CLA and hormonal imbalances -
Normal reduction mammoplastys and malignant human breast tissues were obtained through the Tissue Procurement Program at The Ohio State University Hospital in Columbus, Ohio.
Isolation of epithelial and stromal cells from human breast tissues and culture conditions were described previously [ 5 , 6 ]. Briefly, tissues were minced and digested in 0. The digested mixture was centrifuged at × g for 5 min at 25°C.
The cell pellet was re-suspended and allowed to settle by gravity for 3 times. Cancer epithelial cells in the initial sedimented part were re-suspended in keratinocyte serum free medium Keratinocyte-SFM, 0.
Finally, cells were harvested for performing assays described in the following sections. Co-cultures of epithelial cells, MCF-7, MDA-MB or MDA-MBERα, with stromal cells, non-cancerous or cancerous breast stromal cells, were performed using flat-bottomed cell culture plates with the nucleopore polycarbonate membrane 0.
Culture condition for co-culture system was described previously [ 5 ]. At the end of the treatment period, cells were washed with ice-cold PBS and then lysed with extraction reagent Pierce, Rockford, IL and protease inhibitor Pierce, Rockford, IL on ice.
The performance of western blot analysis was described previously [ 5 ]. Bcl-2 rabbit polyclonal antibody sc, Santa Cruz, CA, and β-actin goat polyclonal antibody sc, Santa Cruz, CA, were utilized in this experiment.
This assay measures the amount of dehydrogenase enzymes found in metabolically active cells by adding enzyme substrate MTS, 3- 4,5-dimethylthiazolyl 3-carboxymethoxyphenyl 4-sulfophenyl -2H-tetrazolium, inner salt and electron coupling reagent PMS, phenazine methosulfate.
Briefly, 1 × 10 4 cells in μl medium were seeded and treated in well plate. Then, 20 μl of MTS:PMS solution was added to each well. Plates were incubated at 37°C for 1. Finally, optical density was read at nm OD nm using an ELISA plate reader. Hoechst , a DNA intercalating dye, fluoresces blue when bound to DNA.
For this part of the study, 2 × 10 4 cells were seeded on coverslips in triplicate. The cells were washed again with 1X PBS and mounted on glass slides. Under confocal fluorescence microscopy excitation nm and emission nm , apoptotic cells showed condensed chromatin that was bright blue.
Samples were stained and counted in triplicate. The basal expression of Bcl-2 in 14 normal and 14 cancerous human breast tissue samples were fixed, dehydrated, embedded in paraffin, and sectioned for immunohistochemical staining. Immunostaining was carried out using the Vectastain Universal Quick kit Vector Laboratories, Burlingame, CA followed by the DAB Substrate Kit for Peroxidase Vector Laboratories, Burlingame, CA according to manufacturer's instructions.
Antibody against Bcl-2 is a rabbit polyclonal antibody raised against a peptide mapping at the N-terminus of Bcl-2 of human origin sc Santa Cruz, CA. To test the specificity of Bcl-2 antibody, the primary antibody was substituted with non-immune serum.
Bcl-2 intensity was evaluated by Allred scoring, which is a method that conveys estimated proportion score and intensity score [ 22 ]. Caspase-3 and -7 are members of the cysteine aspartic acid-specific protease family and play important roles in apoptosis in mammalian cells [ 23 ].
Each well contained 10 4 cells in 50 μl of medium were seeded and treated in 96 well-plates. Briefly, 50 μl reagent fluorometric substrate: buffer in the ratio of was added to each well. Plates then were incubated at 37°C for 5 hours and the intensity of the emitted fluorescence was determined with the use of a fluorescence spectrometer excitation nm and emission nm.
p-value less than 0. One cell group consisted of three replicate wells. Based on CLA concentration in normal physiologic human serum 10—70 μM and in humans who take CLA long-term supplementation 50— μM , CLA concentrations used in in vitro studies has ranged from Our previous study showed that the effective dose range for inhibiting the proliferation of human breast cancerous epithelial and stromal cells was 10—80 μM for three days and t 10, c CLA was more potent than c 9, t CLA unpublished data.
Therefore, t 10, c CLA was used in the current study and a relatively lower but effective dose, 40 μM of t 10, c CLA, was chosen to investigate whether CLA potentiates the anti-proliferative and pro-apoptotic effects of Tam.
