Thursday 6 February 2014

Breast cancer in Vitamin D's Points of View

 Kyle J. Norton

Vitamin D is a fat-soluble secosteroids found in small amount in few foods, including salmon, mackerel, sardines and tuna. The vitamin plays an important role in modulation of cellular proliferation, apoptosis induction, tumor growth suppression and promotion in absorption of minerals, including calcium, iron, magnesium, phosphate and zinc.
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) which supply the ducts with milk. There is also rare cases of breast cancer started in other areas of the breast.

Epidemiological studies, linking vitamin D in reduced risk of breast caner focused in levels and plasma levels of vitamin D are still on debates. It may be due to age of subjects, menstrual stage, race,  etc.. But the prevalence and wide spread of breast cancer have caused some concerns in the governments and researched community. Every year, 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.

Levels of free circulation of vitamin D are correlated with risk of Breast cancer
 Suggestions of levels of plasma 25-hydroxyvitamin D (25(OH)D)  in a breast cancer risk differentiation by menopause, showed an inverse association beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL(1)and low levels of 25(OH)D  are at higher risk of breast cancer(1). In Chinese breast cancer patients low vitamin D status was found to be associated to increased risk  of breast cancer(2).  In breast cancer risk in an Australian population, in differentiation of plasma vitamin D levels indicated that 25(OH)D concentration below 75 nmol/L was  associated with a significantly higher risk of breast cancer(3). In progesterone receptor negative breast cancer, restricted to premenopausal women only, plasma 25(OH)D concentrations. significant inverse association in breast cancer risk(4) In post postmenopausal breast cancer risk, Circulating 25(OH)D3 and 25(OH)D were found to associated with a reduced risk among whites, but not in other ethnic groups(5). In Genetic factor study, some vitamin D receptor (VDR) gene polymorphisms, such as Bsm1, poly(A), Taq1, Apa1 are associated to risk of breast cancer(6). 2,000 IU vitamin D-3 intake inhibited breast cancer proliferation through reduced COX2 expression(correlated with primary tumor size)(6a). Unfortunately, some suggested that  vitamin D, regardless to dosage do not significantly affect breast cancer risk, treatment efficacy depending to highest dosage of vitamin D and in combination with calcium(6b).

The benefits
In a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development, suggested that the  vitamin D intake or  serum levels of 25 hydroxyvitamin D (25OHD) reduced risk of cancers by exhibiting its anticancer effects, through the impact in a number of cellular mechanisms(7). In triple negative/basal-like breast cancer, 1,25-dihydroxyvitamin D3 (1,25D) suppressed multiple proteins that are required for survival of triple-negative/basal-like breast cancer cells through VDR in down regulated breast cancer invasion and metastasis and up regulated anti-profilaerative and apoptic expression(8). In Two VDRKO (KO240, KO288) and two WT (WT145, WT276) cell lines, 1,25-Dihydroxyvitamin D(3) (1,25D(3)), the active metabolite of vitamin D(3), inhibited the protein expression of VDR through induced G(0)/G(1) arrest and apoptosis in knockout (VDRKO) and wild type (WT) mice(9). In ER negative, invasive human breast cancer cell line SUM-159PT, 1,25(OH)(2)D(3) (1,25D(3)) and EB1089, a novel vitamin D analogue, reduced SUM-159PT cell growth subsequent to elevation of p27(regulator of cell cycle progression at G1 and S phase) and p21(cell cycle inhibitor) levels and inhibited SUM-159PT cell invasion through an 8 microM Matrigel (extract in measurement of the invasive activity of tumor cells)(10). In  human breast cancer cell line MCF-7, Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191), the synthetic version of vitamin D, showed the antiproliferative activity. At higher doses of PRI-2202 or PRI-2205, the analog expressed their anti breast cancer activity similar to Tamoxifen through diminished mitochondrial membrane potential( in cell proliferation), as well as the increased phosphatidylserine (cell death) expression with increase in VDR expression in PRI-2201, but not PRI-219,(11). In MCF-7 breast cancer cells, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), a vitamin D analog(1000-fold more active than 1α,25(OH)2D3) suppressed MCF-7 cells growth through cell cycle arrest and apoptotic induction through the upregulation of E-cadherin(tumor suppressors), and the downregulation of Snail, Slug, and Twist, the transcription in  regulate the expression of tumor suppressors such as E-cadherin(12). In BRCA1-deficient(loss of the DNA repair protein 53BP1) breast cancer cells, 1α,25(OH)2D3, an active form of vitamin D, stabilized 53BP1 levels in tumor cells and restored the levels of 53BP1, resulting in increased genomic instability in response to PARPi or radiation, and reduced proliferation(13). GcMAF, the vitamin D-binding protein-derived macrophage activating factor exhibited its anti breast cancers effects through stimulation of macrophages(a large white blood cell )in induction of apoptosis and eventually phagocytize them(14). HER2, accounted for approximately 20% of human breast cancer cases,  Gemini vitamin D analog BXL0124, decreased activation of ErbB2 as well as other ErbB receptors, ErbB1 and ErbB3, through repression of activated-Erk1/2(cell regulation), activated-Akt(multiple cellular processes, including apoptosis), c-Myc(a regulator gene), CycD1(regulating cell cycle progression), and Bcl2(family of regulator proteins that regulate cell death)(15). In  ER+ BCa., vitamin D suppressed the ER expression and estrogen-mediated signaling in BCa cells(16). In MCF-7 and MCF-7/VD(R) breast cancer cells, insulin-like growth factor I (IGF-I) in 1, 25-dihydroxyvitamin D3 (1, 25-D3)inhibited IGF-I/Akt pathways to cause apoptosis(17). In MCF10DCIS cells, Gemini vitamin D BXL0124 is found to decrease CD44 protein level(a transmembrane glycoprotein, is a major receptor for extracellular proteins involved in invasion and metastasis of human cancers), suppressed STAT3 (development, progression, and maintenance of many human tumors)signaling, and inhibited invasion and proliferation(18) and inhibited the growth of ErbB2 overexpressing mammary tumors through regulating the ErbB2/AKT/ERK(proliferation) signaling pathways in ErbB2-positive mammary tumor growth(18). In MCF-7 breast cancer cells, L-buthionine-S,R-sulfoximine, a glutathione-depleting drug enhanced inhibition of 1,25(OH)(2)D(3) in all transformed breast cell lines through ROS mediation induced apoptosis(19).

