Sunday, October 11, 2015

Most Common Diseases of Ages of 50 Plus - Musculoskeletal disorders (MSDs) - Osteoporosis Prevention Diet

By Kyle J. Norton(Scholar)
Osteoporosis is condition of thinning of bone and bone tissues as a result of the loss of bone density over a long period of time.

The Diet
1. Green tea
In the study to investigate whether black tea polyphenol, theaflavin-3,3′-digallate (TFDG) and green tea, epigallocatechin-3-gallate (EGCG)affect MMP activity and osteoclast formation and differentiation in vitro, showed that TFDG and EGCG inhibited the formation and differentiation of osteoclasts via inhibition of MMPs. TFDG may suppress actin ring formation more effectively than EGCG. Thus, TFDG and EGCG may be suitable agents or lead compounds for the treatment of bone resorption diseases(1).

2. Organic Soy
In the study to clarify the effect of ingesting soy isoflavone extracts (not soy protein or foods containing isoflavones) on bone mineral density (BMD) in menopausal women, found that the varying effects of isoflavones on spine BMD across trials might be 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). No significant effects on femoral neck, hip total, and trochanter BMD were found. Soy isoflavone extract supplements increased lumbar spine BMD in menopausal women(2).

3. Orange juice
In the study to evaluate the possible variations in antioxidant enzymes, lipid peroxidation and erythrocyte deformability in experimentally induced osteoporosis in female rats and to assess the effects of vitamin C supplementation on those variations, indicated that BMD was significantly lower in the group O than in the group C (p = 0.015), whereas it was significantly higher in the group OVC than in the group O (p = 0.003). MDA activity was significantly higher in the group O than in the group C (p = 0.032), whereas it was significantly lower in the group OVC than in the group O (p = 0.025). SOD activity was significantly higher in the group O than in the group C (p = 0.032). Erythrocyte deformability was significantly higher in the group O than in the group C and OVC (p = 0.008, p = 0.021, respectively)(3).

4. Milk thistle seeds
In the study to investigate that silibinin had bone-forming and osteoprotective effects in in vitro cell systems of murine osteoblastic MC3T3-E1 cells and RAW 264.7 murine macrophages, found that that silibinin retarded tartrate-resistant acid phosphatase and cathepsin K induction and matrix metalloproteinase-9 activity elevated by RANKL through disturbing TRAF6-c-Src signaling pathways. These results demonstrate that silibinin was a potential therapeutic agent promoting bone-forming osteoblastogenesis and encumbering osteoclastic bone resorption(4).

5. Skin and seed of grape
In the study to investigate the molecular mechanism of how resveratrol can modulate the lineage commitment of human mesenchymal stem cells to osteogenesis other than adipogenesis, showed that
resveratrol promoted spontaneous osteogenesis but prevented adipogenesis in human embryonic stem cell-derived mesenchymal progenitors. Resveratrol upregulated the expression of osteo-lineage genes RUNX2 and osteocalcin while suppressing adipo-lineage genes PPARγ2 and LEPTIN in adipogenic medium. Furthermore, the osteogenic effect of resveratrol was mediated mainly through SIRT1/FOXO3A with a smaller contribution from the estrogenic pathway(5).

Saturday, October 10, 2015

Most Common Diseases of Ages of 50 Plus - Musculoskeletal disorders (MSDs) - Osteoporosis: The Diagnosis and Complications

By Kyle J. Norton(Scholar)

Osteoporosis is condition of thinning of bone and bone tissues as a result of the loss of bone density over a long period of time.

III. Diagnosis
According to the Clinical practice guidelines for the diagnosis and management of osteoporosis. Scientific Advisory Board, Osteoporosis Society of Canada, Screening and diagnostic methods: risk-factor assessment, clinical evaluation, measurement of bone mineral density, laboratory investigations.

If you are experience certain symptom of osteoporosis, the tests which your doctor order include
1. Blood and urinary tests
The aim of the tests are to check for the bone metabolism and the progression of bone (loss) diseases.

