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Gallbladder Cancer Types of Cancer About 90 percent of gallbladder cancers are adenocarcinomas, which start in glandular cells. There are a number of steps you can take to live a more sustainable lifestyle. You M et al. Premium soluble collagen is meticulously blended with a natural oil complex in a formula that allows for perfect penetration for moist, supple skin. Various means of assessment i. The plaques themselves can also rupture due to a spike in blood pressure or a tremor along an arterial wall, and the body responds to this perceived injury by forming blood clots. Stretching not only improves your range of motion, it also promotes better posture, and helps you perform activities that can require greater flexibility, such as chores around the house.

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One study of 40 patients with high-grade prostate intraepithelial neoplasia HGPIN received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in men treated with lycopene supplements, compared with those who did not take the supplementation. During follow-up, adenocarcinomas were diagnosed more often in patients who had not received the supplements 6 of 20 than in men who had received lycopene 2 of These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.

No statistically-significant difference was observed in serum PSA levels between the two treatment groups. No overall clinical benefit was seen in decreasing the rate of progression to prostate cancer. Baseline PSA levels showed no significant change. Prostatic lycopene concentration was the only difference between those whose repeat biopsy showed HGPIN, prostatitis , or prostate cancer.

Other studies have examined the potential therapeutic effect of lycopene-containing products in men with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in men with localized prostate cancer in a pilot study. Mean plasma PSA levels were lower in the intervention group compared with the control group.

In a phase II, randomized, placebo-controlled trial,[ 45 ] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene Lyc-O-Mato or no supplement from time of biopsy to prostatectomy 30 days. Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm.

No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, compared with disease-free controls, and similar to levels observed in previous studies in men with prostate cancer. However, serum testosterone and SHBG levels in the control group remained unchanged.

The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki, compared with the control group. These changes were not statistically significant , compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.

Analysis of the PSA-doubling time pretreatment vs. Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization.

Although this was a small study without a control group , the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer. Only one patient in this study exhibited a decrease in PSA level. Several episodes of gastrointestinal side effects were noted after eating the tomato paste or drinking the tomato juice. Perhaps, future clinical trials should include longer duration of consistent lycopene exposure, while accounting for variations in individual absorption of carotenoids and heterogeneity of high-risk HGPIN, atypical small acinar proliferation and prostate cancer patient populations indolent vs.

Studies evaluating lycopene in randomized clinical trials targeting men at high risk for prostate cancer and populations with prostate cancer have indicated relatively few toxicities at the dose and duration of intervention. When adverse effects occurred, they tended to present as gastrointestinal symptoms [ 48 ] and, in one study, the symptoms resolved when lycopene was taken with meals. Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. Plant pectin is used in food processing as a gelling agent and also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.

Some research suggests that MCP may be protective against various types of cancer, including colon , lung , and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis. MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.

In a study, pectins were investigated for their anticancer properties. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP.

This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.

The researchers postulated that, because it has a lower molecular weight, PectaSol-C may have better bioavailability than PeS. In one study, the role of galectin-3, a multifunctional endogenous lectin , in cisplatin -treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 via silencing RNA knockdown of galectin-3 expression or treatment with MCP were susceptible to cisplatin-induced apoptosis.

These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacy of cisplatin treatment in prostate cancer may be improved by inhibiting galectin Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer. In the study, rats were given 0. The analysis revealed that treatment with 0.

In a pilot study , patients with advanced solid tumors various types of cancers were represented, including prostate cancer received MCP 5 g MCP powder dissolved in water 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life , including physical functioning, global health status, fatigue , pain, and insomnia. In one prospective pilot study , MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus , dyspepsia , and flatulence.

The pomegranate tree Punica granatum L. The arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoids present in arils, are responsible for the red color of the fruit and its juice. Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[ 6 ] and may also have positive effects on oral or dental health.

Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease. Ellagitannins the main polyphenols in pomegranate juice are hydrolyzed to ellagic acid , and then to urolithin A UA derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration 0.

Ellagic acid EA was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract 0. Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid a major constituent of pomegranate seeds being the strongest inducer of apoptosis. Additionally, findings from this study suggested that punicic acid may activate apoptosis by a caspase-dependent pathway.

Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro. All four treatments resulted in statistically significant increases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. As a result, CYP1B1 inhibitors may be effective anticarcinogenic targets. In a study reported in , the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined.

In addition, the insulin-like growth factor IGF system has been implicated in prostate cancer. However, these substances may have induced apoptosis by different mechanisms. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration.

These findings suggested that PJ may be beneficial in slowing down or preventing cancer cell metastasis. The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ 0.

Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ 8 days vs. Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only. In a study reported in , 6-week-old transgenic adenocarcinoma of the mouse prostate TRAMP mice received normal drinking water or PJ 0.

The PJ-supplemented mice exhibited significantly increased life spans compared with the water-fed mice. Three clinical studies have examined the effect of interventions with pomegranate products on changes in PSADT in patients with biochemically recurrent prostate cancer who had a rising PSA after surgery or radiation therapy for presumed localized cancer.

The second phase II study was published in and randomly assigned 92 patients to either 1 g polyphenol gallic acid content equivalent to 8 ounces of pomegranate juice [47 patients] or 3 g 45 patients of pomegranate extract powder for up to 18 months.

