Research Review: 3,5-diiodothyronine (3,5-T2) and Metabolism

At least 13 million Americans have some form of thyroid disorders--more than 80% of these are attributable to an under-active thyroid gland — hypothyroidism. The condition is more common in women, and the rate rises with age, reaching 20% in women over 65 [Harvard Health Publications].

From Wikipedia, here is a brief overview of thyroid function:

The thyroid gland is an endocrine gland in the neck, and consists of two lobes connected by an isthmus. It is found at the front of the neck, below the Adam's apple. The thyroid gland secretes thyroid hormones, which primarily influence the metabolic rate and protein synthesis. The hormones also have many other effects including those on development. The thyroid hormones T₃ and T₄ are synthesized from iodine and tyrosine. The thyroid also produces the hormone calcitonin, which plays a role in calcium homeostasis.^[1]

Hormonal output from the thyroid is regulated by thyroid-stimulating hormone (TSH) secreted from the anterior pituitary, which itself is regulated by thyrotropin-releasing hormone (TRH) produced by the hypothalamus.^[2]

The thyroid may be affected by several diseases. Hyperthyroidism occurs when the gland produces excessive amounts of thyroid hormones, the most common cause being Graves' disease—an autoimmune disorder. In contrast, hypothyroidism is a state of insufficient thyroid hormone production. Worldwide, the most common cause is iodine deficiency. Thyroid hormones are important for development, and hypothyroidism secondary to iodine deficiency remains the leading cause of preventable intellectual disability.^[3] In iodine-sufficient regions, the most common cause of hypothyroidism is Hashimoto's thyroiditis—also an autoimmune disease. In addition, the thyroid gland may also develop several types of nodules and cancer.

Thyroid hormones are important throughout the body, acting to increase the basal metabolic rate and protein synthesis, assist in regulating long bone growth (with growth hormone), and increase the body's sensitivity to catecholamines (such as adrenaline). Thyroid hormones regulate protein, fat, and carbohydrate metabolism, stimulate vitamin metabolism, and decrease LDL cholesterol levels. As many people diagnosed with hypothyroidism can attest, thyroid hormone impact heat generation in humans (cold hands and feet are symptomatic of low thyroid levels).

The symptoms of hypothyroidism are variable and may include fatigue, sluggishness, cold intolerance, weight gain, constipation, muscle or joint pain, thin and brittle hair or fingernails, reduced sexual drive, high blood pressure, high cholesterol, slow heart rate, problems with concentration and memory, and depression.

In fact, if you go to your psychiatrist or family doctor with concerns about depression, before accepting any antidepressant medications, request a thyroid panel (total T₄ (thyroxine), free T₄, total T₃ (triiodothyronine), free T₃, and TSH). Most tests will only look at totals of T₃, T₄, and TSH, which can be very misleading. Only free (unbound) T₃ is functionally biologically active (3- to 5-fold more active than T₄).

Thyroxine (T₄) is the prohormone to triiodothyronine (T₃), both of which are tyrosine-based hormones and partially composed of iodine (see molecular model). In fact, most cases of hypothyroidism can be linked to low iodine levels.

        
triiodothyronine (T₃)                             thyroxine (T₄)

Treating Low Thyroid

Unless you are medically shown to have low thyroid levels that require pharmaceutical intervention, your best bet is to start with natural supplementation with l-tyrosine (an amino acid) and iodine (sea kelp is often the best choice as some iodine supplements are dosed too high and make hypothyroidism worse).

Jill Grunewald, who was diagnosed with Hashimoto's disease and is in remission solely through nutritional interventions, offers the following advise, condensed to bullet points - [I've added some comments in brackets].

1. Just say no to the dietary bungee cord (reduce or eliminate caffeine and sugar, including refined carbohydrates like flour, which the body treats like sugar, and grains).

2. Up the protein. Protein transports thyroid hormone to all your tissues and enjoying it at each meal can help normalize thyroid function. [My Note: Not soy, which is known to disrupt thyroid function.]