The disagreement of amount of vitamin D intake and plasma level in reduced risk and treatment of breast cancer may still need further studies, but the effective of vitamin D may not be denied. Over doses of vitamin D supplement may cause excessive calcium absorption, calcification, Urinary stones etc. please make sure to follow the guideline of the Institute of Medicine of the National Academies.


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References
(1) Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies by Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL.(Pubnmed)
(2) Correlates of 25-Hydroxyvitamin D among Chinese Breast Cancer Patients by Shi L1, Nechuta S2, Gao YT3, Zheng Y4, Dorjgochoo T2, Wu J2, Cai Q2, Zheng W2, Lu W4, Shu XO2.(PubMed)
(3) Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case-control study by Bilinski K, Boyages J.(PubMed)
(4) Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study by Abbas S, Chang-Claude J, Linseisen J.(PubMed)
(5) Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case-control study in the multiethnic cohort study by Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Cooney RV, Lurie G, Maskarinec G, Hernandez BY, Le Marchand L, Henderson BE, Kolonel LN, Goodman MT.(PubMed)
(6) Vitamin D receptor gene polymorphisms in breast and renal cancer: Current state and future approaches (Review) by Khan MI1, Bielecka ZF1, Najm MZ2, Bartnik E3, Czarnecki JS4, Czarnecka AM1, Szczylik C (PubMed)
(6a) Vitamin D favorably alters the cancer promoting prostaglandin cascade by Qin W, Smith C, Jensen M, Holick MF, Sauter ER.(PubMed)
(6b) Vitamin d supplementation and breast cancer prevention: a systematic review and meta-analysis of randomized clinical trials by Sperati F, Vici P, Maugeri-Saccà M, Stranges S, Santesso N, Mariani L, Giordano A, Sergi D, Pizzuti L, Di Lauro L, Montella M, Crispo A, Mottolese M, Barba M.(PubMed)
(7) Vitamin D and cancer: the promise not yet fulfilled by Bikle DD(PubMed).
(8) Modeling vitamin D actions in triple negative/basal-like breast cancer by Laporta E, Welsh J.(PubMed)
(9) Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice by Zinser GM, McEleney K, Welsh J.(PubMed)
(10) Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion by Flanagan L, Packman K, Juba B, O'Neill S, Tenniswood M, Welsh J.(PubMed).
(11) Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells. by Milczarek M, Chodyński M, Filip-Psurska B, Martowicz A, Krupa M, Krajewski K, Kutner A, Wietrzyk J.(PubMed)
(12) MART-10, a less calcemic vitamin D analog, is more potent than 1α,25-dihydroxyvitamin D3 in inhibiting the metastatic potential of MCF-7 breast cancer cells in vitro by Chiang KC, Chen SC, Yeh CN, Pang JH, Shen SC, Hsu JT, Liu YY, Chen LW, Kuo SF, Takano M, Kittaka A, Sun CC, Juang HH, Chen TC.(PubMed)
(13) Novel roles of 1α,25(OH)2D3 on DNA repair provide new strategies for breast cancer treatment by Gonzalo S.(PubMed).
(14) A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages by Thyer L, Ward E, Smith R, Fiore MG, Magherini S, Branca JJ, Morucci G, Gulisano M, Ruggiero M, Pacini S.(PubMed)
(15) Oral administration of a gemini vitamin D analog, a synthetic triterpenoid and the combination prevents mammary tumorigenesis driven by ErbB2 overexpression by So JY, Wahler JE, Yoon T, Smolarek AK, Lin Y, Shih WJ, Maehr H, Uskokovic M, Liby KT, Sporn MB, Suh N.(PubMed).
(16) Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements by Swami S, Krishnan AV, Peng L, Lundqvist J, Feldman D.(PubMed).
(17) Role of insulin-like growth factor binding protein-3 in 1, 25-dihydroxyvitamin-d 3 -induced breast cancer cell apoptosis by Brosseau C, Pirianov G, Colston KW.(PubMed)
(18) Targeting CD44-STAT3 signaling by Gemini vitamin D analog leads to inhibition of invasion in basal-like breast cancer by So JY, Smolarek AK, Salerno DM, Maehr H, Uskokovic M, Liu F, Suh N.(PubMed)
(19) Buthionine sulfoximine and 1,25-dihydroxyvitamin D induce apoptosis in breast cancer cells via induction of reactive oxygen species by Bohl LP, Liaudat AC, Picotto G, Marchionatti AM, Narvaez CJ, Welsh J, Rodriguez VA, Tolosa de Talamoni NG.(PubMed)