2. Dual energy X-ray absorptiometry (DXA)
Dual energy X-ray absorptiometry (DXA) is one most common test to measure the total bone density of including spine, hip, wrist etc. with accurate result.
3. Quantitative Ultrasound and computed tomography (QCT)
The evaluation of bone density at the lumbar spine and hip.using a standard X-ray Computed Tomography (CT) scanner. Quantitative ultrasound (QUS), a technology
for measuring properties of bone at peripheral skeletal sites, is more portable and less expensive than DXA, without the use of ionizing radiation(23).
Dr. Riggs BL and the research team in the study of Better tools for assessing osteoporosis indicated that a whole new field of research into the determinants of bone loss and fractures in the axial skeleton and set the stage for subsequent development of dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT), which are now the standard methods for assessing osteoporosis severity and treatment efficacy(24), but other study found that in cross-sectional study of males with glucocorticoid-induced osteoporosis (GIO, quantitative computed tomography (QCT), High-resolution quantitative computed tomography (HRQCT)-based measurements and finite element analysis (FEA) variables were superior to DXA in discriminating between patients of differing prevalent vertebral fracture status(25).
4. Etc.

IV. Complication associated with Osteoporosis
Pain, Fractures, Vertebral, Wrist, Rib fractures are associated with Osteoporosis, according to the study of New advances in imaging osteoporosis and its complications, said “We, as clinicians, should aim to increase awareness of this fracture type both as a frequent and varied source of pain in patients with osteoporosis and as the ultimate marker of severely impaired bone strength.”(26)

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Sources

(a) http://www.ncbi.nlm.nih.gov/pubmed/7864688
(23) http://www.iscd.org/visitors/pdfs/10-QuantitativeUltrasoundintheMgmtofOsteo.pdf
(24) http://www.ncbi.nlm.nih.gov/pubmed/23154276
(25) http://www.ncbi.nlm.nih.gov/pubmed/23149277
(26) http://www.ncbi.nlm.nih.gov/pubmed/22618377

Friday, October 9, 2015

Most Common Diseases of Ages of 50 Plus - Musculoskeletal disorders (MSDs) - Osteoporosis: The Causes and Risk Factors


By Kyle J. Norton(Scholar)

Osteoporosis is condition of thinning of bone and bone tissues as a result of the loss of bone density over a long period of time.

II. Causes and Risk Factors
A. Causes
1. Process of wear and repair
Osteoarthritis (OA) is a widespread degenerative disease of skeletal joints and often associated with senescence in vertebrates due to excessive or abnormal mechanical loading of weight-bearing joints, arising from heavy long-term use or specific injuries(6).
Improper repair process of injure of joints can also result of symptoms of Osteoarthritis (OA) in old age, according to TCM.

2. Nutrient deficiency
Poor nutritional conditions in early life are linked to greater prevalence of OA due the gradual deterioration of function(9).

3. Cartilage
Cartilage is a flexible connective tissue which cushions the ends of bones in your joints to allow the joints to move smoothly. If the cartilage becomes rough or wears down due to aging or damage, it can cause pain as a result of bone in the joint rubbing against another bone.


4. Etc.

B. Risk factors
1. Young Age at Diagnosis, Male Sex, and Decreased Lean Mass
According to Korea Cancer Center Hospital, Seoul,
a. Diagnosed before attainment of puberty, were showed to have a higher prevalence of osteoporosis
b. If you are males, you are at increased risk of osteopenia or osteoporosis than females
c. Regional lean mass was significantly associated to the reduce risk of affecting the limbs
(12).

2. Adult growth hormone replacement
Adult growth hormone replacement, were identified to associated to increased risk of osteoporosis and osteopenia, according to the study by Seoul National University College of Medicine(13).

3. Aging
Risk of osteoporosis increases with age.
Bone loss occurs during the normal aging process. In women, natural menopause also effect the additional bone losses, according to the study by Department of Medicine, College of Physicians and Surgeons, Columbia University(14).

4. Chlamydia pneumoniae
Individual presented of Chlamydia pneumoniae DNA are alsp associated to both in osteoporotic bone tissue(15).

5. Race
Lactose maldigestion showed a greater affect on low bone density. Extensive lactose maldigestion among Hispanic-American and Asian-American populations may elevate the risk for osteoporosis(16).

