spectroscopy].[Article in Chinese] by Yang BW1, Lin YM, Wang SY, Yeh DC.(PubMed)
(34) Regulation of collagen synthesis in human dermal fibroblasts in contracted collagen gels by ascorbic acid, growth factors, and inhibitors of lipid peroxidation by Gessin JC1, Brown LJ, Gordon JS, Berg RA(PubMed)
(35) Electroporation-mediated topical delivery of vitamin C for cosmetic applications by Zhang L1, Lerner S, Rustrum WV, Hofmann GA.(PubMed)
(36) Liver Spot Removal: Vitamin C Products(Skin care guide)
(37) Lack of vitamin leads to brown spot on hand(livestrong)
(38) A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation by Murray JC1, Burch JA, Streilein RD, Iannacchione MA, Hall RP, Pinnell SR.(PubMed)
(39) UV photoprotection by combination topical antioxidants vitamin C and vitamin E by Lin JY1, Selim MA, Shea CR, Grichnik JM, Omar MM, Monteiro-Riviere NA, Pinnell SR.(PubMed)
(40) Protective effects of topical antioxidants in humans by Dreher F1, Maibach H.(PubMed)
(41) Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants by Darr D1, Dunston S, Faust H, Pinnell S.(PubMed)
(42) Successful short-term and long-term treatment of melasma and postinflammatory hyperpigmentation using vitamin C with a full-face iontophoresis mask and a mandelic/malic acid skin care regimen by Taylor MB1, Yanaki JS, Draper DO, Shurtz JC, Coglianese M.(PubMed)
(43) Intravenous vitamin C in the treatment of post-laser hyperpigmentation for melasma: a short report by Lee GS.(PubMed)
(44) A randomized, double-blind, placebo-controlled trial of vitamin C iontophoresis in melisma by Huh CH1, Seo KI, Park JY, Lim JG, Eun HC, Park KC.(PubMed)

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Phytochemical Polysulfides

Kyle J. Norton

Polysulfides are phytochemicals in a class of chemical compounds containing chains of sulfur atoms, belonging to the group of Organosulfides found abundantly in ioxidized product, including beer, wine, whiskey, garlic oil, etc.
1. Phytochemical Polysulfides and colon cancer
Bowel cancer also known as colorectal cancer, is defined as a condition of the abnormal proliferation of cells in the colon, rectum, or vermiform appendix. Bowl is divided in 2 parts, the first part of the bowel, the small bowl, is involved with the digestion and absorption of food. The 2nd part, the large bowel which consist the the colon and rectum, is involved in absorption of water from the small bowel contents and broken down of certain materials in the feces into substances of which some of them to be re absorbed and reused by the body. Bowel cancer is relatively very common and slowly growing and progress cancer and in predictable way.
Bowel cancer is the third most commonly diagnosed cancer in developed countries, including U>S and Canada.
According to the study of the University of the Saarland, coumarin polysulfides showed to inhibit cell growth and induce apoptosis in HCT116 colon cancer cells, through regulated the phosphatase activity of the cell cycle regulating cdc25(Cell division cycle 25, family of dual-specificity phosphatases) family members(1). Diallylsulfides, another family member of Garlic-derived organo sulphur compounds, also inhibited HCT116 human colon cancer cells, through reduced cell viability, cell cycle arrest and apoptosis(2) and colo 205 human colon cancer cells through affected resistant gene expression(3)

(1) Coumarin polysulfides inhibit cell growth and induce apoptosis in HCT116 colon cancer cells by Saidu NE1, Valente S, Bana E, Kirsch G, Bagrel D, Montenarh M.(PubMed)
(2) Diallylpolysulfides induce growth arrest and apoptosis by Busch C1, Jacob C, Anwar A, Burkholz T, Aicha Ba L, Cerella C, Diederich M, Brandt W, Wessjohann L, Montenarh M.(PubMed)
(3). Diallyl sulfide, diallyl disulfide and diallyl trisulfide affect drug resistant gene expression in colo 205 human colon cancer cells in vitro and in vivo by Lai KC1, Kuo CL, Ho HC, Yang JS, Ma CY, Lu HF, Huang HY, Chueh FS, Yu CC, Chung JG.(PubMed)

2. . Phytochemical Polysulfides and breast cancer
Breast cancer (malignant breast neoplasm) is a cancer started in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast. In 2010, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.
Eating garlic daily and regularly is associated to reduced risk of cancer due to its properties in stimulated cells arrest at G2/M phase, the cells with a sub-G1 DNA content, and the cells with caspase-3 activity(1). In sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells , Diallyl- and dipropyltetrasulfides showed to inhibit growth of both cancer cell lines, through cell cycle arrest associated to antiproliferative effect(2). The Alexandria University study also supported the role of diallyl trisulfide in inhibition of MCF-7 breast cancer but throught enhanced the expression levels of FAS and cyclin D1, but in contrast, downregulated the expression levels of Akt and Bcl-2(3).

(1) Anticancer effects of diallyl trisulfide derived from garlic by Seki T1, Hosono T, Hosono-Fukao T, Inada K, Tanaka R, Ogihara J, Ariga T.(PubMed)
(1) Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases by Viry E1, Anwar A, Kirsch G, Jacob C, Diederich M, Bagrel D.(PubMed)
(2) Garlic constituent diallyl trisulfide induced apoptosis in MCF7 human breast cancer cells by Malki A1, El-Saadani M, Sultan AS.(PubMed)

3. Polysulfides and skin cancer
Skin cancer is a medical condition of uncontrolled growth of abnormal skin cells and often detected at an early stage.
In skin cancer progression, diallyl trisulfide (DATS) is more potent than mono- and disulfides against skin cancer, through inhibited cell growth of human melanoma A375 cells and basal cell carcinoma (BCC) cells by increasing the levels of intracellular reactive oxygen species (ROS) and DNA damage and by inducing G2/M arrest, endoplasmic reticulum (ER) stress, and mitochondria-mediated apoptosis(1). The study by the National Taiwan University, also showed that Diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), extracted from crushed garlic, inhibited skin cancer cell growth through involved in G(2)/M arrest and apoptosis via activation of p53 pathway in response to the oxidative DNA damage(2). The Chung Shan Medical University Hospital, study also insisted that DAS protect against ultraviolet B (UVB)-induced skin tumor formation through anti photocarcinogenesis effect accompanied by the down-regulation of cell-proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-κB, and of inflammatory responses involving COX-2, PGE2, and NO, and up-regulation of p53, p21/Cip1 to prevent DNA damage and facilitate DNA repair in hairless mice(3).

(1) Molecular mechanisms of garlic-derived allyl sulfides in the inhibition of skin cancer progression by Wang HC1, Pao J, Lin SY, Sheen LY.(PubMed)
(2) Allyl sulfides inhibit cell growth of skin cancer cells through induction of DNA damage mediated G2/M arrest and apoptosis By Wang HC1, Yang JH, Hsieh SC, Sheen LY.(PubMed)
(3) Diallyl sulfide protects against ultraviolet B-induced skin cancers in SKH-1 hairless mouse: analysis of early molecular events in carcinogenesis by Cherng JM1, Tsai KD, Perng DS, Wang JS, Wei CC, Lin JC.(PubMed)

4. Phytochemical Polysulfides and cardiovascular diseases
There are many causes of heart diseases. Most of heart diseases are caused by high blood pressure contributes to hardening of the arteries. High levels of bad cholesterol (LDL) build up in the arteries as a result of uncontrolled diet with high levels of saturated fat and trans fat. Beside cancer, heart disease kills more than 2,000 Americans everyday. Approximately 60 million Americans have heart disease.
Epidemiologic studies link intake of garlic in association to reduce risk as well as progression of cardiovascular disease(1).
According to the Institute of Preventive and Clinical Medicine, polysulfides from garlic are converted into hydrogen sulfide which has the unique property for relaxing vascular smooth muscle, inducing vasodilation of blood vessels, and significant reducing blood pressure(2), probably through its anti-apoptotic, anti-inflammatory and antioxidant effects(3). The 1Semmelweis University Institute of Human Physiology and Clinical Experimental Research, suggested that H2S as a novel gasotransmitter in the central nervous and cardiovascular systems, similarly to nitric oxide (NO) and carbon monoxide (CO), may be of value in cytoprotection during the evolution of myocardial infarction(4).