Wednesday 5 February 2014

Breast cancer in Vitamin C's Point of View

By Kyle J. Norton


Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support.
Epidemiological studies linking vitamin C in reduced risk of breast cancer may be inconclusive(1)(1a)(1b), but no doubt in acceptance of improved quality of life(2).
 Macro nutrients intake may form an important parts in breast cancer patients in providing vital support for treatment.(3). There was a report of intake of supplementation of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc in postmenopausal women for 10 or more years may protect women from developing breast cancer(3a). 
Women with breast cancer in the Indian population, were found to have a lower levels of mean vitamin C, vitamin E and selenium than controls. if the levels of mean vitamin C, vitamin E and selenium increased by 1 unit, the risk of breast cancer was reduced by 7%(3b).
In breast cancer survival, dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. but not in post-diagnosis(4). High intake of ascorbic acid was in associated to reduce risk of breast cancer incidence in overweight women and women with high consumption of linoleic acid (average consumption of more than 6 grams of linoleic acid per day)(5) and insignificant risk in other breast cancer patients(6). On inflammation in cancer patients, high dose intravenous ascorbic acid therapy, decreased the levels of C-reactive protein thus reduced inflammation correlated with decreases in tumor marker levels(7). Vitamin C supplements and Anthocyanin (Ixor®) at a dose of 2 tablets/day, starting from 10 days before the radiation treatment until 10 days after the end of treatment was found to be protective against skin damage to patient undergoing adjuvant chemotherapy(8).
In estrogen-induced breast carcinogenesis, vitamin C (Vit C) and butylated hydroxyanisole (BHA) found to be effective in inhibition of 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage by preventing the decreasing NRF2(antioxidant response pathway) and OGG1(base excision repair.) levels(9). In the study of the same but in MCF-10A cells, the combination also decreased E2-mediated increase in 8-OHdG(Marker detected in cancer patients) levels in the mammary tissues, induced SOD3 (Extracellular superoxide dismutase [Cu-Zn]) through NRF2 Pathway to defense against oxidative stress and in the prevention of estrogen-mediated breast cancer(10).
 An increased expression of the miR-93(Regulate Expression of Tumor Suppressor Gene) was found in 17β-estradiol (E2)-treated mammary tissues and in human breast cell lines, treatment with vitamin C reverted E2-mediated increase in miR-93 levels by upregulating expression NRF2 antioxidant response pathway(11). In 4T1 breast cancer cells in vitamin C-deficient mice, Ascorbic acid delayed the progress of metastasis, tumor growth and inflammatory cytokine secretion (decreased serum inflammatory cytokine interleukin (IL)-6) as well as enhanced encapsulation of tumors(12). In L-ascorbate (L-ascorbic acid, vitamin C), increasing the concentration exhibited the autophagic damage to functional SVCT-2(antibody) sensitizes breast cancer cells(13). In B16F10, L-ascorbate also caused induction of a prooxidant state,  subsequent reduction in mitochondrial membrane potential to induced apoptosis in a caspase-8(Cell apoptosis)-independent manner(14). In  the usage of glucan, resveratrol and vitamin C,  the combination showed the strongest activator of phagocytosis (immune cell activation) and antibody formation to suppress the growth of breast and lung tumors, through stimulation of apoptosis(15). In  4T1 cancer cell line, combined with ascorbate, Mn(III)N-alkylpyridylporphyrins (MnPs) inhibited cancer cells via peroxide produced outside of the cell through enhancing tumour oxidative stress and tumor growth suppression(16). In Ataxia telangiectasia mutated (ATM)  diplotype on the breast cancer, vitamin C enhanced the increase of ATM to reduce the risk of breast cancer.(17). In E(2) metabolism and oxidant stress in involved in estrogen-induced breast cancer development, vitamin C reducesd the incidence of estrogen-induced mammary tumors, increased tumor latency and decreases oxidative stress in vivo(18). In SK-BR3 and Hs578T breast cancer cell lines, Vitamin C treatment induced AIF(apoptosis-inducing factor) mediation of cell death pathway of the breast cancer cell lines independent to caspase pathway(19).
In human breast cancer cell line MCF-7, combination of Retinoic acid and ascorbic acid inhibited the proliferation of human breast cancer cells through altering their gene expression related to antioxidation processes and the proliferation inhibitory pathway(20).