The third trial was a randomized, double-blinded , placebo controlled study published in Of the patients who enrolled, 64 patients were treated with placebo, 17 patients were treated with PJ, and patients were treated with pomegranate liquid extract, which contained the same compounds found in PJ, with the exception of a higher proportional content of pomegranate polyphenol and a lower anthocyanidin content.

The differences in results between the trials may be partly because of less aggressive disease in the patient population with lower starting PSA values, but may also be because the first two trials lacked a placebo arm. All three trials found that pomegranate extract was safe to consume. In light of these findings, researchers wondered if there may be a sensitive subpopulation that might benefit from PJ. One potential genetic biomarker candidate is manganese superoxide dismutase MnSOD , which is the primary antioxidant enzyme in mitochondria.

The AA genotype has been associated with more aggressive prostate cancer and with more sensitivity to antioxidants than the VA or VV genotype. In summary, the finding that men with the AA genotype who received pomegranate extract had greater lengthening of PSADT than did men in the placebo arm, along with the safe profile of PJ and extract in three large studies, suggest that there may be benefit in further studies in the AA MnSOD subpopulation.

In a study of prostate cancer patients reported in , the PJ intervention was well tolerated and no serious adverse effects were observed. In a pilot study reported in , the safety of PJ in patients with erectile dysfunction was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse side effects.

In the analysis of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the placebo arm. Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in and named after the Greek goddess of the moon, Selene. Food sources of selenium include meat, vegetables, and nuts.

The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant.

Selenium is implicated in a number of disease states. Selenium deficiency may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone disorder. Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.

The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of lung , colorectal , and prostate cancer were significantly reduced. There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and SEPP have been observed in some tumors , while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.

Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells. Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds.

One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor , which led to apoptosis and growth inhibition. In a study, prostate cancer cells treated with sodium selenite a natural form of selenium exhibited increased levels of p53 a tumor suppressor. Findings also revealed that p53 may play a key role in selenium-induced apoptosis.

In a second study, the prostate cancer cell line LNCaP was modified to separately overexpress each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase MnSOD were the only ones able to suppress selenite-induced apoptosis.

These findings suggest that superoxide production in mitochondria may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine the effectiveness of selenium in inhibiting those cells. One study treated prostate cancer cells and benign prostatic hyperplasia BPH cells with sodium selenite.

Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in PC-3 cells at these concentrations—prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer—selenium supplementation may have adverse effects in hormone-sensitive prostate cancer.

A study investigated whether various forms of selenium i. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.

At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite. Mice were fed selenium-depleted or selenium-containing at nutritional or supranutritional levels diets for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells.

Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more necrosis and inflammation compared with selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less aggressive prostate cancer than did mice that started treatment at 16 weeks, suggesting early intervention with MSeA may be more effective than later treatment.

The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA mainly affected proteins related to prostate differentiation , androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in phase II detoxification or cytoprotection.

The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the European Prospective Investigation into Cancer and Nutrition EPIC -Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years.

The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations. Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer.

A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status. Two SNPs were significantly associated with prostate cancer incidence: For men with the alanine-alanine AA genotype , higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a valine V allele. The authors recommended caution in the use of selenium supplements among men with prostate cancer.

Risk of prostate cancer mortality rose at all levels of selenium consumption. The authors reported no statistically significant association between selenium supplement use and biochemical recurrence , cardiovascular disease mortality, or overall mortality. Blood samples were collected at the start and end of the study. Compared with the placebo group, men who received selenium supplements exhibited significantly increased activity of two blood selenium enzymes and significantly decreased levels of prostate-specific antigen PSA at the end of the study.

A meta-analysis published in reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. While there was no change in PSA levels between the groups after 6 months, the participants receiving supplements reported improved quality of life and showed decreases in low-density lipoprotein cholesterol and total cholesterol. Selenium was given in the form of Se-yeast. Men receiving the high-dose selenium, and who had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group.

There was not a significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium. In , results of a phase III randomized, placebo-controlled trial investigating the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease were reported.

They were monitored every 6 months, up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.

The results suggested that selenium supplementation had no effect on prostate cancer risk. The primary endpoint of the clinical trial was incidence of prostate cancer. There were no statistically significant differences in rates of prostate cancer in the four groups. On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements. Updated results were published in There was also greater incidence of prostate cancer in men who had taken selenium than in men who took placebo, but those differences were not statistically significant.

A number of explanations have been suggested, including the dose and form of vitamin E that was used in the trial as well as the specific form of selenium chosen for the study.

SELECT researchers chose selenomethionine because it was the major component of Se-yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes. Toenail selenium concentration was inversely associated with risk of total prostate cancer odds ratio , 0.

Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups. Although records of soy use in China date back to the 11th century BC, it was not until the 18th century that the plant reached Europe and the United States.

The soybean is an incredibly versatile plant: Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity. Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours after soy product consumption.

Some studies suggest that soy may have health benefits, including decreasing risk of cardiovascular disease and cancer. A link between isoflavones and cancer was discovered in when it was shown that genistein inhibited a protein tyrosine kinase that is often overexpressed in cancer cells. A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle carrier or isoflavones.

Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 PGE2 and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.

The isoflavones were shown to down regulate growth factors involved in angiogenesis e. These findings suggest that genistein and daidzein may have chemopreventive properties. However, during the 72 hours of incubation , only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells.

No such effects were observed for daidzein at the same dose. Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one study, human prostate cancer cells were treated with a soy extract containing genistin, daidzin, and glycitin , genistein, or daidzein.