(1) Garlic and cardiovascular disease: a critical review by Rahman K1, Lowe GM.(PubMed)
(2) Garlic (Allium sativum L.) and cardiovascular diseases by Ginter E1, Simko V.(PubMed)
(3) Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential by Lavu M1, Bhushan S, Lefer DJ.(PubMed)(4) The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury (review) by Dongó E1, Hornyák I, Benko Z, Kiss L.(PubMed)

5. Polysulfides and Immunity
A range of sulfur-containing natural products showed to inhibit their antioxidant, antibacterial, antimicrobial, antifungal and anticancer properties, through specific chemical properties which converge in chemotypes, including polysulfides(1).
Garlic extracts and individual components, i.e., allicin, ajoen, polysulfides, essential oil, showed a significant antifungal activity, according to 1Katedra farmaceutické botaniky a ekologie Farmaceutické fakulty Univerzity Karlovy(2). Polysulfides, through its biological activity, showed effectively against candidosis in mice, according to the 1Pharmaceutical Research Laboratories III, Takeda Chemical Industries, Japan(3).

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(1) A scent of therapy: pharmacological implications of natural products containing redox-active sulfur atoms by Jacob C.(PubMed)
(1) [Pharmaceutical significance of Allium sativum L. 4. Antifungal effects].[Article in Czech]by Sovová M1, Sova P.(PubMed)
(2) Optically active antifungal azoles. II. Synthesis and antifungal activity of polysulfide derivatives of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H- 1,2,4-triazol-1-yl)-2-butanol by Tasaka A1, Tamura N, Matsushita Y, Hayashi R, Okonogi K, Itoh K.(PubMed)

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The Science of Soy – The East Viewpoints: Part A5 – Soy and Menopause Symptoms in Japanese

By Kyle J. Norton

Soy foods, including tofu have been in traditional Chinese diet over thousands of year, according to Chinese literature. The reduced risk of chronic disease, including metabolic syndrome such as cardiovascular diseases, obesity and diabetes and lesser menopause symptoms in advanced age, may be aided by eating a lot of soy food accompanied with large portion of vegetables and fruits. Indeed, according to the study, only 10% of women in the East are experience symptoms of menopause in advanced age compared to over 70% of their Western counterparts.
According to Dr. Mark Messina, Ph.D., Soy foods contributed from 6.5%8 to 12.8%7 of total protein intake in older adult in Japan.(b)

The approval of cardiovascular benefit of soy by FDA in 1999 accompanied with the discovery of health benefits in clinical studies over past decade, prompted the promotion and advertisement of soy’s health benefits in every aspect in Western society. Evidences could be seen by walking through the supermarkets and drug stores. Soy supplements and products such as tofu, soy milk, soy-based infant formula, and meatless “texturized vegetable protein” burgers were widely available. According to the United Soybean Board’s 2004–2005, 25% of Americans consume soy foods or beverages at least once per week, and 74% view soy products as healthy.

Today, the promotion of soy are no longer existed, it may be results of discovery of adverse effect in single ingredient and animal studies, as intake of soy is associated to induce risk certain mammary cancers and infertility. The publication of the result have drawn many criticisms. According to Thomas Badger, director and senior investigator at the Arkansas Children’s Nutrition Center in Little Rock, these effects are seen only under certain experimental conditions that are not likely to occur in humans—and therein lies the crux of the debate(a). Equol (4′,7-isoflavandiol), an isoflavandiol metabolized from daidzein may be the causes, as 90% of Eastern population are equol producers but only 30% in the West.
The explanation of the positive effect of soy isoflavones in reduced risk of mammary cancers by University of Goettingen may be interesting, as researchers said” Most importantly, there is dispute as to whether isoflavones derived from soy or red clover have negative, positive or any effect at all on the mammary gland or endometrium. It is beyond any doubt that soy products may have cancer preventing properties in a variety of organs including the mammary gland. However, these properties may only be exerted if the developing organ was under the influence of isoflavones during childhood and puberty.

Soybean is the genus Glycine, belonging to 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 profits.
1. Carbohydrates
2. Dietary fiber
3. Fat
4. Protein
5. Essential amino acid
6. Vitamin A
7. Vitamin B6
8. Vitamin B12
9. Vitamin C
10. Vitamin K
11. Calcium
12. Iron
13. Magnesium
14. Phosphorus
15. Potassium
16. Sodium
17. Zinc
18. Etc.
1. Isoflavones
2. Genistein
3. Saponins
4. Beta-sitosterol
5. Daidzein

I. Soy in Eastern population
A. The Japanese population
Japan, an island nation in the Pacific Ocean, lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south(1c). According to Moriyama, Japanese women and men live longer and healthier than everyone else on Earth, it may be result of healthier Japanese diet and lifestyle. According to the World Health Organization, the Japanese have an average of 75 years healthy living with disability-free, it may be due to average soy intake 10 to 70 times higher than in Western people(1a)(1b).

A5. Soy and menopause symptom in Japan
Menopause is defined as a condition in which women have not had a menstrual period in a minimum of 12 months period as a result of the inactive ovaries, assuming the women are not pregnant and experience the ease of visible symptoms of menopause such as hot flashes and night sweats but not the invisible effects of menopause. During post menopause, any bleeding or spotting should be reported to your doctor immediately, it may be caused by tumors rarely but it is possible. Symptoms may include Bleeding or spotting, Vagina itching and dryness, Hot flash, Bone pain and fracture, Bladder infection, Skin wrinkle, Hypertension, Bone density loss, etc.

Eppidemiological studies, linking soy effect on menopause symptoms have been inconclusive(1)(2)(3)(4). In japanese women, phytochemicals in soy found effectively in reduced vasomotor symptoms of menopause. In a supplement containing equol on the menopausal symptoms of Japanese, researchers at the Tokyo Medical and Dental University, showed that The equol-ingesting grou, noy only significantly reduced severity and frequency of hot flashes as, the severity of neck or shoulder but also exhibit trends of improvement in sweating and irritability and a significant improvement in the somatic category symptoms(5). Administration of 10-mg natural S-(-)equol supplement consumed daily for 12 weeks also indicated an reduction of hot flushes and neck or shoulder muscle stiffness, in postmenopausal Japanese women(6). And fermented soy products hhave been also showed to alleviate the severity of hot flushes(14).
Some researchers suggested that the effectiveness of soy isoflavone in relieved symptoms of menopause may link to equol-producing status. In a 1-year double-blind, randomized trial in comparison of the effects of isoflavone (75 mg of isoflavone conjugates/day) with those of placebo on bone mineral density, fat mass, and serum isoflavone concentrations in early postmenopausal equol-producer phenotype.Japanese women, found that isoflavones exhibited the preventive effects of isoflavones on bone loss and fat accumulation in early postmenopausal women depend on an individual’s equol-producing capacity(7) and S-equol supplement improved mood-related symptoms in perimenopausal/postmenopausal even in equol nonproducers in Japan women, in total of 127 participants completed the trial(8).

Soy isoflavone extracts on testing on lumbar spine or hip BMD in menopausal women of controlled trials published in English, Japanese, or Chinese, showed a result of varying effects of isoflavones on spine BMD across trials associated with study characteristics of intervention duration (6 vs. 12 months), region of participant (Asian vs. Western), and basal BMD (normal bone mass vs. osteopenia or osteoporosis)(9). In ciompared the symptom of hot flash and chilliness in menopause women, Dr. Melby MK. suggested that Japanese women are experience important vasomotor symptom than hot flushes and sweats, it may be result of dietary high in soy(10).