Taking all together, without going into reviews, vitamin C is found to be effective in reduced risk and a potent agent for treatment of breast cancer. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(21)(22).


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References
(1) Vitamin C suppresses cell death in MCF-7 human breast cancer cells induced by tamoxifen by Subramani T, Yeap SK, Ho WY, Ho CL, Omar AR, Aziz SA, Rahman NM, Alitheen NB.(PubMed)
(1a) Vitamin supplement consumption and breast cancer risk: a review by Misotti AM, Gnagnarella P.(PubMed)
(1b) Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study by Rohan TE, Howe GR, Friedenreich CM, Jain M, Miller AB.(PubMed)
(2) Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany by Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J.(PubMed)
(3) Nutritional assessment of selected patients with cancer.
Surwillo A, Wawrzyniak A.(PubMed)
(3a) Antioxidants and breast cancer risk- a population-based case-control study in Canada by Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG].(PubMed)
(3b) Association between breast cancer and vitamin C, vitamin E and selenium levels: results of a case-control study in India by Singh P, Kapil U, Shukla NK, Deo S, Dwivedi SN.(PubMed)
(4) Vitamin C intake and breast cancer mortality in a cohort of Swedish women by Harris HR, Bergkvist L, Wolk A.(PubMed)
(5) Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women by Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A.(PubMed)
(6) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. by Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA.(PubMed).
(7) Effect of high-dose intravenous vitamin C on inflammation in cancer patients by Mikirova N, Casciari J, Rogers A, Taylor P.(PubMed)
(8) Skin toxicity from external beam radiation therapy in breast cancer patients: protective effects of Resveratrol, Lycopene, Vitamin C and anthocianin (Ixor®) by Di Franco R, Calvanese M, Murino P, Manzo R, Guida C, Di Gennaro D, Anania C, Ravo V.(PubMed)
(9) Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer by Singh B, Chatterjee A, Ronghe AM, Bhat NK, Bhat HK(PubMed).
(10) Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer by Singh B, Bhat HK.(PubMed)
(11) MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis by Singh B, Ronghe AM, Chatterjee A, Bhat NK, Bhat HK.(PubMed)
(12) Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice by Cha J, Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.(PubMed)
(13) SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment by Hong SW, Lee SH, Moon JH, Hwang JJ, Kim DE, Ko E, Kim HS, Cho IJ, Kang JS, Kim DJ, Kim JE, Shin JS, Jung DJ, Jeong YJ, Cho BJ, Kim TW, Lee JS, Kang JS, Hwang YI, Noh DY, Jin DH, Lee WJ.(PubMed)
(14) L-ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8-independent pathway by Kang JS, Cho D, Kim YI, Hahm E, Yang Y, Kim D, Hur D, Park H, Bang S, Hwang YI, Lee WJ.(PubMed)
(15) Combination of glucan, resveratrol and vitamin C demonstrates strong anti-tumor potential.
Vetvicka V, Vetvickova J.(PubMed)
(16) Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate by Ye X, Fels D, Tovmasyan A, Aird KM, Dedeugd C, Allensworth JL, Kos I, Park W, Spasojevic I, Devi GR, Dewhirst MW, Leong KW, Batinic-Haberle I.(PubMed)
(17) Antioxidant vitamins intake, ataxia telangiectasia mutated (ATM) genetic polymorphisms, and breast cancer risk by Lee SA, Lee KM, Lee SJ, Yoo KY, Park SK, Noh DY, Ahn SH, Kang D.(PubMed)
(18) Vitamin C and alpha-naphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats by Mense SM, Singh B, Remotti F, Liu X, Bhat HK.(PubMed)
(19) Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells by Hong SW, Jin DH, Hahm ES, Yim SH, Lim JS, Kim KI, Yang Y, Lee SS, Kang JS, Lee WJ, Lee WK, Lee MS.(PubMed)
(20) Retinoic acid and ascorbic acid act synergistically in inhibiting human breast cancer cell proliferation by Kim KN, Pie JE, Park JH, Park YH, Kim HW, Kim MK.(PubMed)
(21) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)
(22) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)

Tuesday 4 February 2014

Phytochemical Piperine and Immunity

Piperine is a phytochemical alkaloid in the class of organosulfur compound, found abundantly in white and black pepper, long pepper, etc.
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.

The effects

Ethanolic extract of fruits of Piper longum L.(PLE) and piperine was found to inhibit the lethal action of venom both in the in vitro lethality neutralization assay and in vivo lethality neutralization assay against Russell's viper venom in mice by enhancing production of antigen and antibodies response.
In the study of the same subject, administration of PLE and piperine significantly (p<0.01) inhibited venom induced lethality, haemorrhage, necrosis, defibrinogenation and inflammatory paw edema in mice in a dose dependent manner, reduced venom induced mast cell degranulation in rats.