Moreover, we observed that the combination of CLA and Tam caused more apoptosis than treated alone in MCF-7 cells, as measured using apoptotic indicators Figs. These results suggested that CLA may enhance the therapeutic efficiency of Tam in estrogen-responsive human breast cancer patients.
CLA stands for 40 μM t 10, c CLA; Tam stands for 1 μM 4-Hydroxytamoxifen; E 2 stands for 10 nM 17β-estradiol. CLA exerts combinative effects with tamoxifen in MCF-7 cells. Equal amounts of isolated protein from both cell extracts were subjected to immunoblot with anti-ERα antibodies.
β-actin was used as loading control. Since CLA, a naturally occurring food component, will be consumed by normal individuals as well, we examined the effects of CLA on normal human breast epithelial cells. The estrogen receptor positivity of the normal breast epithelial cells was determined based on their ERα protein expression.
MCF-7 ERα positive and MDA-MB ERα negative were used as positive and negative control, respectively in the determination of ERα expression in normal breast epithelial cells.
CLA treatment suppressed the ability of E 2 to stimulate proliferation Fig. These results suggested that CLA may be chemopreventive in vivo.
In our in vitro system, neither CLA at 40 μM, Tam nor E 2 caused considerable changes of cell growth or apoptosis in the ERα - human breast cancer cell line, MDA-MB, Figs.
Based on this observation, we suspect that CLA treatment resulted in decreased cell growth and increased cell apoptosis is mainly mediated through ERα.
To test this possibility, we examined whether CLA exerted the same effects in MDA-MB stably transfected with ERα MDA-MBERα cells as in MCF-7 cells. Our results showed that CLA induced apoptosis in MCF-7 and MDA-MBERα cells but did not have significant effects on parental MDA-MB cells Figs.
Effects of CLA, Tam and E 2 on cell proliferation and apoptosis of ERα negative human breast epithelial cells. A and histogram in C are MTS assay for the effects of CLA, Tam and E 2 for 3 days of treatment on cell proliferation of MDA-MB and ERα negative normal human breast epithelial cells ERα - NEC , respectively.
C Western blot analysis of basal ERα protein expression in MCF-7 and primary cultured ERα negative normal human breast epithelial cells ERα - NEC. CLA stands for 40 μM t 10, c CLA. Tam stands for 1 μM 4-Hydroxytamoxifen; E 2 stands for 10 nM 17β-estradiol.
Docetaxel, the commonly used anti-cancer drug, was used as the positive control in the assay of cell proliferation and apoptotic activity. CLA induces apoptosis in ERα positive human breast cancer cell line.
A ERα protein expression was examined by western blot of whole cell lysate isolated from MCF-7, MDA-MB parental , and MDA-MBERα ERα transfected MDA-MB Equal amounts of isolated protein from cell extracts of all three cell lines were subjected to immunoblot with anti-ERα antibodies.
Since Bcl-2 is an anti-apoptotic protein, we would expect to see higher Bcl-2 expression in cancerous human breast tissues. To examine this speculation, immunohistochemical staining for Bcl-2 expression was performed on 14 normal and 14 cancerous human breast tissue samples. Bcl-2 expression was localized to cytoplasm and perinuclear area of cells mainly in mammary ductal epithelium with slight staining of stromal cells surrounding the mammary ducts Fig.
Under the same magnification, Bcl-2 staining intensity was greater in cancerous tissue compared with normal tissues, which might be due to the larger cytoplasmic volume and larger mammary duct compartment in the malignant samples. To quantify Bcl-2 expression, we isolated epithelial cells and stromal cells from both cancerous and normal breast tissues.
Whole cell lysates were electrophoresed and Bcl-2 protein expression was determined by western blot. In agreement with immunohistochemical staining results, Bcl-2 protein was detected in epithelial cells that lined the mammary duct but was very weak in stromal cells Fig. Interestingly, Bcl-2 expression was higher in primary cultured normal breast epithelial cells NEC than in primary cultured cancerous human breast epithelial cells CAEC Fig.
These results suggest that Bcl-2 may be important in maintaining normal breast function. Bcl-2 expression in human breast. A Patients' information and Bcl-2 immunohistochemistry staining on both normal and cancerous breast tissues from human patients.
Blue staining represents nuclei. C Western blot analysis of Bcl-2 protein expression in primary cultured human breast cells. CAEC stands for cancer epithelial cells; NEC stands for normal epithelial cells; CASC stands for cancer stromal cells; NSC stands normal stromal cells. Equal amounts of isolated protein from whole cell lysate were subjected to immunoblot with anti-Bcl-2 antibodies.