In Osteoporosis, menaquinone-7, the major chemical compound found Japanese fermented soybeans, showed to prevent postmenopausal bone loss(11) and promotion of bone formation(13)(15) as well eleviating early postmenopausal women, such as in palpitation and backaches(15). Other study also suggested that intake of supplementation of isoflavones (ISO) regulary associated to risk reduction of osteoporosis in middle-aged Japanese menopausal Japanese women(12).

In fact, according to the study of cross-sectional relationships of dietary and other lifestyle variables to menopause by the Gifu University School of Medicine, such as smoking, calcium and soy product intakes, intakes of fat, cholesterol, and coffee were significantly associated with the onset menopause in Japanese women(16).

Taken altogether, High soy food intakes are associated to reduce symptoms of menopause in Japanese women, chilliness. In take of supplement containing equol are effective in symptom reduction even in non equol producers in these population as well. According to the Royal Hospital for Women, highest soy consumption in Japan lowered the rates of diseases, such as breast, endometrial, colon and prostatic cancers atherosclerotic, etc. but induced extremely high urinary levels of phytoestrogen metabolites may be a result of isoflavones in exhibited bioactivity when intake of high concentrations.(17)

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(a) The Science of Soy: What Do We Really Know? by Julia R. Barrett
(b) Guideline for healthy soy intake(the Unite Soybean board)
(1c) Japan, Wikipedia
(1a) Erdman JW Jr. AHA Science Advisory: soy protein and cardiovascular disease: a statement for healthcare professionals from the Nutrition Committee of the AHA. Circulation. 2000; 102: 2555–2559
(Soy protein and cardiovascular disease)
(1b) van der Schouw YT, Kreijkamp-Kaspers S, Peeters PH, Keinan-Boker L, Rimm EB, Grobbee DE. Prospective study on usual dietary phytoestrogen intake and cardiovascular disease risk in Western women. Circulation. 2005; 111: 465–471(Cardiovascular diseases in women)
(1) S-equol and the fermented soy product SE5-OH containing S-equol similarly decrease ovariectomy-induced increase in rat tail skin temperature in an animal model of hot flushes by Yoneda T1, Ueno T, Uchiyama S.(PubMed)
(2) A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency by Jenks BH1, Iwashita S, Nakagawa Y, Ragland K, Lee J, Carson WH, Ueno T, Uchiyama S.(PubMed)
(3) Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials by Taku K1, Melby MK, Kronenberg F, Kurzer MS, Messina M.(PubMed)
(4) Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial by Newton KM1, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J.(PubMed)
(5) Equol improves menopausal symptoms in Japanese women by Aso T.(PubMed)
(6) A natural S-equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women by Aso T1, Uchiyama S, Matsumura Y, Taguchi M, Nozaki M, Takamatsu K, Ishizuka B, Kubota T, Mizunuma H, Ohta H.(PubMed)
(7) Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial by Wu J1, Oka J, Ezaki J, Ohtomo T, Ueno T, Uchiyama S, Toda T, Uehara M, Ishimi Y.(PubMed)
(8) New equol supplement for relieving menopausal symptoms: randomized, placebo-controlled trial of Japanese women by Ishiwata N1, Melby MK, Mizuno S, Watanabe S.(PubMed)
(9) Effect of soy isoflavone extract supplements on bone mineral density in menopausal women: meta-analysis of randomized controlled trials by Taku K1, Melby MK, Takebayashi J, Mizuno S, Ishimi Y, Omori T, Watanabe S.(PubMed)
(10) Chilliness: a vasomotor symptom in Japan by Melby MK.(PubMed)
(11) Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study by Ikeda Y1, Iki M, Morita A, Kajita E, Kagamimori S, Kagawa Y, Yoneshima H.(PubMed)
(12) Soy isoflavone tablets reduce osteoporosis risk factors and obesity in middle-aged Japanese women by Mori M1, Aizawa T, Tokoro M, Miki T, Yamori Y.(PubMed)
(13) Promotion of bone formation by fermented soybean (Natto) intake in premenopausal women by Katsuyama H1, Ideguchi S, Fukunaga M, Fukunaga T, Saijoh K, Sunami S.(PubMed)
(14) Hot flushes and other menopausal symptoms in relation to soy product intake in Japanese women by Nagata C1, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K.(PubMed)
(15) Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women by Somekawa Y1, Chiguchi M, Ishibashi T, Aso T.(PubMed)
(16) Association of diet and other lifestyle with onset of menopause in Japanese women by Nagata C1, Takatsuka N, Inaba S, Kawakami N, Shimizu H.(PubMed)
(17) Phytoestrogens and the menopause by Mackey R1, Eden J.(PubMed)

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Phytochemical therapy – Phytochemicals Dithiolthiones (isothiocyanates)

Dithiolthiones are phytochemicals in the class of Organosulfides, found abundantly in cruciferous vegetables, garden sorrel, horseradish, etc.

The study of the hepatoprotective drug anisyldithiolthione was showed to be effective in acting as hepoprotective agent in inhibited lipid peroxidation induced in rat liver microsomes either chemically by FeSO4 and reducing agents (cysteine or ascorbate) or enzymatically, probably through the presence of its dithiolthione function(1) Other medication such as Anethol dithiolthione (ADT), usually prescribed as a choleretic drug, also exhibited an hepatoprotective potency at doses as low as 10 mg/kg relative to serum aminotransferase activities and hepatic glutathione related enzyme system in in Swiss female mice(2)

(1) A new potent inhibitor of lipid peroxidation in vitro and in vivo, the hepatoprotective drug anisyldithiolthione by Mansuy D, Sassi A, Dansette PM, Plat M.(PubMed)
(2) Protective effect of anethol dithiolthione against acetaminophen hepatotoxicity in mice by Warnet JM1, Christen MO, Thevenin M, Biard D, Jacqueson A, Claude JR.(PubMed).

2. Isothiocyanates and cancers
Cancer is a class of diseases in which a group of cells growing and multiplying disordered and uncontrollable way in our body, have become progressively worse and damaged other healthy tissues, sometimes spreads to other organs in the body via lymph or blood and results may be in death.
In a case-control study conducted in urban Shanghai. The cases (from December 2006 to December 2008, ITC consumption from cruciferous vegetables intake showed a positive effect in reduce risk of pancreatic cancer after adjusting for possible confounding factors such as age, sex, history of diabetes and pancreatitis(1). Thiazolo, the synthesis of a novel class of quinazoline, produced by the reaction of 4,6-dichloro-5-aminopyrimidine with isothiocyanates in presence of 20 mol% KF/alumina, showed to exhibit antiproliferative activity in lung (NCI-H322 and A549), epidermal (A431) and glioblastoma (T98G), HL-60 cell lines at 20 μM. The effect of compound 4a on mitochondrial potential loss in HL-60 cells probably through cleavage of PARP-1 and procaspase-3 inhibition(2).
The study by Campus Morro do Cruzeiro suggested that the phytochemical inhibited the cell viability of human cervical cancer cells, human pancreatic cancer cells, human hepatocellular carcinoma cells, human ovarian cancer cells, and have antiinflammatory properties in the treatment of human T-cell leukemia cells(3).