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References
(1) Production of high titre antibody response against Russell's viper venom in mice immunized with ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine by Shenoy PA, Nipate SS, Sonpetkar JM, Salvi NC, Waghmare AB, Chaudhari PD.(PubMed)
(2) Anti-snake venom activities of ethanolic extract of fruits of Piper longum L. (Piperaceae) against Russell's viper venom: characterization of piperine as active principle by Shenoy PA, Nipate SS, Sonpetkar JM, Salvi NC, Waghmare AB, Chaudhari PD.(PubMed)

Phytochemical Allicin and hyper cholesterol

Allicin is phytochemical containing sulfur in the class of organosulfur compound, found abundantly in onion and garlic.
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 health benefits
Evidences emerging that allicin may not only benefit in preventing and treating cardiovascular disease but also lower the blood cholesterol. In the study of the effect of allicin on hypercholesterolemia in male ICR mice, the chemical constituent of garlic showed a positive effect not  in reducing blood cholesterol, triglycerides, and glucose levels , as well as lowering the hepatic cholesterol storage, but also decreasing appetite daily. Other in the study of the same but woth rat fed with high cholesterol diet, showed a reduction of blood cholesterol, triglycerides levels and systolic blood pressure in hypercholesterolemic rats. These result showed that allicin may be considered as a potent agent in treating hypercholesterol in the future.



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References
(1) Cholesterol-lowering effect of allicin on hypercholesterolemic ICR mice, Lu Y, He Z, Shen X, Xu X, Fan J, Wu S, Zhang D.(PubMed)
(2) Effect of allicin from garlic powder on serum lipids and blood pressure in rats fed with a high cholesterol diet by Ali M, Al-Qattan KK, Al-Enezi F, Khanafer RM, Mustafa T.(PubMed)

Cruciferous vegetables and bladder cancer

Cruciferous vegetables are the group of  vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc.
The bladder is a hollow elastic organ in the center of the lower abdomen that collects urine from the kidneys and excreted them through the urethra.
Bladder cancer is most common type of cancer that effect men twice as frequently as it effects women. Usually it starts from the lining the bladder caused by several types of malignant growths of the urinary bladder cells
Nutrients and chemical constituents
1. Carbohydrates
2. Sugars
3. Dietary fiber
4. Omega 3 fatty acid
5. Protein
6. Beta-carotene
7. Lutein and
8. Zeaxanthin
9. Thiamine (Vitamin B1)
10. Riboflavin (Vitamin B2)
11. Niacin (Vitamin B3)
12. Pantothenic acid (B5)
13. Vitamin B6
14. Folate (Vit. B9)
15. Vitamin C
16. Calcium
17. Tryptophan
18. Iron
19. Magnesium
20. Phosphorus
21.Potassium
22. Zinc
23. Etc.
Its chemical constutuents include  glucosinolates, dithiolthiones, indoles , glucoraphanin, s-methyl cysteine sulfoxide, isothiocyanates, indole-3-carbinol, etc..

The effects
Epidemiologic evidence found the reduced incidence of bladder caner with intake of cruciferous vegetables as the result of phytochemicals consisted in them. The study of the effects of isothiocyanates in  normal, noninvasive (RT4), and invasive (J82, UMUC3) human urothelial cell, showed a positive Sulforaphane and erucin reduced the tumor weight. On the other hand, Sulforaphane (SF) activated the Nrf2, the master of antioxidant response in the bladder as well inhibition of the N-butyl-N-(4-hydroxybutyl)nitrosamine, a major human bladder carcinogen in smokers to prevent the bladder cancer development. These results suggest that SF is a highly promising agent for bladder cancer prevention.

The Side effects1. People who has over production of IgM immunoglobulins which makes blood thicken should talk to their doctor before taking high amount of broccoli.
2. Allergic reaction??
3. Etc.



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References
(1) Inhibition of bladder cancer by broccoli isothiocyanates sulforaphane and erucin: characterization, metabolism, and interconversion by Abbaoui B, Riedl KM, Ralston RA, Thomas-Ahner JM, Schwartz SJ, Clinton SK, Mortazavi A.(PubMed)
(2) Sulforaphane inhibits 4-aminobiphenyl-induced DNA damage in bladder cells and tissues by Ding Y, Paonessa JD, Randall KL, Argoti D, Chen L, Vouros P, Zhang Y.(PubMed)

Herbal Cascara Sagrada (Rhamnus purshiana) and Liver cancer


Cascara sagrada is a species of buckthorn, genus Rhamnus, belonging to the family Rhamnaceae, native to western North America, it's bark has been used in traditional medicine for gastrointestinal support. and it is thought to have a laxative and natural cleansing, etc..
Liver cancer is defined as a condition of out of controlled growth of hepatocellular cells in the liver. Since the organ is a soft tissue with less nerve, most liver cancer patient are diagnosed in the later stage of the cancer. According to the statistic, liver cancer remains the fifth most common malignancy in men and the eighth in women worldwide.
Hepatocellular carcinoma (HCC) is a common form of primary liver cancer.