6. Family history
According to the reported physician-diagnosed osteoporosis and family history in a representative sample of U.S., family history is associated to a significant, independent risk factor for osteoporosis in U.S. women aged>or=35 years(17).

7. Body size
Large body size is associated to the risk of the development of osteoporosis and a salutary effect on BMD in both blacks and whites, in a study of three groups of postmenopausal women: 104 healthy black women, 45 healthy white women, and 52 osteoporotic white (18).

8. Diet and lifestyle
BMD was higher in habits of alcohol drinking, green tea drinking, and physical activity and lower in those with the habits of smoking and cheese consumption, in a study of total of 632 women age > or =60 years(19).

9. Heavy alcohol intake or alcoholism
Heavy alcohol intake or alcoholism, however, frequently disrupts calcium and bone homeostasis, leading to reduce bone mineral density and increase the incidence of fragility fracture, according to the study by Department of Endocrinology and Metabolism, Saitama Medical School(20).

10. Smoking and lower serum IGF-I levels
A lower BMI is found in patient who are current smoking history and lower serum IGF-I levels in middle-aged Korean men(21).

11. Other risk factors
The frequency of decreased bone mineral density, low vitamin and calcium diet content and insufficiency with vitamins are found among patients suffering from chronic diseases (of cardiovascular system, gastrointestinal tract, osteopenia and osteoporosis)(22).

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References
(6) http://www.ncbi.nlm.nih.gov/pubmed/21079541
(7) http://www.ncbi.nlm.nih.gov/pubmed/23095987
(8) http://www.ncbi.nlm.nih.gov/pubmed/23149863
(7) http://www.ncbi.nlm.nih.gov/pubmed/20618843
(12) http://www.ncbi.nlm.nih.gov/pubmed/23128330
(13) http://www.ncbi.nlm.nih.gov/pubmed/22057549
(14) http://www.ncbi.nlm.nih.gov/pubmed/12699295
(15) http://www.ncbi.nlm.nih.gov/pubmed/23160916
(16) http://www.ncbi.nlm.nih.gov/pubmed/11349943
(17) http://www.ncbi.nlm.nih.gov/pubmed/18541176

Thursday, October 8, 2015

Most Common Diseases of Ages of 50 Plus - Musculoskeletal disorders (MSDs) - Osteoporosis: The symptoms

By Kyle J. Norton

Osteoporosis is condition of thinning of bone and bone tissues as a result of the loss of bone density over a long period of time.

I. Symptoms
1. Lower back pain, as a result of fractured or collapsed vertebra
People with Osteoporosis are susceptible to lower back pain than those without osteoporosis, according to a cross-sectional study, conducted from October 2002 to March 2003 to gather data from 24,435 adults aged 20 years and older selected randomly from Taiwan’s general population. TheOsteoporosis rate of frequent low back pain in association with osteoporosis in men and women were 5.77 and 3.49 respectively(1).

2. Loss of height over time
Vertebral fracture cause of spinal core damage is associated to significant height loss in patients with osteoporosis, according to a study of 231 men and women over the age of 65 underwent DXA scan of their spine and hip (2).
Osteoporosis patients with chronic obstructive pulmonary disease (COPD) are found to associate to excessive height loss(3).

3. A stooped posture
Postural deformity of patients with osteoporosis is associated to contributed risk factor for postural instability and falls. Spinal curvature on postural instability in patients with osteoporosis may influence lumbar kyphosis(lower back curvature) in spinal inclination(4).

4. Easy bone fracture
Easy bone fracture may be results of a gradual loss of bone density.
Intravenous infusion of zoledronic acid (5 mg) at 12 months, found that Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture(fractures in the spine, hip and wrist), among men with osteoporosis, according to a multicenter, double-blind, placebo-controlled trial of randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age(5).

5. Neck and low back pain
Neck and low back pain, frequent in female are prevalent and highly associated in patients with headache and osteoporosis, according to 1-year prevalence of neck pain and low back pain in the Spanish population(6).