The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia BPH cells, but the soy extract had no effect on those cells.

These findings suggested that products containing a combination of active compounds e. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.

At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.

Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.

Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.

In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice.

These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer. Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only.

Nude mice were implanted with prostate cancer cells and treated by gavage with genistein Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth.

In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.

Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants from healthy control subjects to prostate cancer patients at various stages of the disease and have used a number of different interventions such as soy supplements, beverages, and breads.

In , a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods e.

No association was found between high consumption of fermented soy foods e. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol a metabolite of daidzein were at a lower risk of prostate cancer than men who were nonproducers.

Overall, there were no differences in PSA levels between the placebo and the treatment groups. Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions.

In one study, healthy men were randomly assigned to consume a low-soy usual diet or high-soy soy servings bid diet for 3 months.

Following a 1-month washout period, the men crossed over to the other treatment. Reductions approaching statistical significance were seen in PSA levels following the high-soy diet.

These findings suggest that this type of soy intervention study is feasible i. In one study, men at risk of prostate cancer or with low-grade prostate cancer received one of three types of protein isolate soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate that results in some loss of isoflavones], or milk protein for 6 months.

Soy protein consumption did not alter prostate tissue biomarkers , alcohol-washed soy protein exerted mixed effects, and less prostate cancer was detected after 6 months in men who had consumed soy proteins compared with men who consumed milk protein.

Japanese men who had serum PSA levels between 2. There were no differences in PSA values or in incidence of biopsy-detectable prostate cancer before and after treatment in the isoflavone or placebo groups.

Other plants also contain some of the same isoflavones found in soy. In addition, the isoflavone intervention was well tolerated by the patients and did not cause side effects.

In a study reported in , patients with rising PSA levels who had been treated with radiation as the primary treatment for prostate cancer drank a soy beverage daily providing approximately mg isoflavones for 6 months. The results showed that the soy beverage was well-tolerated and was associated with an increase in PSA doubling time. These findings suggested that drinking the soy beverage may have helped to slow the progression of prostate cancer.

Then, for an additional 6 months, all participants received the isoflavone supplement. Although treatment with the supplements raised serum concentration levels of genistein and daidzein, there was no effect on PSA levels.

In a study reported in , prostate cancer patients scheduled for radical prostatectomy were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7. The investigators noted that the 12 genes involved in cell cycle control and the 9 genes involved in apoptosis were down regulated in the tumor tissues of the isoflavone-treated men, compared with the controls.

In a second phase II, multidose, randomized placebo-controlled trial,[ 34 , 36 ] 45 men with localized prostate cancer received supplements with either 40, 60, or 80 mg of purified isoflavones or no supplement from the time of biopsy to prostatectomy. Significant increases in plasma isoflavones were observed with all isoflavone doses, compared with placebo, and significant increases in serum total estradiol were observed in the 40 mg and 60 mg isoflavone-treated arms.

However, significant increases in serum-free testosterone were observed in the 60 mg isoflavone-treated arm. Compared with the control group and other treatment arms, the 40 mg isoflavone-treated arm had the lowest percentage of cells expressing Ki, although this was not statistically significant for this sample size and duration of intervention. This study concluded that 40 mg of isoflavones may be the best dose to use in a future definitive, larger phase II clinical trial to evaluate purified isoflavones in prostate carcinogenesis.

Patients who received the soy protein supplement exhibited larger decreases in total serum PSA and free testosterone than did patients who received the placebo, but these differences were not statistically significant. Clinical studies have been conducted in prostate cancer patients to test soy as a possible treatment for prostate cancer. In one study, prostate cancer patients scheduled to undergo radical prostatectomy were randomly assigned to receive soy supplements three The isoflavone concentration in prostatic tissue was sixfold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially anticarcinogenic levels of isoflavones.

Patients who ate the high-phytoestrogen bread saw more favorable changes in PSA levels than did patients who ate the wheat bread, indicating that diets rich in phytoestrogens may help to reduce risk of prostate cancer development and progression. In a small study, ten men with prostate cancer recurrence were advised to consume three 8-ounce glasses of soy milk every day for 2 years.

Androgen deprivation therapy is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life , and changes in cognition. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo treatment.

The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters e. Prostaglandins promote inflammation and may contribute to cancer by increasing cell proliferation and inhibiting apoptosis.

The findings of a study reported in suggest that soy isoflavones may have chemopreventive effects via inhibition of the prostaglandin pathway. In the study, prostate cancer patients scheduled to undergo prostatectomy were randomly assigned to receive a placebo or a soy isoflavone supplement providing isoflavones, Overall, soy was well tolerated in clinical studies of prostate cancer patients. Vitamin D, also called calciferol, cholecalciferol D3 , or ergocalciferol D2 , is a fat-soluble vitamin found in fatty fish, fish liver oil, eggs, and fortified dairy products.

Vitamin D is made naturally by the body when exposed to sunlight. In , researchers discovered that heated, oxidized cod-liver oil, called fat-soluble factor A and later known as vitamin D, played an important role in curing rickets in rats.

Vitamin D is needed for bone growth and protects against osteoporosis in adults. To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,alpha-dihydroxyvitamin D3 1,D3 suppressed adhesion of prostate cancer cells in the microtube system.