The Ingredients
The chemical constituents of Cascara Sagrada include Aloe-emodin, Anthrquinone glycosides (Barbaloin Cascarosides A, B, C and D ChrysaloinFrangul), Chrysophanol, Emodin, Heterodianthrones palmidin A, B, and C, dianthrones, Oxanthrone, Rhein, Tannins, etc.

The health benefits
It is believe that the Gene CXC12 with diverted cellular functions and CXCR4, a protein in the cell surface chemical reactions may involve in the process of development of liver cancer. Down regulation of CXCR4 expression in these reaction may be considered in  prevention and treatment the spread of liver cancer. Emodin, a major chemical constituent found in Cascara Sagrada exerted its anti cancer activities by inhibiting the NF-κB activation (inflammation, immunity, cell proliferation and apoptosis) and suppression of CXCL12-induced the spread and invasion in HCC cell lines. In HepG2 cells, in doses depending manner, emodin increased the protein level of cellular tumor antigen (P53) and decreased the protein level of NF-κB/p65 (mutation of gene causes of cancers) in HepG2 cells, a liver cancer cell line. The search team at  Wuhan University, also found that emodin not only down regulated expression of (a protein in regulating and contributing to programmed cell death or apoptosis, but also inhibited the heterodimerization of Bcl-2 with Bax (pro-apoptotic Bax protein). Through these results, emodin suppression of CXCR4 signaling pathway as well as controlling the process of a multifaceted complex cascade of events in liver progression may be another choices in treating liver cancer. The other chemical constituent, Aloe-emodin, also is found to exert its anti cancer effect on the proliferation of hepatic hepatocellular carcinoma cells as it inhibited
the Huh-7 cells (an inherited disorder) in dose- and time-dependent manners and  anti proliferative effect via induction of DNA damage and apoptosis.


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The Side effects
1. Cascara Sagrada can be liver toxic.
2. It may cause Postal hypertension
Cascara sagrada (CS) has been associated with the development of cholestatic hepatitis, complicated by portal hypertension.
3. Fresh cut, dried bark may cause vomiting and diarrhea.
4. It may allergic effect.
5. Etc.


References
(1) Emodin suppresses migration and invasion through the modulation of CXCR4 expression in an orthotopic model of human hepatocellular carcinoma by Manu KA, Shanmugam MK, Ong TH, Subramaniam A, Siveen KS, Perumal E, Samy RP, Bist P, Lim LH, Kumar AP, Hui KM, Sethi G.(PubMed)
(2) Emodin regulates apoptotic pathway in human liver cancer cells by Yu JQ, Bao W, Lei JC.(PubMed)
(3) Apoptosis by aloe-emodin is mediated through down-regulation of calpain-2 and ubiquitin-protein ligase E3A in human hepatoma Huh-7 cells by Jeon W, Jeon YK, Nam MJ.(PubMed)

Monday 3 February 2014

Breast cancer in Vitamin A's Points of View

By Kyle J. Norton

Vitamins form an important part in human diet. Epidemiological studies, linking vitamin A in reduced risk of breast cancer have produced uncleared result(1)(1a)(1b). But in certain studies, vitamin A in form of retinoids and carotenoids is effective in inhibition of breast cancer cell lines through many anti porfilerative and apoptotic pathways.

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

1. Retinols
Lack of the retinoic acid receptor beta (RAR beta) gene expression causes of abnormal regulation by retinoic acid (RA) are common features in human lung cancer and breast cancer cells(2)
Suggestion of using retinoids, the natural and synthetic vitamin A derivatives in chemoprevention because of its function in modification of abnormal dell growth in Cancer tissues(3) by exerting anticancer effects through its retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs)in regualating the target gene causes of the diseases(4). In SK-BR-3 and T47D human breast cancer cells, retinoid showed to be effectively in regulates mammary epithelial cell growth and differentiation through signaling via retinoic acid (RA) and retinoid X receptors (RARs and RXRs) leading to apoptosis in ER- SK-BR-3 and ER+ T47D breast cancer cells(5). All-trans retinoic acid(ATRA), a synthetic version of vitamin A, showed effectively in inhibition of  breast cancer stem cells, NCSCs and CSCs, through impairment of the self-renewing ability of CSCs and promotion of  CSCs to differentiate(6). In human breast cancer cell lines of MDA-MB-468 and MCF-7, ATRA inhibited the proliferation and the expression of BP1(expression of BP1 protein correlated with breast tumor progression and invasion) in breast cancer cells(7).
 In human breast cancer MDA-MB-231 cells, the synthetic retinoid 4-amino-2-tri-fluoromethyl-phenyl ester (ATPR) inhibited cells reduced migration and reduced phosphorylation of ERK(cellular proliferation, differentiation, and survival), JNK(cellular apoptosis) and p38(highly expressed in aggressive and invasive breast cancers) in breast cancer(8). Retinoic acid (RA), a vitamin A metabolite, induced breast cancer cell apoptosis through type I IFN autocrine (activation of T cells, B cells, and natural killer cells)signaling, caspase-8 and caspase-3(Cell apoptosis) activation, as well as TRAIL(induces the process of cell death) signaling(9). Taking to these accounts, Retinols may be beneficial as a potent agent in preventing and treating breast cancer.