Bcl-2 expression was measured by immunohistochemical staining and western blot. CLA treatment decreased E 2 -stimulated Bcl-2 expression in tissues after three days of treatment Fig. This was confirmed by quantification of western blot Bcl-2 protein results Fig.
CLA which is in combination with Tam further suppressed E 2 -induced Bcl-2 protein expression in both MCF-7 Fig. Interestingly, there are two bands of Bcl-2 were detected by western blot analysis in MCF-7 cells Fig. Different migration of the same protein may be caused by the post-translational modification, such as phosphorylation.
It has been suggested that phosphorylation will stabilize Bcl-2 which may lead to anti-apoptosis of the cell [ 26 , 27 ]. By contrast, de-phosphorylation of Bcl-2 will sensitize cell to apoptosis inducing agent.
CLA stands for 40 μM t 10, c CLA; E 2 stands for 10 nM 17β-estradiol. Studies have shown that the local micro-environment is crucial for cancer progression, because cancer epithelial cells are surrounded by various types of stromal cells [ 28 ].
The interaction between epithelial cells and extracellular matrix is important for cells to make life or death decisions [ 29 ]. Apoptosis of co-cultured MCF-7 cells was not changed in comparison with MCF-7 cells cultured alone.
CLA treatment induced apoptosis in MCF-7 cells cultured alone and stimulated further apoptosis when these cells were co-cultured with stromal cells Fig. A similar pattern of response also was shown in MDA-MBERα cells Fig.
In agreement with the results in Figs. Furthermore, Bcl-2 expression was decreased in the co-cultured cells treated with CLA.
CLA induced apoptosis of breast cancer epithelial cells is associated with estrogen receptor α ERα in co-culture. MCF-7 A , MDA-MB B , ERα transfected MDA-MB, and MDA-MBERα C , were cultured alone or co-cultured with normal human breast stromal cells NSC , or co-cultured with cancerous human breast stromal cells CASC.
D Bcl-2 protein expression of MCF-7, MDA-MB or MDA-MBERα was determined by western blot analysis. Evidence from epidemiological studies has shown that the duration of estrogen exposure is an important risk factor for development of breast cancer. Estrogens are involved in initiation, promotion, and progression of breast carcinogenesis [ 30 ].
It has been shown that CLA exerts little to no inhibitory effect on MDA-MB cells compared to MCF-7 cells suggesting the possible involvement of anti-estrogenic effects of CLA on human breast cancers [ 24 , 31 , 32 ].
Using MCF-7 cells transiently transfected with the estrogen responsive element ERE , Tanmahasamut et al. More recently, Liu and Sidell [ 33 ] showed that CLA suppressed phosphorylation of the estrogen receptor, which may inhibit receptor-ERE interactions in MCF-7 cells.
Potentiation of Tam by combination with CLA was observed in MCF-7 cells. It was observed that CLA reduced cell proliferation in normal mammary gland but did not induce apoptosis of cells within the terminal end buds and lobular epithelium in rats [ 34 — 36 ].
In contrast, CLA induced apoptosis in mammary tumor cells and premalignant rat mammary gland [ 37 ]. We speculate that dietary long-term consumption of CLA may have moderate chemopreventive activities in healthy individuals.
Furthermore, in breast cancer patients, CLA also might have less of an effect on normal parts of the mammary gland, resulting in a lesser degree of cytotoxicity in these patients. CLA exerted anti-estrogenic effects in MCF-7 and MDA-MBERα cells but treatment did not induce considerable effects in MDA-MB cells.
E 2 treatment inhibited the growth of MDA-MBERα and CLA counteracted E 2 -induced growth inhibitory effect unpublished data. According to these and results shown in Fig.
This might explain epidemiological findings showing that CLA intake may be correlated with reduced risk of having an estrogen receptor negative cancer in premenopausal breast cancer patients [ 20 ].
The carcinogenic effects of estrogens in breast cancer include the stimulation of breast tissue growth and the protection of cells from apoptosis [ 30 ].
A higher proliferative rate in tumors has been correlated with metastasis, death from neoplasia, low disease-free survival rates, and low overall survival rate in human cancer models [ 31 ].
Immunohistochemical staining studies suggested that Bcl-2 expression is linked to hormonal regulation in human breast cancers [ 38 ].