In addition, it was shown that 1,D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation. By the end of the 12 weeks, the fasting female rats had lost 19 percent of their body weight, their blood glucose levels were lower, and their ovaries had shrunk.

While kisspeptin production went down in both male and female fasting rats, in the females, LH absolutely plummeted, while estradiol, a hormone that inhibits GnRH in humans, skyrocketed to four times higher than the normal level. You might be thinking: The female reproductive system and metabolism are deeply intertwined. In general, women tend to eat less protein than men.

Fasting women, obviously, will consume even less. Amino acids are needed to activate estrogen receptors and synthesize insulin-like growth factor IGF-1 in the liver.

IGF-1 triggers the uterine wall lining to thicken and the progression of the reproductive cycle. We have estrogen receptors throughout our bodies, including in our brains, GI tract, and bones.

Change estrogen balance and you change metabolic function all over: First, in the brainstem, estrogens modify the peptides that signal you to feel full cholecystokinin or hungry ghrelin. In the hypothalamus, estrogens also stimulate neurons that halt production of appetite-regulating peptides. Do something that causes your estrogen to drop, and you could find yourself feeling a lot hungrier — and eating a lot more — than you would under normal circumstances.

Yes, estrogens , plural. Because the ratios of the estrogenic metabolites estriol, estradiol, and estrone change over time. Before menopause, estradiol is the big player. After menopause, it drops, while estrone stays about the same. The exact roles of each of these estrogens remain unclear. But some theorize that a drop in estradiol may trigger an increase in fat storage. Because fat is used to make estradiol. This may partly explain why some women find it harder to lose fat after menopause.

Low-energy diets can reduce fertility in women. Being too lean is a reproductive disadvantage. Female bodies are exquisitely tuned to any threats to energy and fertility. Human females are totally unique in the mammalian world. Nearly all other mammals can terminate or pause a pregnancy pretty much whenever they need to. In humans, the placenta breaches the maternal blood vessels, and the fetus is in complete control. The baby can block the action of insulin in order to hoard more glucose for itself.

That baby is determined to survive no matter what the cost to the mother. Fertility at the wrong time — like, during a famine — could be fatal. The idea was that if your fat reserve dipped below a certain percentage somewhere around 11 percent might be a reasonable guess , hormones would get messed up and your period would stop.

This makes a lot of sense. But the situation is actually more complicated than that. After all, food availability can change quickly. Any combination of these stressors could be enough to put you into negative energy balance and stop ovulation: Meanwhile, progesterone is converted to cortisol during stress, so more cortisol means less progesterone.

This leads to estrogen dominance in the HPG axis. You could be hovering at 30 percent fat. Based on what we know, intermittent fasting probably affects reproductive health if the body sees it as a significant stressor.

But intermittent fasting protocols vary, with some being much more extreme than others. And factors such as your age, your nutritional status, the length of time you fast, and the other stresses in your life—including exercise—are also likely relevant. Pregnant women have extra energy needs. Your body needs nurturing, not additional stress. Learn the essentials of good nutrition.

Cook and eat whole foods. This may explain why human babies are so fat. These graphs are from a paper exploring different hypotheses about baby fat [Kuz] , one of them being to supply the brain energy in the form of ketones. The one on the right is what percent of oxygen metabolised by the whole body is going to the brain: Another consideration is building materials, since our brains are made mostly of fat and cholesterol and we know that ketones are used to synthesize those in situ.

The diagram here [Cot] shows pathways of how ketones can be generated, oxidized, or used to make fat and cholesterol. Fetuses and newborns use ketone bodies extensively, as I mentioned previously. In light of that, It seems like a reasonable hypothesis that ketogenic capacity in humans is so pronounced in childhood because the brain is developing, And ketones are for some reason the preferred material.

Other species tend to wean at the time when brain growth stops. That means that for them ketogenesis stops at the same time brain growth stops.

Even after it reaches about full size in adolescence, it continues to change structurally well into adulthood. However, quantitatively, this structural cost is very small compared to energy considerations [Kuz] , And so that hypothesis seems relatively weak on its own. Another set of ideas comes from the metabolic effects we see in the lab and clinic.

These are just a few metabolic changes relative to a high carb diet. Each can have profound effects on the workings of the brain. I do want to draw attention to the last one about availability of arachadonic acid and DHA. These are important for the brain as they make up the phospholipids, and they are subject to a lot of turnover.

Each of these effects has been proposed as a solution to the mystery of why a ketogenic diet treats epilepsy so effectively [Bou] , [Nyl] , [Mas] , [deL].

Epilepsy is just the condition with the most research, and the widest acknowledgment. Other conditions for which at least some evidence supports improvement via a ketogenic diet include neurological disabilities in cognition and motor control [Sta] ; the benefit here may have to do with the proper maintenance of brain structures such as myelination Recall phases: Survival after brain damage, the hypoxia of stroke or blows to the head is improved in animal models [Sta].

There is even animal evidence that brain damage due to nerve gas is largely mitigated by being in a state of ketosis during the insult [Lan].

Again, this suggests a structural support and resilience provided by a ketogenic metabolism. Resilience comes in part from not being as susceptible to damage in the first place, and that could be from reduced oxidative stress when using ketones for fuel. Ketogenic diets as a treatment for cancer are controversial, but some of the best evidence in support of it comes from glioblastomas.