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, though to play an important role in prevention and treatment of some diseases through it antioxidant effects.
In postmenopausal women, dietary beta-carotene intake is found to be effective in reduced risk of breast caner with or without high alcohol intake(11)(12)(13)(16). Other studies of circulating carotenoids, also showed that high levels of beta carotene circulation are associated to decreased risk of breast cancer(14).
In the risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR),  β-carotene intakes were inversely associated with the risk of ER-negative (ER-)but not ER- positive breast cancer cell lines(15). In genetic polymorphisms of NOS3, intake of β-carotene modified and protected against risk of breast cancer predominantly in individuals with the TG:TG diplotype of NOS3(17). In related with other supplements, intake of multivitamins including  beta-carotene, vitamin C, vitamin E and zinc for 10 Years or more may protect from developing breast cancer in postmenopausal women(18). biologically, the protection of antioxidants including β-carotene against breast cancer was associated to activation of  immune response in the course of the disease(19). In smokers, dietary alpha-carotene and beta-carotene are associated with reduced risk of breast cancer among women who do not use dietary supplements(20).
In estrogen receptor (ER) and progesterone receptor (PR) status, intakes of α-carotene was associated with reduced risk of ER-, but not ER+, breast cancer(15). In women with high mammographic density, using a computer-assisted thresholding method, total carotenoids were associated with a 50% reduction in breast cancer risk(21). In a total of 969 cases of breast cancer diagnosed after blood draw and prior to June 1, 1998, alpha carotene was inversely associated in reduced risk of breast cancer greater for invasive cancers with nodal metastasis(22). In invasive breast cancer, high consumption of carotenoids may reduce risk of of breast cancer in premenopausal but not postmenopausal women, particularly among smokers, including alpha-carotene(23). In comparison of blood concentrations of carotenoids and carotenoids assessed by dietary questionnaires, showed strong relationship between biomarkers and the reduced risk of breast cancer(24). In breast cancers defined by estrogen receptor (ER) and progesterone receptor (PR) status, dietary alpha-carotene was inversely associated with risk of ER+PR+breast cancer, but not with other breast cancer groups jointly defined by ER and PR status(25). In the study of gene O(6)-methylguanine DNA methyl-transferase (MGMT) involved in cellular defense against, dietary antioxidants are associated to inversely reduce risk of breast cancer through possible modulation of polymorphisms in MGMT(26).
In malignant melanoma, mammary carcinoma and lung adenocarcinoma cells growth, water and ethanol extracts from glaucophyte Cyanophora paradoxa (Cp) with Pheophorbide a, β-cryptoxanthin and zeaxanthin were found to significantly inhibit the growth of the three cancer cell lines mentioned above in vitro, at 100 µg · mL..(27). In the study of the associations of plasma levels of tocopherols, retinol, carotenoids with the risk of developing breast cancer among Chinese women, researcers found that high levels of plasma lycopene other than trans, 5- and 7-cis or trans alpha-cryptoxanthin were inversely associated with the risk of developing breast cancer(28).

Dietary vitamin A, includes retinol, retinal, retinoic acid, and several provitamin A carotenoids has been found significantly in reduced risk and treatment of  breast cancer through modification of malignant cell growth, expression of down-regulation of pro proliferative and up-regualtion of apoptotic pathway. Regardless to its anti-breast cancer effects, overdoses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Vitamin supplement consumption and breast cancer risk: a review by Misotti AM, Gnagnarella P.(PubMed)
(1a) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study by Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA.(PubMed)
(1b)Micronutrient intake and breast cancer characteristics among postmenopausal women by Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjønneland A.(PubMed)
(2) Retinoid receptors in human lung cancer and breast cancer by Zhang XK, Liu Y, Lee MO.(PubMed)
(3) Retinoids in cancer chemoprevention by Okuno M, Kojima S, Matsushima-Nishiwaki R, Tsurumi H, Muto Y, Friedman SL, Moriwaki H.(PubMed)
(4) Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids by Wu Q, Dawson MI, Zheng Y, Hobbs PD, Agadir A, Jong L, Li Y, Liu R, Lin B, Zhang XK.(PubMed)
(5) Activation of retinoic acid receptor alpha is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells by Schneider SM, Offterdinger M, Huber H, Grunt TW.(PubMed)
(6) [All-trans retinoic acid effectively inhibits breast cancer stem cells growth in vitro].