6. Depression
Spine BMD was negative correlations between anxiety, stress, butdepression was found to have a unique significant contribution to the explained variance in right and left hip BMD(7).

7. Other symptoms
Women with osteoporosis re more likely to experience certainpsychosomatic, gastrointestinal and swelling and vasomotor symptoms, especially depressive symptom if compared to women in generally good health(8).
8. Etc.

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Wednesday, October 7, 2015

Ranch Pretzel Bites

Recipe contributed by Quick and easy family favorites by Vickie and JoAnn

This snack mix is a variation on one that uses oyster crackers. Whichever you use, eat up, because it won't last for long!
16-oz. pkg. large pretzels
2-oz. pkg. ranch salad dressing mix
3/4 c. oil
11/2 t. garlic powder
11/2 t, dill weed

Break pretzels into bite-size pieces; place in a large mixing bowl. Combined remaining ingredients in a separate mixing bowl and pour over pretzels; toss to coat, Pour into an ungreased baking sheet.
bake at 200 degrees for 1 hour, stirring every 15 minutes.
Make 16 serving
Note: small bite-size pretzels may be substituted for a large pretzels.

Susan Young
Madison, AL

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The effects of Phytochemicals against Choriocarcinoma and Hydatidiform Mole(Tumors and Placenta) By Kyle J. Norton



Phytochemials are defined as a group of chemical compound found naturally in plants, including fruits, vegetables, beans, grains, etc.
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 in death.
Food intake can help to prevent and treat cancers. Many studies have proven that they can because of certain phytochemicals, but for what ever reason, there are either no clinical trials follow through or the studies can not make to stage of clinical trials. Do not expect the pharmateutical or foods industrial companies to pay for the researches, as the discovery of the phytochemicals to cure cancers can only dampen the profits of both industries as phytochemicals can not be patented.

I. Choriocarinma
Cancer of Choriocarinma is a malignant and aggressive cancer, started from the abnormal and uncontrollable cells growth in the trophoblatistic tissue, that is part of embryo and normally become the placenta as a result of something going wrong during pregnancy due to random chance.
Placenta is the organ by which the fetus received nutrients and oxygen from the mother.

II. Molar pregnancy or Hydatidiffrom mole
Molar pregnancy or Hydatidiffrom mole is also started from the trophoblastic tissue, normally is non cancerous but sometimes, it may invade the uterine wall (invasive mole) as a result of a sperm fusing with an with nucleus or something going wrong during pregnancy causing forming of a mass resembling the bunch of grape.

The two types of molar pregnancy are complete molar and partial molar pregnancy.

a. Complete mole pregnancy happens when a single sperm combining with an egg which is deficient with lost its DNA. The sperm that would otherwise fertilize the egg are then left to reduplicate themselves to form a complete 46 chromosome set.

Generally no fetus results from a complete molar pregnancy. Complete hydatidiform moles have a higher risk of developing into choriocarcinoma and happened in 1 out of 1200 pregnancy.

b. Partial mole pregnancy
A partial mole pregnancy occurs when two separate sperm fertilize the same egg, resulting of the nucleus containing one maternal set of genes and two paternal sets. With a partial molar pregnancy, there may result an actual fetus and placenta but fetus is most likely to develop into a partial mole.
Types of foods to prevent and treat Choriocarcinoma and Hydatidiform Mole

III. Types of foods to prevent and treat Hydatidiform Mole
1. Carnot
Retinoic acid, a types of vitamin A found abundantly in carrot has exerted the protective effect against
Hydatidiform Mole. At clinical trial as many as 67 cases met the requirements for the study. Two cases were lost from observation and three experienced pregnancy. The incidence rate of malignant trophoblastic disease in the control group was 28.6%, and in the therapy group was 6.3%. No difference was found in the changes of SGOT and SGPT levels of the therapy group compared with the control group. The rate of malignant trophoblastic disease (MTD) was reduced in the group receiving vitamin A therapy(1).