This could be due mostly to the hypoglycemia stalling the rate of tumour development. And to venture into an area less well studied, but of critical importance given the epidemic that would be more apparent were it less taboo, there is preliminary evidence in the form of case studies that ketogenic diets may be promising treatments for many psychiatric illnesses too, for example, [Kra] , [Phe]. Given that anticonvulsants are also used to treat bipolar, and the solid results of ketogenic diets on epilepsy, this may not be surprising.

Additionally, the enhanced availability of AA and DHA may play a crucial role Because these fatty acids are critical for the brain, and dysregulation in their flux has been associated with bipolar disorder and schizophrenia. The question of how and why humans are so ketosis prone may lead to interesting new insights about us as a species.

We seem to avoid giving up ketosis as long as possible. It seems likely that it facilitated the evolution of our brains, that organ that makes us so different from other animals that we sometimes forget we are animals. Returning to the importance of metabolic switching between glucose and ketone mode, there seems to be a false dichotomy. The absorptive phase on a high carb diet lasts about 4 hours. Only after that can you start the postabsorptive phase, Marked by using glycogen as your source of blood sugar.

But if you are on a protein and calorie sufficient very low carb diet, then even after eating, your glycogen stores don't get that full in the first place. You can accentuate this by demanding more energy between meals exercise or eating less frequently, for example only once or twice a day.

Interestingly, this often naturally happens to ketogenic dieters. In the interest of time, I did not do my usual practice of end-to-end citations. I will probably return to fix that later! According to many plant-eating enthusiasts, we must eat fibre to be healthy for the following reasons:. These are not the only arguments people make for eating fibre. These are only reasons related to butyrate. Of the above statements, only one of them seems well-justified to me, but it also seems irrelevant.

Let's start from the end. This idea a quote from Wikipedia seems to to be an exaggerated interpretation of a study by Donohoe et al. The authors are studying germ-free mice, who don't, of course, have bacteria synthesising butyrate. They describe what looks to them like impaired colon cell energetics in the mice and ultimately autophagy upregulation, meaning the cells are eating themselves. They reverse these effects with butyrate. I've already written about some of the curious paradoxes inherent in the study.

To summarise, other studies consistently find germ-free mice to be healthier than wild mice by many a measure, including appearing to be more energetic, and living longer. There seems to have been a conflation of cell energy with mitochondrial energy, by not looking for mitochondrial density changes. So, I'm not convinced the butyrate made things better. Likewise, the reported evidence of autophagy increased autophagosomes attributed to upregulation of AMPK , insofar as it indicates autophagy, could equally be a desirable result, given the role of autophagy in maintaining healthy tissues.

Certainly unrestrained autophagy, with no homeostatic mechanism, should result in total loss of tissue, but that doesn't seem to happen with the germ-free mice.

Germ-free rodents have freakishly large caecums, and somewhat reduced small intestines, but so far as I can tell, no colon abnormalities worth mentioning. For an extensive review of the data already available in on germ-free animals, including the structure and function of various organs, see The gnotobiotic animal as a tool in the study of host microbial relationships. In any case, if the colons of germ-free mice are at any disadvantage there are clearly more differences that might be attributable to than mere lack of butyrate.

Are there other reasons to worry about colon cells that don't get any? If you haven't read my thoughts on the term "preferred" , the point is that what a cell will consume first isn't necessarily the fuel that is the healthiest, though it certainly can be.

Other reasons could be to get rid of it, or to access the metabolites. I'm not really suggesting that butyrate is toxic to colon cells. Though as soon as that thought occurred to me I looked for evidence that it can be, which, of course there is [Pen]. Apparently it can accumulate due to maldigestion or bacterial overgrowth and cause serious epithelial damage. All I'm saying is that habitual heavy use doesn't imply something is needed.

It's still possible that other fuels are as good or better than butyrate for the colonocyte. Normally, colonocytes do metabolise butyrate, mostly into CO2 and ketone bodies, but this is impaired in ulcerative colitis [Roe] , [Roe] , [Ahm] , such that ketogenesis is is inversely proportional to the severity of the disease [Roe].

This impairment may explain the mixed results in treatments involving butyrate. Some researchers have tried to treat colitis by adding more butyrate for substrate, by enema. Perhaps unsurprisingly, that has not met with much success.

I read a somewhat confusing review [Mal] that has several citations in it that don't appear to line up with the claims preceded by the citations, including citing the same paper that I've cited above Roe , as showing "that restoration of butyrate levels by intracolonic infusion treats UC", which I can find no mention of in the paper, and citing a single paper twice, [Ham] , once to say that enemas had very limited effect which I think is correct and once, later, to say it was a "well demonstrated" "cure".

These are probably just simple citation errors on my part or theirs. There have been some successes using enemas, but the results are mixed [Ham]. Insofar as there are successes, it is worth noting that the butyrate was taken in by rectal cells, not colon cells, and so the effect was post-absorptive. In other words, it must have come systemically. In fact, when the butyrate is applied directly to impaired cells it seems to worsen the situation.

These points are noted in the review, and motivates their own contribution. The researchers used intraperitoneal injections of butyrate to apparently almost completely restore colonocyte integrity in rodent models of colitis. At face value, this would suggest that it is not the butyrate that helped, but a metabolite of butyrate, i. If it's systemic ketone bodies we want, we know how to do that! Also, this method is rarely used in humans, so it may not be easy to make any practical use of.