(1) [A case-control study on the association between urinary levels of isothiocyanates and the risk of pancreatic cancer].[Article in Chinese] by Wang J1, Han L, Zhang W, Wang J, Ni Q, Shen M, Gao Y2.(PubMed)
(2) Synthesis, antiproliferative and apoptosis-inducing activity of thiazolo[5,4-d]pyrimidines by Singh B1, Guru SK, Kour S, Jain SK, Sharma R, Sharma PR, Singh SK, Bhushan S, Bharate SB, Vishwakarma RA.(PubMed)
(3) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM1, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)

3. Isothiocyanates as Antioxidants
Free radicals are atoms, molecules, or ions with unpaired electrons through chemical bonds with other atoms or molecules during a chemical reaction. They may have positive, negative or zero charge. The unpaired electrons cause radicals to be highly chemically reactive in the human body, leading to aging and cancers.
In Fuchs endothelial corneal dystrophy (FECD), an oxidative stress disorder, treatment with Sulforaphane, a molecule within the isothiocyanate group, decreased CEC apoptosis by 55% in unstressed group and by 43% in tBHP-treated specimens, through inhibition of oxidative stress(1).
The Universidade Federal de Ouro Preto study also indicated the similar result of sulforaphane in improvement of antioxidant status in the testing of number of cancer cell lines(2). Other study suggested that isothiocyanates (ITCs), found abundantly in cruciferous vegetables, may be effective as a cancer chemopreventive agent through modulation of phase II detoxifying/antioxidant enzyme activities(3).

(1) Sulforaphane decreases endothelial cell apoptosis in fuchs endothelial corneal dystrophy: a novel treatment by Ziaei A1, Schmedt T, Chen Y, Jurkunas UV.(PubMed)
(2) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM1, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)
(3) Structural influence of isothiocyanates on the antioxidant response element (ARE)-mediated heme oxygenase-1 (HO-1) expression by Prawan A1, Keum YS, Khor TO, Yu S, Nair S, Li W, Hu L, Kong AN.(PubMed)

4. Isothiocyanates and heart diseases
Beside cancer, heart disease kills more than 2,000 Americans everyday. Approximately 60 million Americans have heart disease.
There are many causes of heart diseases. Most of heart diseases are caused by high blood pressure contributes to hardening of the arteries. High levels of bad cholesterol (LDL) build up in the arteries as a result of uncontrolled diet with high levels of saturated fat and trans fat.
In human immunodeficiency virus (HIV) patients, showed to improve AIDS-related heart dysfunction through inhibition of apoptosis by decreasing iNOS and Bax expression through suppression of NF-κB.(1). In ischemic injury of hearts patients, showed to inhibit reactive oxygen species mediators in exerting a toxic effect during ischemia-reperfusion through mitochondrial K(ATP) channels and antioxidant pathway(2). On ischaemia-reperfusion-induced cardiac injury. steamed broccoli showed a superior cardioprotective properties over cooked broccoli, probably through through the redox signalling of sulphoraphane(3). the phytochemical also found to trduce risk of vascular disease due to aging by inhibiting oxidative stress (4).

(1) Isothiocyanates ameliorate the symptom of heart dysfunction and mortality in a murine AIDS model by inhibiting apoptosis in the left ventricle. by Ho JN1, Yoon HG, Park CS, Kim S, Jun W, Choue R, Lee J.(PubMed)
(2) Sulforaphane protects ischemic injury of hearts through antioxidant pathway and mitochondrial K(ATP) Piao CS1, Gao S, Lee GH, Kim do S, Park BH, Chae SW, Chae HJ, Kim SH.(PubMed)
(3) Comparison of the protective effects of steamed and cooked broccolis on ischaemia-reperfusion-induced cardiac injury. by Mukherjee S1, Lekli I, Ray D, Gangopadhyay H, Raychaudhuri U, Das DK.(PubMed)
(4) Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging by Chapple SJ1, Siow RC, Mann GE.(PubMed)

5. Isothiocyanates and neuroprotective effect
Sulforaphane, a naturally organosulfur compound found in broccoli, showed to exert its neuroprotective effects through significantly attenuated the scopolamine-induced memory impairment and improved cholinergic system reactivity, as indicated by an increased ACh level, decreased AChE activity, and increased choline acetyltransferase (ChAT) expression in the hippocampus and frontal cortex(1). in a variety of acute and chronic neurodegenerative diseases, phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, demonstrated its neuroprotective effects in several in vitro and in vivo studies, may be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway(2). In dopaminergic neurotoxicity in mice induced by 6-hydroxydopamine (6-OHDA), the phytochemical showed the neuroprotective effect through its ability to enhance glutathione levels and its dependent enzymes (glutathione-S-transferase and glutathione reductase) and to modulate neuronal survival pathways(3).

(1) Sulforaphane alleviates scopolamine-induced memory impairment in mice by Lee S1, Kim J1, Seo SG2, Choi BR3, Han JS3, Lee KW4, Kim J5.(PubMed)
(2) Sulforaphane as a potential protective phytochemical against neurodegenerative diseases byTarozzi A1, Angeloni C, Malaguti M, Morroni F, Hrelia S, Hrelia P.(PubMed)
(3) Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson’s disease byMorroni F1, Tarozzi A, Sita G, Bolondi C, Zolezzi Moraga JM, Cantelli-Forti G, Hrelia P.(PubMed)

6. Sulforaphane and Obesity
Obesity is defined as a medical condition of excess body fat has accumulated overtime, while overweight is a condition of excess body weight relatively to the height. According to the Body Mass Index(BMI), a BMI between 25 to 29.9 is considered over weight, while a BMI of over 30 is an indication of obesity. According to the statistic, 68% of American population are either overweight or obese.
Taking foods containing sulforaphane may be effective in managing weight loss for obese patients accompanied with change of lifestyle with more vegetables and fruits into diet. Sulforaphane, a molecule within the isothiocyanate group, according to Chungbuk National University, showed to prevent high-fat diet (HFD)-induced obesity in C57BL/6N mice. through inhibiting adipogenesis( the cells differentiation for a vital role in energy homeostasis and process the largest energy reserve in the body of animals). via down-regulation of PPARγ(regulation of metabolism) and C/EBPα (inflammatory process) and by suppressing lipogenesis( protein as an intermediate stage in metabolism of simple sugars) through activation of the AMPK(in cellular energy homeostasis) pathway(1). Chronic oral administration of sulforaphane, on obesity and insulin resistance induced by a highly palatable (HP) diet in male Wistar rats, at the specific dose was able to accentuate glucose intolerance and may affect GLUT3 expression involed neuronal glucose transport in the cerebral cortex and hypothalamus(2). The Chonbuk National University also suggested that Sulforaphane suppressed AMPK phosphorylation(cellular energy homeostasis) at Thr-172 in a dose-dependent manner(3).

(1) Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice by Choi KM1, Lee YS1, Kim W1, Kim SJ2, Shin KO1, Yu JY3, Lee MK1, Lee YM1, Hong JT1, Yun YP1, Yoo HS4.(PubMed)(2) Chronic sulforaphane oral treatment accentuates blood glucose impairment and may affect GLUT3 expression in the cerebral cortex and hypothalamus of rats fed with a highly palatable diet by Souza CG1, Riboldi BP, Hansen F, Moreira JD, Souza DG, de Assis AM, Brum LM, Perry ML, Souza DO.(PubMed)
(3) Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway by Lee JH1, Moon MH, Jeong JK, Park YG, Lee YJ, Seol JW, Park SY.(PubMed)

7. Sulforaphane and Lung diseases
Lung diseases is defined as a condition, affecting the upper respiratory tract, trachea, bronchi, bronchioles, alveoli, pleura and pleural cavity, and the nerves and muscles of breathing.
Sulforaphane may be used as a preventive chemical constituent of pulmonary damage for patient who exposure to arsenic. According to China Medical University, arsenic-containing dust resulted in ; all of which were blocked by sulforaphane (SF) blocked pathological alterations, oxidative DNA damage, and mild apoptotic cell death in the lung caused by 2 weeks of exposure to arsenic through activation of Nrf2(master regulator of the total antioxidant system)(1). In wildtype neonatal mice exposed to hyperoxia. SF also found to activated Nrf2 activation through induced expression of anti-oxidant genes,(2). In the lungs of the arrhythmic Clock(Δ19) mice, SF also activated it anti ovidative damage effect through activation of NRF2/glutathione defense pathway in combating oxidative/fibrotic lung damage(3).