Interestingly, several studies showed Bcl-2 protein expression in normal as well as hyperplastic and neoplastic breast epithelial cells [ 38 — 40 ]. In agreement with these findings, our results showed that Bcl-2 protein is expressed in both cancerous and normal human breast tissues Fig.
In normal breast tissue samples, 12 out of 14 were from patients under 40 years of age; 10 were diagnosed as macromastia and the remaining four were diagnosed as hypertrophy Fig. Accordingly, we speculate that Bcl-2 may be important to maintain mammary gland function in these normal patients and Bcl-2 may be involved in the occurrence of mammary hypertrophy and mammary macromastia.
It has been suggested that cells express Bcl-2 are immature and may be part of the stem-cell subpopulation in normal mammary gland [ 40 ].
Bcl-2 is important for maintenance and development of normal mammary gland. However, Bcl-2 expression is increased when cell proliferation in tissues is dysregulated in hyperplastic and neoplastic disorders.
Bcl-2 localization in normal breast tissue may be related to the origin of malignant breast disease [ 40 ]. We have observed that CLA also blocks the estrogenic effects of environmental hormones such as Zeranol, a nonsteroidal agent with estrogenic activity used as a growth promoter in the US beef and veal industries unpublished data.
Taken together, the results suggest that CLA is an excellent candidate for prevention and therapy of estrogen responsive breast cancer. From experimental cancer models, the extracellular microenvironment has been demonstrated to influence tumor formation, the rate of cellular proliferation, the ability of the cancer cells to metastasize and the extent of invasiveness.
In many cancers, the influences of the microenvironment are mediated in part by paracrine signaling between epithelial cancer cells and the surrounding stromal cells [ 41 , 42 ].
Although Bcl-2 is expressed highest in malignant epithelial cells, stromal cells also express Bcl-2 but in lesser amounts, which may indicate both autocrine and paracrine effects of Bcl-2 in the tumor microenvironment Fig. It appeared that CLA was able to interrupt this paracrine signal Figs. However, the involvement of stromal cells did not alter the effects of CLA in MDA-MB cells Fig.
Although CLA possesses apoptotic effect in both normal and cancerous stromal cells data not shown , cancerous ERα negative breast epithelial cells may acquire independent self-regulation from the surrounding stromal compartment.
Preclinical studies [ 43 , 44 ] showed promising anti-mammary tumor activity in mouse ~3. It is clear that women consume ~ times less than the amount of CLA estimated to provide protection. A moderate but effective influence may occur after low level long term consumption of CLA.
Since CLA is a natural by-product of rumen fermentation and is found in foods derived from ruminants, consumption of CLA from foods for the purposes of chemoprevention likely will not affect the safety of consumers.
It is interested to note that special diet of cow is able to increase CLA in milk fat [ 2 ]. Whether CLA will cause any toxic effects on these cows? We speculate that CLA will be less likely to induce cell apoptosis in the udder of these cows because CLA in the circulation will not reach the doses used in in vitro cell culture models nor the concentrations of CLA-enriched diet in animal studies.
We investigated the role of ERα in CLA induced apoptosis in human breast tissue. By contrast, ERα - cells and tissue failed to respond to the treatments. This result was further confirmed by the transfection of ERα into these cells which restored their response to CLA. Therefore, our findings demonstrate that CLA exert anti-estrogenic effects and ERα plays important roles in CLA induced apoptosis in human breast tissues.
Future study examine the knock down of ERα in MCF-7 cells to confirm the loss of response of these cells to CLA are crucial to support the proposed mechanism — ERα plays important role in CLA's anti-cancer activity.
MacDonald HB: Conjugated linoleic acid and disease prevention: a review of current knowledge. J Am Coll Nutr. Article CAS PubMed Google Scholar. Ip MM, Masso-Welch PA, Ip C: Prevention of mammary cancer with conjugated linoleic acid: role of the stroma and the epithelium.
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FASEB J. Consuming foods high in CLA or taking CLA supplements for 12 weeks seems to improve symptoms and overall well-being in people with seasonal allergy symptoms.
Similarly, some research shows that for people with asthma, CLA might be a natural treatment method for asthma-related symptoms, due to its ability to help control inflammation. Twelve weeks of supplementation seems to improve airway sensitivity and ability to exercise.
Early research suggests that CLA is beneficial for lowering inflammation and therefore autoimmune diseases like rheumatoid arthritis. Taking conjugated linoleic acid alone or along with other supplements like vitamin E benefits those with arthritis by reducing symptoms, including pain and morning stiffness.