In any case, none of this would suggest that eating plant fibre will help colitis in any way, given that the issue appears to depend on inability to use the butyrate. There is not clear evidence that fibre intake helps with IBD, and in fact, "low residue" or "low fibre" diets are usually recommended see below.

In case you were wondering, "residue" means anything that survives digestion, and comes all the way through the intestines.

That includes fibre , but also microorganisms, and secretions and cells shed from the alimentary tract. While there are studies that support the benefit of fibre in IBD, there are others showing harm. The evidence is mixed enough to be called weak and inconclusive [Kap].

Anecdotes such as the " Crohn's Carnivore " suggest a different solution might hold for some:. That experience runs both with and possibly against current dietary guidelines for IBD. In a review [Bro] , the authors show that most guidelines advise low fibre intake, especially during flares.

Some also advise low fat intake, and in particular, to eat lean meat. I'm not sure whether the Crohn's Carnivore was eating lean or fatty meat during his year of healing. At first blush, the low fat advisory looks like just another "extra-mile" kind of recommendation, in which guideline writers are throwing in other ideas about healthy diet for good measure.

However, they state that it comes from the reported reactions of some patients. One wonders if there are conflations. Later, the authors specifically say that there is little to support or refute a low fat recommendation. Another anecdote, this time elevated to "case study" level, because physicians penned it, comes from the Evolutionary Medicine Working Group, in Budapest, Hungary [Tot]. They report complete resolution of symptoms in a child with Crohn's and cessation of medications from an essentially meat-only diet.

The exception was that patient was allowed some honey, but it was low enough that ketosis was maintained. This was a 2: The child had previously tried low fat, low fibre, and several medications without improvement. It is interesting to note that even one dose of "paleo approved" fibre caused a flare up. In other words, a fibre-free ketogenic diet appears help IBD more than a diet including fibre, even a ketogenic diet including fibre.

The idea that butyrate might be protective of colon cancer seems to have started in the s see, e. This area of research is extensive, and I am by no means an expert. If you haven't guessed, that butyrate has a protective effect on colon cancer is the one statement I think is entirely defensible. For example butyrate's histone deacelytase HDAC inhibition is considered an important mechanism [Hin] , [Blo].

Gpra receptor activation is a recently identified mechanism [Sin]. In fact, the argument behind the relevance of the Gpra discovery is just as strong an argument for a ketogenic diet as for eating fibre! This sentence is incorrect. That is, the researchers demonstrated that butyrate could substitute for niacin in activating these receptors, and that just as niacin activation of Gpra in fat cells is protective of cardiovascular disease, it may also be in diseases of the colon, and this argues for eating fibre to substitute for pharmalogic doses of niacin.

From a press release:. Their search for other activators identified butyrate, which led Ganapathy to find that not only is the Gpra receptor expressed on the surface of colon cells, but that with sufficient fiber intake, butyrate levels in the colon can activate it.

A critic pointed out that the cell receptors for SCFAs are facing the lumen, and therefore argued that beta-hydroxybutyrate from the portal side would be irrelevant. Indeed, the researchers using niacin also assume that the extremely high dose of niacin does not act sytemically, but rather reaches the lumen because of the super-high doses.

So the statement I made above, about the argument for beta-hydroxybutyrate being equal to that for niacin is not correct. The argument still stands that the beta-hydroxybutyrate metabolites activating targets inside could be where the majority of the benefits of butyate come from. That is where the HDAC inhibition occurs and where the immune cell receptors are. At least one research group agrees with my speculation that the interior metabolites may be important for the effect [Siv].

SCFAs are low-affinity agonists for these receptors, and the normal luminal concentrations of these bacterial metabolites are in the millimolar levels, sufficient to activate these receptors from the luminal side.

However, some of the molecular targets for these metabolites are either inside the cells e. Therefore, concentrations of these metabolites inside the colonic epithelial cells and in the lamina propria are relevant to impact these molecular targets. The intracellular target HDAC is inhibited by butyrate and propionate at low micromolar concentrations. There are effective transport systems for SCFAs in the apical membrane of colonic epithelial cells e. Even though the luminal concentrations of SCFAs are in the millimolar range, it is unlikely that they reach lamina propria at significant levels to activate the cell-surface receptors present on the mucosal immune cells.

These metabolites are present only at micromolar levels in the portal blood [57], indicating that they undergo robust metabolism inside the colonic epithelial cells. This raises the question as to the physiological relevance of these bacterial metabolites to the activation of the cell-surface SCFA receptors in immune cells located in the lamina propria.

This ketone body is released from the cells into portal blood. Interestingly, as in the case of colitis, colorectal cancer appears to involve a dysfunction in ability to use butyrate. Specifically, there are detrimental changes in membrane transport that reduce its entry into the cell [Gon].

Therefore, it's unclear that once the disease process has begun, increased fibre intake will be of any use. Beta-hydroxybutyrate in the bloodstream, however, might. There is at least some preliminary evidence that butyrate in the bloodstream has similar effects on intestinal tissue as butyrate coming from the colon itself [Kor] , [Rol] , [Bar] , as does infusion of glutamine and acetoacetate, another ketone body [Rom].

Ketogenic diets do increase blood acetoacetate. These common mechanisms suggest that much or even all of the benefits obtainable by butyrate are equally achievable simply through ketogenic diets, making additional butyrate in the context of a ketogenic diet potentially superfluous.