(1) Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response. by Zheng Y1, Tao S, Lian F, Chau BT, Chen J, Sun G, Fang D, Lantz RC, Zhang DD.(PubMed)
(2) Transcriptional responses of neonatal mouse lung to hyperoxia by Nrf2 status by McGrath-Morrow SA1, Lauer T, Collaco JM, Lopez A, Malhotra D, Alekseyev YO, Neptune E, Wise R, Biswal S.(PubMed)
(3) The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis by Pekovic-Vaughan V1, Gibbs J, Yoshitane H, Yang N, Pathiranage D, Guo B, Sagami A, Taguchi K, Bechtold D, Loudon A, Yamamoto M, Chan J, van der Horst GT, Fukada Y, Meng QJ.(PubMed)

8. Sulforaphane and Liver disease
Liver disease in most cases are linked to alcohol or drugs. In fact, it can be caused by a variety of factors and affecting everyone from infants to older adults.
In CYP2E1-dependent binge alcohol-induced liver steatosis, oral treatment of sulforphane sulforaphane showed to activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels(1). In the comparison of the effectiveness of Sulforaphane and glucoraphanin in modulating carcinogen-metabolising enzymes in Hep G2 cells, Dr Abdull Razis AF1, and Noor NM found that sulforphane is superior to glucoraphanin in modulators of various phase I and phase II enzymes involved in carcinogen-metabolising enzyme systems in vitro(2). The University of Rhode Island, Kingston study also insisted that SF activate Nrf2 activation in inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lep(ob/ob) mice(3)..

(1) Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis by Zhou R1, Lin J, Wu D.(PubMed)
(2) Sulforaphane is superior to glucoraphanin in modulating carcinogen-metabolising enzymes in Hep G2 cells by Abdull Razis AF1, Noor NM.(PubMed)
(3) Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice by Xu J1, Kulkarni SR, Donepudi AC, More VR, Slitt AL.(PubMed)

9. Sulforaphane and Breast cancer
Breast cancer (malignant breast neoplasm) is a cancer that starts in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast. In 2010, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.
The University of Michigan, also insisted that ingestion of sulforaphane at a dose of 50 mg/kg for 2 weeks inhibited breast cancer stem cells(1). According to Manipal University, Sulforaphane inhibited growth of human breast cancer cell line MCF-7 cells, through induces apoptosis and anti-inflammatory effects on MCF-7 cells via downregulation of Bcl-2 (anti-apoptotic protein) and COX-2 (inlvoved inflammatory process) respectively(2). Also in testing of MCF-7 breast cancer cells, researchers at the The Catholic University of Korea, showed that sulforaphane induced the inhibition of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression(involved in keratinocyte migration and granulation tissue remodeling during wound healing) and cell invasion by via the suppression of the NF-κB (nvolved in cellular responses)pathway in MCF-7 cells(3).

(1) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells by Li Y1, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D.(PubMed)
(2) Sulforaphane inhibits growth of human breast cancer cells and augments the therapeutic index of the chemotherapeutic drug, gemcitabine by Hussain A1, Mohsin J, Prabhu SA, Begum S, Nusri Qel-A, Harish G, Javed E, Khan MA, Sharma C.(PubMed)
(3) Sulforaphane controls TPA-induced MMP-9 expression through the NF-κB signaling pathway, but not AP-1, in MCF-7 breast cancer cells by Lee YR1, Noh EM, Han JH, Kim JM, Hwang BM, Kim BS, Lee SH, Jung SH, Youn HJ, Chung EY, Kim JS.(PubMed)

10. Sulforaphane and Prostate cancer
Prostate cancer is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth which spread to the distant parts of the body. Most prostate cancers are slow growing and enlarged prostate and prostate cancer may be detected during the Physical (rectum) exams.
Oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC)., according to the University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine(1)
In advanced prostate cancer stem-like cells, sulforaphane showed to inhibit tumor engraftment and tumor growth, without the induction of liver necrosis or other obvious side effects, In vivo(2).
In the comparison of the effect of sulforaphane(SFN) and 3,3′-diindolylmethane(DIM) in normal prostate epithelial cells and prostate cancer cells, researchers at the Oregon State University found that SFN and DIM reversed many of the cancer-associated methylation alterations, including aberrantly methylated genes that are dysregulated or are highly involved in cancer progression(3).

(1) Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy by Vyas AR1, Hahm ER, Arlotti JA, Watkins S, Stolz DB, Desai D, Amin S, Singh SV.(PubMed)
(2) Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells by Labsch S, Liu L, Bauer N, Zhang Y, Aleksandrowicz E, Gladkich J, Schönsiegel F, Herr I.(PubMed)
(3) Effects of sulforaphane and 3,3′-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells by Wong CP1, Hsu A1, Buchanan A2, Palomera-Sanchez Z1, Beaver LM1, Houseman EA2, Williams DE3, Dashwood RH3, Ho E4.(PubMed)

11. Sulforaphane and colon cancer
Bowel cancer is relatively very common and slowly growing and progress cancer and in predictable way. Bowel cancer is the third most commonly diagnosed cancer in developed countries, including US and Canada.
According to 1INRA, Laboratoire des Xénobiotiques, sulforaphane inhibited colon cancer cell line (HT29) through cell cycle arrest via an apoptotic process(1). GE132+Natural, a novel supplement consisting Resveratrol, Ganoderma lucidum, Sulforaphane, Lycopene and Royal jelly, in the testing of tested cancer cell lines (PC3, MCF7 and SW480), is found to be effective in inhibiting all tested cancer cell proliferation, the University of Belgrade insisted(2). Other study also showed the effective of sulforaphane and related dietary isothiocyanates in treating colon cancer cells via included cell growth arrest, autophagy and apoptosis depending to Depending on the isothiocyanates (ITCs) and treatment conditions(3).

(1) Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells by Gamet-Payrastre L1, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, Gasc N, Tulliez J, Tercé F.(PubMed)
(2) GE132+Natural: Novel promising dietetic supplement with antiproliferative influence on prostate, colon, and breast cancer cells by Okic-Djordjevic I1, Trivanovic D, Krstic J, Jaukovic A, Mojsilovic S, Santibanez JF, Terzic M, Vesovic D, Bugarski D.(PubMed)
(3) HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates by Rajendran P1, Kidane AI, Yu TW, Dashwood WM, Bisson WH, Löhr CV, Ho E, Williams DE, Dashwood RH.(PubMed)

12. Sulforaphane and cervical cancer
Cervix is the lower part of uterus that opens at the top of the vagina. Cervix acts an transition area for vaginal lining (squamous epithelium) change to uterus type (columnar epithelium) through the transitional area (squamous columnar epithelium) to host the development of the fetus. Cervical cancer is malignant neoplasm of the cervix uteri or cervical area caused by abnormal cells growth with alternation of cells DNA.
According to the Manipal University in the study of the effect of sulforaphane and eugenol effects on human cervical cancer cells, found that combined treatment with variable dose combinations resulted in differential effects with an antagonistic effect at lower and synergistic at higher sub-lethal doses as reflected in cell cytotoxicity and apoptosis induction(1). The Manipal University also showed that application of SFN inhibited human cervical cancer cell lines through apoptosis induction and anti-inflammatory properties(2). In human cervical carcinoma HeLa, treatment with SFN inhibit the cancer cell through down-regulation of anti-apoptotic Bcl-2 and Bcl-XL, and the up-regulation of pro-apoptotic Bax expression(3).