[Article in Chinese] by Zeng WG, Hu P, Wang JN, Liu RB.(PubMed)
(7) [Effects of all trans retinoic acid on the expression alterations of beta-protein 1 in human breast cancer cell lines of MDA-MB-468 and MCF-7].[Article in Chinese by Su J, Li MQ, Zhong GS.(PubMed)
(8) A novel all-trans retinoid acid derivatives inhibits the migration of breast cancer cell lines MDA-MB-231 via myosin light chain kinase involving p38-MAPK pathway by Wang B, Yan Y, Zhou J, Zhou Q, Gui S, Wang Y.(PubMed)
(9) Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells by Bernardo AR, Cosgaya JM, Aranda A, Jiménez-Lara AM.(PubMed)
(10) Cis-retinol dehydrogenase: 9-cis-retinol metabolism and its effect on proliferation of human MCF7 breast cancer cells by Paik J, Blaner WS, Swisshelm K.(PubMed)
(11) Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) by Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjønneland A, Olsen A, Roswall N, Witt PM, Overvad K, Rohrmann S, Kaaks R, Drogan D, Boeing H, Trichopoulou A, Stratigakou V, Zylis D, Engeset D, Lund E, Skeie G, Berrino F, Grioni S, Mattiello A, Masala G, Tumino R, Zanetti R, Ros MM, Bueno-de-Mesquita HB, Ardanaz E, Sánchez MJ, Huerta JM, Amiano P, Rodríguez L, Manjer J, Wirfält E, Lenner P, Hallmans G, Spencer EA, Key TJ, Bingham S, Khaw KT, Rinaldi S, Slimani N, Boffetta P, Gallo V, Norat T, Riboli E.(PubMed)
(12) Beta-carotene intake and risk of postmenopausal breast cancer by Jumaan AO, Holmberg L, Zack M, Mokdad AH, Ohlander EM, Wolk A, Byers T.(PubMed)
(13) Dietary carotenoids and risk of breast cancer in Chinese women by Huang JP, Zhang M, Holman CD, Xie X.(PubMed)
(14) Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies by Eliassen AH, Hendrickson SJ, Brinton LA, Buring JE, Campos H, Dai Q, Dorgan JF, Franke AA, Gao YT, Goodman MT, Hallmans G, Helzlsouer KJ, Hoffman-Bolton J, Hultén K, Sesso HD, Sowell AL, Tamimi RM, Toniolo P, Wilkens LR, Winkvist A, Zeleniuch-Jacquotte A(PubMed)
(15). Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a pooled analysis of 18 prospective cohort studies by Zhang X, Spiegelman D, Baglietto L, Bernstein L, Boggs DA, van den Brandt PA, Buring JE, Gapstur SM, Giles GG, Giovannucci E, Goodman G, Hankinson SE, Helzlsouer KJ, Horn-Ross PL, Inoue M, Jung S, Khudyakov P, Larsson SC, Lof M, McCullough ML, Miller AB, Neuhouser ML, Palmer JR, Park Y, Robien K, Rohan TE, Ross JA, Schouten LJ, Shikany JM, Tsugane S, Visvanathan K, Weiderpass E, Wolk A, Willett WC, Zhang SM, Ziegler RG, Smith-Warner SA.(PubMed)
(16) Carotenoids and breast cancer risk: a meta-analysis and meta-regression by Hu F, Wang Yi B, Zhang W, Liang J, Lin C, Li D, Wang F, Pang D, Zhao Y.(PubMed)
(17) Combined effects of antioxidant vitamin and NOS3 genetic polymorphisms on breast cancer risk in women by Lee SA, Lee KM, Yoo KY, Noh DY, Ahn SH, Kang D.(PubMed)
(18) Antioxidants and breast cancer risk- a population-based case-control study in Canada by Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG].(PubMed).
(19) Antioxidant vitamins and cytokines are altered in breast cancer by Abranches MV, Mendes MC, Pena Gd, Maia YC, Ribeiro SM, Franceschini Sdo C, de Paula SO, de Freitas RN, Peluzio MC.(PubMed)
(20) Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women by Larsson SC, Bergkvist L, Wolk A.(PubMed)
(21) Circulating carotenoids, mammographic density, and subsequent risk of breast cancer by Tamimi RM, Colditz GA, Hankinson SE.(PubMed)
(22) Plasma carotenoids, retinol, and tocopherols and risk of breast cancer by Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ.(PubMed)
(23) Dietary carotenoids and the risk of invasive breast cancer by Mignone LI, Giovannucci E, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Hampton JM, Willett WC, Egan KM.(PubMed)
(24) Dietary compared with blood concentrations of carotenoids and breast cancer risk: a systematic review and meta-analysis of prospective studies by Aune D, Chan DS, Vieira AR, Navarro Rosenblatt DA, Vieira R, Greenwood DC, Norat T.(PubMed)
(25) Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study by Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE.(PubMed)
(26) MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk by Shen J, Terry MB, Gammon MD, Gaudet MM, Teitelbaum SL, Eng SM, Sagiv SK, Neugut AI, Santella RM.(PubMed)
(27) Antiproliferative activity of Cyanophora paradoxa pigments in melanoma, breast and lung cancer cells by Baudelet PH, Gagez AL, Bérard JB, Juin C, Bridiau N, Kaas R, Thiéry V, Cadoret JP, Picot L.(PubMed)
(28) Plasma carotenoids, tocopherols, retinol and breast cancer risk: results from the Shanghai Women Health Study (SWHS) by Dorjgochoo T, Gao YT, Chow WH, Shu XO, Li H, Yang G, Cai Q, Rothman N, Cai H, Franke AA, Zheng W, Dai Q.(PubMed)