Even though it seems likely that a fibre-free ketogenic diet is not only sufficient for colon health, but better for treating colon disease, we might feel cautious about going without the butyrate from fibre, given the dire pronouncements from nutritional scientists. Is there any other way to get butyrate? The most significant food source, butter, doesn't give much. That would take about a pound of butter!

Stepping back, it should be obvious that carnivores such as felines and canines provide an important source of data relevant to this question. Carnivores have colons, and they are not normally in ketosis unless food is scarce. Either their colons don't need butyrate, or they are getting sufficient butyrate from some other source. As it happens, there are microbes that ferment amino acids in to short chain fatty acids SCFAs , including butyrate. Carnivores are known to get "animal fibre" from their prey.

That is, amino acids from incompletely digested animal parts reach their colons and are fermented. In particular, in cheetahs, casein, collagen, and glucosamine have been shown to result in butyrate production comparable to fructo-oligosaccharides [Dep]. Beyond poorly digested animal sourced fibre, many amino acids are fermented into SCFAs, including butyrate [Ras] , and these amino acids are abundant in human intestines and colons and are fermented there [Vit] , [Dai] , [Nei] , [Wie].

I was unable to determine how much butyrate this would account for. I did find research comparing the SCFA levels produced in dogs under conditions of high fibre vs. This idea is supported by these observations:. Colonocyte butyrate metabolism was investigated in experimental colitis in mice. Colonocytes isolated from colitic and normal control mice were incubated with [ 14 C]butyrate or glucose, and production of 14 CO 2 , as well as of intermediate metabolites acetoacetate, beta-hydroxybutyrate and lactate , was measured.

The effect of different substrate concentrations on oxidation was also examined. Production of beta-hydroxybutyrate was decreased and production of lactate increased in DSS colitis compared with controls.

Increasing butyrate concentration from 10 to 80 mM enhanced oxidation in DSS colitis 0. Surface and crypt epithelial cells showed similar ratios of butyrate to glucose oxidation. When 1 mM DSS was added to normal colonocytes in vitro, it did not alter butyrate oxidation. The initial histological lesion of DSS administration was very patchy and involved crypt cells. Abnormal butyrate oxidation became apparent only after six days of DSS administration, at which time histological abnormalities were more widespread.

Histological abnormalities preceded measurable defects in butyrate oxidation. It was logical to assume that liver and muscle glycogen could serve as the fermentable substrate for lactate production in the stomach, but most of this should have been digested and absorbed by the small intes tine.

Another possible source of ferment able substance which could survive passage through the small intestine is the protein- polysaccharides of the connective tissue ground substance found in abundance in the meat by-products and whole ground chicken. The ground substance is made up of chondroitin sulfates and hyaluronic acid. The polysaccharide portion of these substances is composed of long chains of disaccharide units consisting of glucosa- mine or galactosamine and glucuronic acid.

The linkages of these polysaccharides are not such that they can be cleaved by the endogenous digestive enzymes found in the gut but they could be split by microbial enzymes. However, the ability and timing of SCFA to augment adaptation in the neonatal intestine is unknown.

Furthermore, the specific SCFA inducing the intestinotrophic effects and underlying regulatory mechanism s are unclear. Within each group, piglets were further randomized to examine acute 4, 12, or 24 hours and chronic 3 or 7 days adaptations. Indices of intestinal adaptation, including crypt-villus architecture, proliferation and apoptosis, and concentration of the intestinotrophic peptide, glucagon-like pepide-2 GLP-2 , were measured. Indicative of an antiapoptotic profile, jejunal Bax: The intestinotrophic mechanism s underlying butyrate's effects may involve GLP Ultimately, butyrate administration may enable an infant with short-bowel syndrome to successfully transition to enteral feedings by maximizing their absorptive area.

The question of whether or not to use probiotics continues to be debated. It may be important to communicate to IBD patients that high-fiber foods are not recommended, especially for those with CD, during flares or in the presence of active disease states, fistulas or strictures. There appears to be a tendency among the dietary guidelines to restrict foods such as raw fruits, raw vegetables, beans, bran, popcorn, seeds, nuts, corn hulls, whole grains, brown rice and wild rice.

Although not mentioned, raw salads would also fall into this category. Few research studies are available to support or refute such a recommendation. The topic needs further investigation because patients with malabsorption may be at risk of not obtaining their necessary essential fatty acids.

Perhaps saturated fats should be limited, with more of an emphasis on more healthy fat intakes. The abundance of the AA-fermenting bacteria in the large intestine is very high and their number can reach up to per gram dry feces Smith and Macfarlane, Using the traditional plate counting technique, the authors have also reported that the dominant bacterial species for the utilization of single AA or pairs of AA are very different.

For instance, Clostridium bifermentans is the predominant bacteria for the utilization of lysine or proline, and pairs of AA e. Many species of bacteria utilize the same AA as substrates for growth Smith and Macfarlane, Overall, bacteria belonging to the Clostridium spp.

The FOS and collagen showed comparable acetate production. Collagen not only had a high production of total SCFA but also resulted in a greater acetate to propionate ratio relative to all other substrates 8.

Considerable variation in BCFA ratios was observed among substrates. So, knowledge on the mechanisms involved in its membrane transport is relevant to both its physiological and pharmacological benefits. Also, changes in transporter expression or function will have an obvious impact on the effect of BT, and therefore, knowledge on the regulation of its membrane transport seems particularly important. More specifically, BT is transported into normal colonic epithelial cells by both MCT1 and SMCT1, but its intracellular concentration is kept low because it is efficiently metabolized and effluxed from these cells by BCRP-mediated transport.