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(1) Concurrent sulforaphane and eugenol induces differential effects on human cervical cancer cells by Hussain A1, Priyani A, Sadrieh L, Brahmbhatt K, Ahmed M, Sharma C.(PubMed)
(2) Anti-carcinogenic effects of sulforaphane in association with its apoptosis-inducing and anti-inflammatory properties in human cervical cancer cells by Sharma C1, Sadrieh L, Priyani A, Ahmed M, Hassan AH, Hussain A.(PubNed)
(3) Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3 by Park SY1, Kim GY, Bae SJ, Yoo YH, Choi YH.(PubMed)

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Food Therapy – Eggplant (Solanum Melongena)

Eggplant is a species of S. melongena, belonging to the family Solanaceae and native to India. The plant has been cultivated in southern and eastern Asia since prehistory. It is famous with its deeply purple and the best eggplant can be found from August through October when it is in season.

Nutritional Supplements
1. Carbohydrates
2. Sugars
3. Fiber
4. Fat
5. Protein
6. Thiamine (Vitamin B1)
7. Riboflavin (Vitamin B2)
8. Niacin (Vitamin B3)
9. Pantothenic acid (B5)
10. Vitamin B6
11. Folate (Vitamin B9)
12. Vitamin C
13. Tryptophan
14. Manganese
15. Calcium
16. Copper
17. Iron
18. Magnesium
19. Phosphorus
20. Potassium
21. Zinc
22. Etc.

Chemical constituents
The vegetable chemical compounds containing include sterols (i.e. typical plant sterols, androstane, pregnane and cholestane derivatives, steroidal alkaloids and sapogenins), phytosterols, triterpenes, δ-amyrin, Chlorogenic acid, Nasunin and other Polyphenolic compounds.

1. Eggplant and cancer
Cancer is a class of diseases in which a group of cells growing and multiplying disordered and uncontrollable way in our body, have become progressively worse and damaged other healthy tissues, sometimes spreads to other organs in the body via lymph or blood and results may be in death.
The study of antiproliferative activities against human colon (HT29) and liver (HepG2) cancer cells conducted by Yeungnam University, the eggplant glycoalkaloids solamargine showed to inhibit both cancer cell lines but greater in colon cancer cell line(1). In human fibrosarcoma HT-1080 cell, delphinidin, a flavonoid pigment contained in the peel of eggplant, slightly inhibited tumor cell invasiveness probably through slight inhibition of the activity of MMPs(secretes matrix metalloproteinase)(2). According to Dr. Shimada A. in an one year (continuous 2 days for 12 months) food surveys held at 5 areas in Japan, the frequency of intake eggplant may associate to increase risk of gastric cancer and gastric cancer mortality rate(3), but may account partly for the geographic variation in gastric cancer mortality in Japan(4).

(1) Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells by Lee KR1, Kozukue N, Han JS, Park JH, Chang EY, Baek EJ, Chang JS, Friedman M.(PubMed)
(2) Inhibitory effect of delphinidin from Solanum melongena on human fibrosarcoma HT-1080 invasiveness in vitro by Nagase H1, Sasaki K, Kito H, Haga A, Sato T.(PubMed)
(3) [Regional differences in gastric cancer mortality and eating habits of people].[Article in Japanese] by Shimada A.(PubMed)
(4) Food consumption and gastric cancer mortality in five regions of Japan by Tsubono Y1, Kobayashi M, Tsugane S.(PubMed)

2. Eggplant and cholesterol
Cholesterol is needed for our body to build cell walls, make hormones and vitamin D, and create bile salts that help you digest fat. However too much of it can be dangerous because cholesterol cannot dissolve in your blood. The special particle called lipoprotein moves this waxy, soft substance from place to place. If you have too much low density lipoprotein LDL that is known as bad cholesterol, overtime cholesterol can build up in your arterial walls causing blockage and leading to heart attack and stroke.
Eggplant (Solanum melongena) has been used as hypocholesterolemic agent in many countries, including Brazil. its phenolic may has the potential to reduce hyperglycemia-induced pathogenesis linked to cellular oxidation stress(1). In a study of 38 hypercholesterolemic human volunteers ingesting S. melongena infusion for five weeks, researchers found no differences when compared to control, but in Intraindividual analysis S. melongena infusion significantly reduced the blood levels of total and LDL cholesterol and of apolipoprotein B(1).
But in a double-blind placebo-controlled study of the effectiveness of oral Solanum melongena (SM) against hyperlipidemia, showed the potential result in decreased serum total cholesterol, LDL-c and LDL-c/HDL-c, but no change in serum triglycerides, HDL-c, VLDL-c, AST, ALT, gGT, glucose and body mass index, after 3 months(2) and according to Universidade Federal de Minas Gerais, eggplant did not alter the total cholesterol and atherogenic lipoproteins after 12 week of intake in its study (3).

(1) In vitro studies of eggplant (Solanum melongena) phenolics as inhibitors of key enzymes relevant for type 2 diabetes and hypertension by Kwon YI1, Apostolidis E, Shetty K.(PubMed)(2) Eggplant (Solanum melongena) infusion has a modest and transitory effect on hypercholesterolemic subjects by Guimarães PR1, Galvão AM, Batista CM, Azevedo GS, Oliveira RD, Lamounier RP, Freire N, Barros AM, Sakurai E, Oliveira JP, Vieira EC, Alvarez-Leite JI.(PubMed)(3) [Absence of hypolipidemic effect of Solanum melongena L. (eggplant) on hyperlipidemic patients].[Article in Portuguese] by Silva GE1, Takahashi MH, Eik Filho W, Albino CC, Tasim GE, Serri Lde A, Assef AH, Cortez DA, Bazotte RB.(PubMed)
(4) Effects of eggplant (Solanum melongena) on the atherogenesis and oxidative stress in LDL receptor knock out mice (LDLR(-/-)) by Botelho FV1, Enéas LR, Cesar GC, Bizzotto CS, Tavares E, Oliveira FA, Gloria MB, Silvestre MP, Arantes RM, Alvarez-Leite JI.(PubMed)

3. Eggplant as antioxidant
Free radicals are atoms, molecules, or ions with unpaired electrons through chemical bonds with other atoms or molecules during a chemical reaction. They may have positive, negative or zero charge. The unpaired electrons cause radicals to be highly chemically reactive in the human body, leading to aging and cancers.
Eggplant fruit contains a rich source of polyphenol compounds endowed with antioxidant properties. According to Università degli Studi di Catania, dry peeled skin combined with 50% aqueous ethanol, irradiated with microwave contained showed a high quantity of flavonoids with good antioxidant activity expressed through its capacity to scavenge superoxide anion and to inhibit lipid peroxidation(1). Solanum anguivi fruit (SAG) exhibited potent and concentration dependent free radical-scavenging activity as well as protected against Ca(2+) (110 μmol/L)-induced mitochondrial swelling and maintained the mitochondrial membrane potential, in the evaluation of the antioxidant and radical scavenging activities of Solanum anguivi fruit (SAG) and its possible effect on mitochondrial permeability transition pore(2).
The City University of New York, in the study of the antioxidant-caffeoylquinic acid isomers in fruits of wild eggplant relatives, 3-O-malonyl-5-O-(E)-caffeoylquinic acid (isomer 1) and 4-O-(E)-caffeoyl-5-O-malonylquinic acid (isomer 2) exhibited free radical scavenging activity, albeit about 4-fold lower than that of the flavonol quercetin dehydrate(3).