2. Chinese cucumber
Trichosanthin found abundantly in Chinese cucumber has been found to be protective against hydatidiform mole."During 1972-1986, 44 of 52 patients (84.6%) with hydatidiform mole were treated successfully with trichosanthin. Of these, 38 (73.1%) had complete spontaneous evacuation and 6 (11.5%) incomplete evacuation. The average time for evacuation of hydatidiform molewas 4.5 +/- 1.64 days. The amount of bleeding was less than 100 ml in 33 patients (75%), while that in 2 of the patients with incomplete evacuation was more than 300 ml. Malignant changes occurred in two of the 44 patients (4.5%). The malignant rate was similar to that (4-12.5, P greater than 0.05) of prophylactic chemotherapy" Dr. Lu PX and Dr. Jin YC. at Shanghai Second Medical University said(2)



3. Kiwifruit
Vitamin C and E found in high amount in Kiwifruit is said to be effective in fighting against hydatidiform mole (CHM). In the study to determine the oxidative status and antioxidative status of plasma of patients with completehydatidiform mole (CHM) and to compare these values with normal pregnancy, showed that total antioxidant potential (TAOP) of plasma was significantly lower in patients with hydatidiform mole than in healthy pregnant women [mean (SD) values were 511.9 (105.8) and 571.7 (109.4) micromol Trolox equiv./L respectively (p <0.05)]. In contrast, mean (SD) total peroxide level of plasma was significantly higher in the patients [21.8 (6.4) micromol H2O2/L] than in healthy pregnant women [15.6 (6.4) micromol H2O2/L (p <0.001)]. The mean oxidative stress index level was significantly higher in patients with CHM than in healthy pregnant women [4.43 (1.70) versus 2.92 (1.50) respectively (p <0.001)] and concluded that Patients with CHM are exposed to oxidative stress, which may have a role in the pathogenesis of the disease. Supplementation with antioxidative vitamins such as C and E could be considered in treatment(3).

4. Etc.

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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/20843153
(2) http://www.ncbi.nlm.nih.gov/pubmed/2164464
(3) http://www.ncbi.nlm.nih.gov/pubmed/14691728

Tuesday, October 6, 2015

The effects of Phytochemicals against Cervical Cancer By Kyle J. Norton



Phytochemials are defined as a group of chemical compound found naturally in plants, including fruits, vegetables, beans, grains, etc.
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 in death.
Food intake can help to prevent and treat cancers. Many studies have proven that they can because of certain phytochemicals, but for what ever reason, there are either no clinical trials follow through or the studies can not make to stage of clinical trials. Do not expect the pharmateutical or foods industrial companies to pay for the researches, as the discovery of the phytochemicals to cure cancers can only dampen the profits of both industries as phytochemicals can not be patented.
I. 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 ismalignant neoplasm of the cervix uteri or cervical area caused by abnormal cells growth with alternation of cells DNA.

II. Pre-cervical cancer
Precervical cancer is the early stage of abnormal cell changes in the cervical tissue, if left untreated, it can develop into true invasive cervical cancer caused by factors connected to male seminal fluid. A vaccine, Gardasil used to prevent pre-cervical cancer from the infection of two types of HPV was approved by the U.S. Food and Drug Administration in 2006. It is for your benefits to take this vaccine if you are sexual active with several partners.

III. Types of Food to Prevent and Treat Cervical Cancer
1. Black raspberry
Black raspberries and their derivatives, have demonstrated a marked ability to inhibit preclinical models of epithelial cancer cell growth and tumor formation. Dr. Zhang Z and the research team at the The Ohio State University, Columbus, showed that non-toxic levels of RO-ET significantly inhibited the growth of human cervical cancer cells, in a dose-dependent and time-dependent manner to a maximum of 54%, 52% and 67%, respectively (p<0.05). Furthermore, cell growth inhibition was persistent following short-term withdrawal of RO-ET from the culture medium. Flow cytometry and fluorescence microscopy demonstrated RO-ET-induced apoptosis in all cell lines(1).