In these cells, BT accumulates intracellularly because it is inefficiently metabolized due to the fact that glucose becomes the primary energy source of these cells and because there is a reduction in BCRP expression.

Butyrate is thought to exert its cellular effects through the induction of histone hyperacetylation. We sought to determine the effects of a variety of the SCFA on colon carcinoma cell growth, differentiation and apoptosis.

HT or HCT wild-type and pdeleted cells were treated with physiologically relevant concentrations of various SCFA, and histone acetylation state was assayed by acid-urea-triton-X gel electrophoresis and immunoblotting. Growth and apoptotic effects were studied by flow cytometry, and differentiation effects were assessed using transient transfections and Northern blotting.

Propionate C3 and valerate C5 caused growth arrest and differentiation in human colon carcinoma cells. The magnitude of their effects was associated with a lesser degree of histone hyperacetylation compared with butyrate. Acetate C2 and caproate C6 , in contrast, did not cause histone hyperacetylation and also had no appreciable effects on cell growth or differentiation.

Butyrate also significantly increased apoptosis, whereas the other SCFA studied did not. The growth arrest induced by the SCFA was characterized by an increase in the expression of the p21 cell-cycle inhibitor and down-regulation of cyclin B1 CB1. These data suggest that the antiproliferative, apoptotic and differentiating properties of the various SCFA are linked to the degree of induced histone hyperacetylation.

Furthermore, SCFA-mediated growth arrest in colon carcinoma cells requires the p21 gene. Since butyrate is expected to impact cellular metabolic pathways in colon cancer cells, we hypothesize that it could exert its antiproliferative properties by altering cellular metabolism. We show that although Caco2 colon cancer cells oxidized both butyrate and glucose into CO2, they displayed a higher oxidation rate with butyrate as substrate than with glucose. Furthermore, butyrate pretreatment led to an increase cell capacity to oxidize butyrate and a decreased capacity to oxidize glucose, suggesting that colon cancer cells, which are initially highly glycolytic, can switch to a butyrate utilizing phenotype, and preferentially oxidize butyrate instead of glucose as energy source to produce acetyl coA.

Butyrate pretreated cells displayed a modulation of glutamine metabolism characterized by an increased incorporation of carbons derived from glutamine into lipids and a reduced lactate production. The butyrate-stimulated glutamine utilization is linked to pyruvate dehydrogenase complex since dichloroacetate reverses this effect. Furthermore, butyrate positively regulates gene expression of pyruvate dehydrogenase kinases and this effect involves a hyperacetylation of histones at PDK4 gene promoter level.

Our data suggest that butyrate exerts two distinct effects to ensure the regulation of glutamine metabolism: As a product of fermentation within the human colon, it serves as the most important energy source for normal colorectal epithelium. It also promotes the differentiation of cultured malignant cells.

A switch from aerobic to anaerobic metabolism accompanies neoplastic transformation in the colorectum. The separate functional roles for n-butyrate may reflect the different metabolic activities of normal and neoplastic tissues. Relatively low intracolonic levels of n-butyrate are associated with a low fibre diet. Deficiency of n-butyrate, coupled to the increased energy requirements of neoplastic tissues, may promote the switch to anaerobic metabolism. The presence of naturally occurring differentiating agents, such as n-butyrate, may modify the patterns of growth and differentiation of gastrointestinal tumours.

This study aims to assess the effects of butyrate on inflammation and oxidative stress in subjects with chronically mildly elevated parameters of inflammation and oxidative stress. Before and after the intervention feces, blood and colonic mucosal biopsies were obtained. Parameters of antioxidant defense and oxidative damage, myeloperoxidase, several cytokines, fecal calprotectin and CRP were determined.

Although in general butyrate did not affect colonic glutathione levels, the effects of butyrate enemas on total colonic glutathione appeared to be dependent on the level of inflammation. The current article adds to this discussion but does not definitively answer the question. Overall, the data suggest that in the absence of a known fibrostenotic stricture with obstructive symptoms, a high fiber diet is likely safe in patients with IBD and may impart a weak benefit.

Yet, answering these clinically relevant questions with more confidence and detail is within our grasp. The advent of e-cohorts offers the potential to transform research in the future by allowing investigators to design cost-efficient Web-based clinical studies, particularly for interventional environmental clinical trials.

Short-chain fatty acids SCFAs are produced in the colon by the fermentation of dietary carbohydrates and fiber polysaccharides and have been shown to stimulate mucosal-cell mitotic activity in the intestine.

This study compared the effects of an intravenous and an intracecal infusion of SCFAs on the small-bowel mucosa. Standard TPN produced significant atrophy of the jejunal and ileal mucosa. The intravenous and intracolonic infusion of SCFAs were equally effective in inhibiting small-bowel mucosal atrophy. Since then, butyrate enemas have popularly been used as medicaments stemming from their potential to impart beneficial attributes to the colon.

This potential involves an increase in mechanical strength of injured colonic mucosa to hasten the healing process Bloemen et al. Much as butyrate tends to impart a protective effect, several authors have indicated failures or limited success of butyrate to relieve IBD patients Harig et al. This is done mainly through intrarectal administration of enemas that contain butyrate.