Pain and inflammation markers including swelling have been improved for adults with arthritis taking CLA compared to their pre-treatment symptoms or people not taking CLA, meaning CLA can naturally treat arthritis. Although findings have also been somewhat conflicting, some research shows that taking conjugated linoleic acid alone or along with supplements like creatine and whey protein can help increase strength and improve lean tissue mass.
This is why CLA is often added to some bodybuilding supplements, protein powders and weight loss formulas. According to a report published in The Journal of Food Composition and Analysis , the top food sources of CLA include :. What an animal eats and the conditions in which they are was raised highly affect how much CLA and other fats or nutrients their meat or milk will supply.
The proportion of CLA ranges from 0. In other words, not all beef or dairy is created equal when it comes to supplying us with healthy fats like CLA. Even the season, quality of the soil on the farms and age of the animal affect the CLA content. One study, for example, found that the CLA content in beef and dairy from grass-fed cows is — percent higher compared to grain-fed cows.
Grass-fed beef contains higher levels of CLA and even more omega-3 fats and vitamins too than beef from factory farm-raised animals. The same goes for dairy products we get from cows, including cream or butter.
Butter, beef and cream are nothing to be scared of, as long as you consume the highest quality you can, just like traditional populations have done for thousands of years.
Should you take CLA supplements? While CLA supplementation has shown some positive effects for managing risk and symptoms for some diseases, most might lack high levels of rumenic acid , which is the predominant form of CLA found in naturally occurring foods.
This comprises approximately 90 percent of CLA found in ruminant meats and dairy products and the most biologically active forms 9,11 and 10,12 isomers. On the other hand, in many cases the CLA found in supplements is made by chemically altering linoleic acid from unhealthy vegetable oils.
for use as a dietary supplement. However, not all research shows that taking high supplemental doses is safe. What are the side effects of taking CLA? CLA is considered safe when eaten as part of whole, natural foods or taken by mouth in moderate amounts that are still larger than those found in foods.
In some animal and human studies, conjugated linoleic acid has been shown to increase accumulation of fat in the liver also called hepatic steatosis and to promote inflammation. However, overall there have been c onflicting findings about whether CLA is mostly inflammatory or not.
The liver may be most impacted by high intake of conjugated linoleic acid because it plays an important role in energy homeostasis and converting excessive dietary glucose from carbs and sugar into fatty acids.
However, food sources like butter and beef are definitely safe and encouraged, since these provide not only CLA, but important nutrients for growth and development, including various fat-soluble vitamins, minerals and protein.
If you are getting surgery or have a history of poor liver function or bleeding disorders, keep in mind that supplementing with CLA might not be safe. Conjugated linoleic acid might slow blood clotting and increase the risk of bruising and bleeding, but again eating foods with CLA should pose no risk.
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Conjugated linoleic acid CLA has imbalancea much Turbocharge your metabolism in imbalanes two decades in CLA and hormonal imbalances area ranging from anticancer activity to obesity. Hormonwl number of research papers have been published recently Antispasmodic Herbs for Nervous System Disorders regard to CLA's additional biological imbalajces as reproductive benefits. However, not much is known how this mixture of isomeric compounds mediates its beneficial effects particularly on fertility. In this study, we demonstrated the cross talk between downstream signaling of CLA and important hormone regulators of endocrine system, i. FSH and IGF1, on buffalo granulosa cell function proliferation and steroidogenesis. Western blot analysis of total cell lysates revealed that CLA intervenes the IGF1 signaling by decreasing p-Akt. In addition, CLA was found to upregulate peroxisome proliferator-activated receptor-gamma PPARG and phosphatase and tensin homolog PTEN level in granulosa cells. Sharp Mind Formula details. This comprehensive review critically evaluates whether supposed health imbalwnces propounded upon wnd consumption of conjugated linoleic Ways to lower blood pressure CLAs are clinically proven or not. CLA and hormonal imbalances a general introduction on the chemistry anf CLA, major clinical evidences pertaining to intervention strategies, body composition, cardio-vascular health, immunity, asthma, cancer and diabetes are evaluated. Supposed adverse effects such as oxidative stress, insulin resistance, irritation of intestinal tract and milk fat depression are also examined. It seems that no consistent result was observed even in similar studies conducted at different laboratories, this may be due to variations in age, gender, racial and geographical disparities, coupled with type and dose of CLA supplemented.
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