(1) Antioxidant activity and phenolic content of microwave-assisted Solanum melongena extracts by Salerno L, Modica MN, Pittalà V, Romeo G, Siracusa MA, Di Giacomo C, Sorrenti V, Acquaviva R.(PubMed)
(2) African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca(2+)-induced mitochondrial swelling by Elekofehinti OO1, Kamdem JP, Bolingon AA, Athayde ML, Lopes SR, Waczuk EP, Kade IJ, Adanlawo IG, Rocha JB.(PubMed)
(3) Two new antioxidant malonated caffeoylquinic acid isomers in fruits of wild eggplant relatives by Ma C1, Dastmalchi K, Whitaker BD, Kennelly EJ.(PubMed)

4. Eggplant and cardiovascular diseases
Beside cancer, heart disease kills more than 2,000 Americans everyday. Approximately 60 million Americans have heart disease. Most of heart diseases are caused by high blood pressure contributes to hardening of the arteries. High levels of bad cholesterol (LDL) build up in the arteries as a result of uncontrolled diet with high levels of saturated fat and trans fat.

Animals fed freeze-dried products of either raw or grilled eggplants for 30 days study showed a positive effect of raw and cooked eggplant (Solanum melongena L) in increase left ventricular function, and reduce myocardial infarct size and cardiomyocyte apoptosis with high potency in grilled eggplants(1). According to Tuskegee University, eggplant containing high sources of phenolic compounds, which might provide anti-oxidative protection against free radicals in the human body and might reduce the risk of chronic diseases(2)

(1) Cardioprotective properties of raw and cooked eggplant (Solanum melongena L) by Das S1, Raychaudhuri U, Falchi M, Bertelli A, Braga PC, Das DK.(PubMed)
(2) Total phenolics and antioxidant capacity of indigenous vegetables in the southeast United States: Alabama Collaboration for Cardiovascular Equality Project by Huang Z1, Wang B, Eaves DH, Shikany JM, Pace RD.(PubMed)

5. Eggplant and Type II diabetes
Diabetes is defined as a condition caused by insufficient insulin entering the bloodstream to regulate the glucose. It is either caused by cells in pancreas dying off or receptor sites clogged up by fat and cholesterol. In some cases, diabetes is also caused by allergic reactions of cells in the immune system.

According to University of Massachusetts, phenolic-enriched extracts of eggplant with moderate free radical scavenging-linked antioxidant activity had high alpha-glucosidase inhibitory activity, through inhibition of key enzymes relevant for type 2 diabetes and hypertension(1). Chlorogenic acids (CGAs (71 compounds), being esters of derivatives of cinnamic acids with quinic acid found in many foods, including eggplant may be associated to reduce risk of the risk of human chronic diseases such as inflammation, diabetes(2).

(1) In vitro studies of eggplant (Solanum melongena) phenolics as inhibitors of key enzymes relevant for type 2 diabetes and hypertension by Kwon YI1, Apostolidis E, Shetty K.(PubMed)
(2) n outlook on chlorogenic acids-occurrence, chemistry, technology, and biological activities by Upadhyay R1, Mohan Rao LJ.(PubMed)

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Herbal Chamomile

By Kyle J. Norton

Chamomile is also known as camomile, common name of many species daisy-like plants in the family Asteraceae. The herb has been used in traditional medicine as antispasmodic and anti-inflammatory constituents and to treat menstrual cramps and sleep disorders, reduce cramping and spastic pain in the bowels, relieve excessive gas and bloating in the intestine, etc.

Guaianolides matricarin and achillin, acetoxyachillin and leucodin (= desacetoxymatricarin), corresponding C-11 stereoisomers(a),(Z)-2-β-d-glucopyranosyloxy-4-methoxycinnamic acid (cis-GMCA), chlorogenic acid, (E)-2-β-d-glucopyranosyloxy-4-methoxycinnamic acid (trans-GMCA), quercetagetin-7-O-β-d-glucopyranoside, luteolin-7-O-β-d-glucoside, apigenin-7-O-β-d-glucoside, chamaemeloside, apigenin 7-O-(6″-O-acetyl-β-d-glucopyranoside), apigenin] and one polyacetylene (tonghaosu)(b).

1. Chamomile and anti inflammatory effect
The immune system is the set of cells and their activity against antigens or infectious agents that comprises of the body’s defense system against diseases. The immune system does a great job of keeping people healthy and preventing infections. Beside foods and nutritional supplements, herbs also play a important role in helping the immune system defend against viruses and bacteria attacks.
In the study at Case Western Reserve University, showed its potential anti-inflammatory mechanisms, through inhibited NO production and iNOS gene expression via inhibiting RelA/p65 activation(1). The study of whether chamomile interferes with the COX-2 pathway, showed a positive effect of the herb in inhibition of COX-2 enzyme activity and causation of reduction in LPS-induced COX-2 mRNA and protein expression(2),
The study of supplement containing 2 flavonoids (>95% pure), luteolin (100 mg/capsule, from chamomile) and quercetin (70 mg/capsule), and the quercetin glycoside rutin (30 mg/capsule) from the Sophora japonica leaf, formulated in olive kernel oil to increase oral absorption, suggested that that the combination of the flavonoids luteolin and quercetin seemed to be effective in reducing ASD symptoms, with no major adverse effects through it anti inflammatory activities(3)

(1) Chamomile: an anti-inflammatory agent inhibits inducible nitric oxide synthase expression by blocking RelA/p65 activity by Bhaskaran N1, Shukla S, Srivastava JK, Gupta S.(PubMed)
(2) Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity by Srivastava JK1, Pandey M, Gupta S.(PubMed)
(3) An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders by Taliou A1, Zintzaras E, Lykouras L, Francis K.(PubMed)

2. Chamomile and dermatitis
Dermatitis or eczema, is defined as a condition of inflammation of skin including itchy, erythematous, vesicular, weeping, and crusting patches.
The use of chamomile oil in folk medicine for treatment of skin disorder may have found to be effect in modern medicine, according to Howon University, application of German chamomile oil to alleviating atopic dermatitis, such as reduced serum IgG1 level and significantly lower serum histamine level through influencing of Th2 cell activation(1).
Dr Dohil MA. in the study of herbal effects on in atopic dermatitis and other inflammatory skin disease, indicated there may be a positive effect of herbal medicine, including chamomile through the present recent multicenter and international clinical studies that support their efficacy and safety profile for a variety of inflammatory skin conditions(2). and herbs containing anti inflammatory activity such as chamomile may be particularly well suited as alternatives to pharmacologic therapies in chronic conditions for which long-term use is required,(3), Dr. Wu J. said.
Although, German chamomile may be effective for treatment of skin disorder, but it was found to allergic effect in some patients in external use of chamomile tea or use of chamomile-containing topical herbal remedies, due to its chemical constituent herniarin(4)

(1) Effect of German chamomile oil application on alleviating atopic dermatitis-like immune alterations in Lee SH1, Heo Y, Kim YC.(PubMed)
(2) Natural ingredients in atopic dermatitis and other inflammatory skin disease.

Dohil MA.(PubMed)
(3) Anti-inflammatory ingredients by Wu J.(PubMed)
(4) The coumarin herniarin as a sensitizer in German chamomile [Chamomilla recutita (L.) Rauschert, Compositae] by Paulsen E1, Otkjaer A, Andersen KE.(PubMed)

4. Chamomile and insomnia
Insomnia is a sign and symptom of sleep disorder and defined as a condition in which a person has a difficulty falling asleep and/or staying asleep or sleep of poor quality that can lead to substantial impairments in the quality of life and functional capacity of an individual. Most adults have experienced insomnia sometimes in their life. According to statistic, more than 30% of the population suffers from insomnia, one in three people suffer from some form of insomnia during their lifetime and women suffer from insomnia more often than men.

Chamomile, one of most popular herb used for sleep disorders in herbal medicine. According to the Dr. Srivastava JK and research team at the Case Western Reserve University, many different preparations of the herb have been developed, the most popular of which is in the form of herbal tea consumed more than one million cups per day(1).
In a standardized chamomile extract for chronic primary insomnia study, in adults with chronic primary insomnia, the herb showed a modest benefits of daytime functioning and mixed benefits on sleep diary(2). According to DR. Wheatley D., the anxiolytic or sedative properties of chamomile chamomile, Ylang-Ylang) would appear to improve sleep, but how practical a form of treatment this may be remains to be determined(3).But in the assessing the benefits of chamomile in sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO), sleep quality, and number of awakenings, researchers at the1University of Michigan, indicated that it may be the modest advantage on daytime functioning, but did not reach statistical significance(4).