2. Green and Black Tea
Phytochemicals present in tea, particularly polyphenols, have anticancer properties against several cancer types. In the study to investigate the mechanism of antiproliferative and apoptotic actions exerted by tea polyphenols on human papilloma virus-18-positive HeLa cervical cancer cells, showed that treatment of green tea polyphenol (-)-epigallocatechin gallate (EGCG) and black tea polyphenol theaflavins (TF) in HeLa cells showed a marked concentration- and time-dependent inhibition of proliferation and induced sub-G1 phase in a dose-dependent manner after 24 h. There was an attenuation of mitochondrial membrane potential with the increase of reactive oxygen species generation, p53 expression, Bax/Bcl-2 ratio, cytochrome-c release, and cleavage of procaspase-3 and -9 and poly(ADP-ribose)-polymerase, indicating the participation of a mitochondria related mechanism. In addition, EGCG as well as TF inhibited activation of Akt and nuclear factor-kappaB (NF-kappaB) via blocking phosphorylation and subsequent degradation of inhibitor of kappaBalpha and kappaBbeta subunits, thereby downregulating cyclooxygenase-2(2).
Flavonoid quercetin found abundantly in green and black tea are associated with cell proliferation and apoptosis. Dr Vidya Priyadarsini R, and the research team at the Annamalai University, in the study of The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition, indicated that quercetin suppressed the viability of HeLa cells in a dose-dependent manner by inducing G2/M phase cell cycle arrest and mitochondrial apoptosis through a p53-dependent mechanism. This involved characteristic changes in nuclear morphology, phosphatidylserine externalization, mitochondrial membrane depolarization, modulation of cell cycle regulatory proteins and NF-κB family members, upregulation of proapoptotic Bcl-2 family proteins, cytochrome C, Apaf-1 and caspases, and downregulation of antiapoptotic Bcl-2 proteins and survivin(3)

3. Epigallocatechin gallate from Tea, Curcumin from curry and Soyaisoflavones
Epidemiological and preclinical evidence suggests that polyphenolicphytochemicals exemplified by epigallocatechin gallate from tea, curcumin from curry and soya isoflavones possess cancer chemopreventive properties. Dr. Thomasset SC and scientists at the University of Leicester, in the review of above showed that the available evidence for tea polyphenols tentatively supports their advancement into phase III clinical intervention trials aimed at the prevention of progression of prostate intraepithelial neoplasia, leukoplakia or premalignant cervical disease. In the case of curcumin and soya isoflavones more studies in premalignacies seem appropriate to optimise the nature and design of suitable phase III trials. The abundance of flavonoids and related polyphenols in the plant kingdom makes it possible that several hitherto uncharacterised agents with chemopreventive efficacy are still to be identified, which may constitute attractive alternatives to currently used chemopreventive drugs(4).

4. Skins of grape and red wine
Resveratrol, a polyphenol found a abundantly in skins of grapes and red wine has been shown to significantly alter the cellular physiology of tumor cells, as well as block the process of initiation and progression, some studies found that tumor cells may exhibit changes in the cellular response to IR following exposure to resveratrol, a naturally occurring compound that inhibits cyclooxygenase-1 (COX-1) activity. Thus, clonogenic cell survival assays were performed using irradiated HeLa and SiHa cells pretreated withresveratrol prior to IR exposure, and resulted in enhanced tumor cell killing by IR in a dose-dependent manner(5).

5. Milk thistle seeds
Silibinin, an effective anti-cancer and chemopreventive agent in various epithelial cancer models, found abundantly in milk thistle seed has been reported to inhibit cancer cell growth through mitogenic. Dr. Zhang Y, and research team at Life Science College, Jilin University, in the study of Cellular and molecular mechanisms of silibinin induces cell-cycle arrest and apoptosis on HeLa cells, indicated that silibinin showed a dose-dependent and a time-dependent apoptotic death in HeLa cells in both the mitochondrial pathway and the death receptor-mediated pathway, providing a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in cervical cancer pre-clinical models(6).

6. Etc.

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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/21831414
(2) http://www.ncbi.nlm.nih.gov/pubmed/21776820
(3) http://www.ncbi.nlm.nih.gov/pubmed/20858478
(4) http://www.ncbi.nlm.nih.gov/pubmed/17131309
(5) http://www.ncbi.nlm.nih.gov/pubmed/11741744
(6) http://www.ncbi.nlm.nih.gov/pubmed/22170400