(1) Chamomile: A herbal medicine of the past with bright future by Srivastava JK1, Shankar E, Gupta S.(PubMed)(2) Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: a randomized placebo-controlled pilot study by Zick SM1, Wright BD, Sen A, Arnedt JT.(PubMed)
(3) Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability. by Wheatley D.(PubMed)
(4) Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: a randomized placebo-controlled pilot study by Zick SM1, Wright BD, Sen A, Arnedt JT.(PubMed)

5. Chamomile and cancer
Cancer is a class of diseases in which a group of cells growing and multiplying disordered and uncontrollable way in our body, have become progressively worse and damaged other healthy tissues, sometimes spreads to other organs in the body via lymph or blood and results may be in death.
According to the study by Dr. Srivastava JK and Dr.Gupta S. in cancer cells, chamomile extract showed to induce minimal growth inhibitory responses in normal cells, but significant decrease in cell viability was observed in various human cancer cell lines, through exhibition of its antiproliferative and apoptotic activities(1). The Harokopio University, study also indicated the effectiveness of chamomile in inhibition of epithelial colon cancer (HT29) cell line probably through regulation of regulate nuclear factor-kappa B(2). The testing of biological activity of 20 essential oils (EOs) from herbal plants for theirs effectiveness in numbers of cancer cell line, including human colon carcinoma, (HCT116), rat basophilic leukemia RBL-2H3 cells, according to Kobe Gakuin University, chamomile showed a significant effects on both cancer cell growth and mast cell degranulation(3).

(1) Antiproliferative and apoptotic effects of chamomile extract in various human cancer cells.
Srivastava JK1, Gupta S.(PubMed)
(2) Herbal infusions; their phenolic profile, antioxidant and anti-inflammatory effects in HT29 and PC3 cells by Kogiannou DA1, Kalogeropoulos N, Kefalas P, Polissiou MG, Kaliora AC.(PubMed)
(3) Effects of essential oils from herbal plants and citrus fruits on DNA polymerase inhibitory, cancer cell growth inhibitory, antiallergic, and antioxidant activities by Mitoshi M1, Kuriyama I, Nakayama H, Miyazato H, Sugimoto K, Kobayashi Y, Jippo T, Kanazawa K, Yoshida H, Mizushina Y.(PubMed)

6. Chamomile and skin cancer
Basal cell cancer is the most common type of skin cancer as a result of abnormal growth of the cells in the lowest layer of the epidermis. The cancer rarely spread and kill but can cause significant destruction and disfigurement to the affected skin area and accounted for more than 90% of all skin cancer in the U.S.
According to statistic, skin cancers accounted for approximately 40% of all cancers reported in the United States and approximately 9,500 deaths per year. Herbal chamomile showed to inhibited skin cancer cell lines through its antioxidant effects via inhibition of reactive oxygen species (ROS) type free radicals probably via downregulation of H2O2-generated free radicals in human skin fibroblasts (1). Apigenin , a chemical constituent of flavonoid found in chamomile, with 10 mumoles apigenin in 200 microliters DMSO:acetone (1:9) prior to each UVB exposure showed a promised resulted in reduction in cancer incidence (52% inhibition), through absorbing ultraviolet light or decreasing DNA damage(2). In support of the above, the National Taiwan University, indicated that a effectiveness of apigenin, in suppression of 12-0-tetradecanoyl-phorbol-13-acetate-(TPA)-mediated tumor promotion of mouse skin, through vary mechanisms(3).

(1) The active natural anti-oxidant properties of chamomile, milk thistle, and halophilic bacterial components in human skin in vitro by Mamalis A1, Nguyen DH, Brody N, Jagdeo J.(PubMed)
(2) Inhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoid by Birt DF1, Mitchell D, Gold B, Pour P, Pinch HC.(PubMed)
(3) Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin by Lin JK1, Chen YC, Huang YT, Lin-Shiau SY.(PubMed)

7. Chamomile and Neuroprotective effect
The evaluation of the neuroprotective effect of German chamomile against aluminium fluoride (AlF₄⁻)-induced oxidative stress in rats. showed a neuroprotective effect of herbal chamomile, through significantly decreased in lipid peroxidation (LPO) and increased in the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and total thiol levels in extract-treated animals(1). The Hanagal Shri Kumareshawr College of Pharmacy study, in support of the above, showed the same effectiveness of the herb also through same mechanisms in extract treated groups but this time in global model of ischemia in rats(2)

(1) Neuroprotective activity of Matricaria recutita against fluoride-induced stress in rats by Ranpariya VL1, Parmar SK, Sheth NR, Chandrashekhar VM.(PubMed)
(2) Neuroprotective activity of Matricaria recutita Linn against global model of ischemia in rats vy Chandrashekhar VM1, Ranpariya VL, Ganapaty S, Parashar A, Muchandi AA(PubMed)

8. Chamomile and hepoprotective effect
Chamomilla recutita flavonoids (chamiloflan) showed to exhibit antioxidant and anti-inflammatory effects through induced decrease of ceramide levels in the liver of old rats, according to the Kharkov Karazin National University(1). Flavonoids of German chamomile also exhibited the hepatoprotective effect, through affect sphingolipid metabolism and reduce the elevated ceramide level in the aged liver by normalized activities of key enzymes of sphingolipid turnover (neutral SMase and ceramidase) and ceramide contents in the damaged liver and liver cells, and stabilized the hepatocyte membranes.(2)

(1) Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats.
Babenko NA1, Shakhova EG.(PubMed)
(2) Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells by Babenko NA1, Shakhova EG.(PubMed)

9. Herbal chamomile and anxiety disorder
According to the Canadian mental health association, Anxiety disordered is a result of a combination of biological, psychological, and other individual factors(1a).
Anxiety is the most commonly reported psychiatric conditions and frequently occur as comorbid disorders.
In a randomized, double-blind, placebo-controlled efficacy and tolerability trial of Matricaria recutita (chamomile) extract on generalized anxiety disorder (GAD) showed to effective of modest anxiolytic activity with patient mild to moderate GAD(1). The University of Ottawa study insisted at Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity at doses of 0.11-0.65 mg/mL(2). The study containing 57 participants in the 2009 trial, 19 had anxiety with comorbid depression; 16 had anxiety with a past history of depression; and 22 had anxiety with no current or past depression, chamomile showed a clinically meaningful antidepressant activity to its previously observed anxiolytic activity(3). Apigenin, a component of Matricaria recutita flowers, in in mice study, exerted its anxiolytic and slight sedative effects through the central benzodiazepine receptors(4).

(a) Guaianolides and volatile compounds in chamomile tea by Tschiggerl C1, Bucar F.(PubMed)
(b) Quantitative determination of phenolic compounds by UHPLC-UV-MS and use of partial least-square discriminant analysis to differentiate chemo-types of Chamomile/Chrysanthemum flower heads by Avula B1, Wang YH, Wang M, Avonto C, Zhao J, Smillie TJ, Rua D, Khan IA.(PubMed)
(1a) Anxiety disorder(Canadian mental health association)
(1) A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder by Amsterdam JD1, Li Y, Soeller I, Rockwell K, Mao JJ, Shults J.(PubMed)
(2) Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system by Awad R1, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT.(PubMed)
(3) Chamomile (Matricaria recutita) may provide antidepressant activity in anxious, depressed humans: an exploratory study by Amsterdam JD1, Shults J, Soeller I, Mao JJ, Rockwell K, Newberg AB.(PubMed)

(4) Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects by Viola H1, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC.(PubMed)

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