3. Get fat. Healthy fats are your friends--if you’re getting insufficient fat and cholesterol, you could be exacerbating hormonal imbalance, which includes thyroid hormones. 

4. Nutrient-up. Not having enough of these micronutrients and minerals can aggravate symptoms: vitamin D, iron, omega-3 fatty acids, selenium, zinc, copper, vitamin A, the B vitamins, and iodine.

• Optimal vitamin D levels are between 50-80 ng/mL; anything below 32 contributes to hormone pathway disruption.
• Omega-3s, found in fish, grass-fed animal products, flaxseeds, and walnuts, are the building blocks for hormones that control immune function and cell growth, are critical to thyroid function, and improve the ability to respond to thyroid hormones. 

[My notes: Men should take a fish oil product higher in DHA than EPA, while women and older adults tend to benefit more from higher EPA. Be care with vitamin D, which is fat soluble and can build up in tissues for some people (1000-2000 iu daily). Selenium can be more harmful than helpful, especially in men. No iron for men, or for post-menopausal women, unless anemic. Supplemental zinc should be dosed low, 30 mg or less (especially in men, where dosing above 100 mg/day or for longer than 10 years can increase prostate cancer risk).]

5. Go 100% gluten-free. For those with Hashimoto’s, eating gluten can increase the autoimmune attack on your thyroid.

6. Be mindful of goitrogens (foods that can interfere with thyroid function), including broccoli, Brussels sprouts, cabbage, cauliflower, kale, kohlrabi, rutabaga, turnips, millet, spinach, strawberries, peaches, watercress, peanuts, radishes, and soybeans.

7. Go for the glutathione. Glutathione can boost your body’s ability to modulate and regulate the immune system, dampen autoimmune flare-ups, and protect and heal thyroid tissue.

8. Address underlying food sensitivities. [My advise: Look into an anti-inflammatory diet.]

9. Do a gut check. [My note: The microbiome is the key to health and may play a central role in Hashimoto's.]

10. Address silent inflammation with whole foods nutrition. Systemic inflammation and autoimmunity often go hand-in-hand. [See #8.]

11. Address adrenal fatigue. It’s uncommon to have hypothyroidism without some level of adrenal fatigue.

12. Look at your stress and practice relaxation. The thyroid is a very sensitive gland and is exceptionally reactive to the stress response.

13. Ask for the thyroid collar. Next time you're getting an x-ray at the dentist, ask for the thyroid collar.

When pharmaceutical intervention is required, there are only two medically accepted options, or less frequently, a combination of the two. This is from T-Nation's The Thyroid Handbook.

Synthroid: L-thyroxine (T₄)

This drug is normally used as a replacement therapy in congenital or acquired hypothyroidism and it's also used to suppress TSH in cases where a person is suffering from hyperthyroidism. It's released in a 20/1 ratio in respect to T₃. T₄ is less potent than T₃, metabolically speaking, and has a half life of six to seven days in euthyroid humans. (That's where a person's thyroid gland is enlarged but it's not associated with inflammation or cancer. Also called goiter.)

Cytomel: L-triiodothyronine (T₃)

This drug is also used to treat hypothyroidism and is even used to determine if someone has hyperthyroidism. It's said to be three to five times more metabolically potent than T₄ and has a half-life of approximately 2.5 days. The usual dosages used to treat hypothyroidism are 5 to 25 mcg daily and gradually increasing the dosage to 60 to 75 mcg daily. Some people need as much as 100 mcg daily – 20 to 25 mcg of T₃ is approximately the same as 100 mcg of T₄.

Bodybuilders have been using these drugs for decades to boost metabolism and shed fat. However, both of these drugs (Cytomel especially) can down-regulate normal thyroid function in the same ways that exogenous androgen can down-regulate normal testosterone production.

Still, these drugs are used to offset the reduced metabolism that occurs in carbohydrate restriction. Depending on one's own physiology, it takes anywhere from 50 to 120 grams of carb intake daily to prevent T₃ decline during low-carb dieting.



Enter 3,5-diiodothyronine (3,5-T₂)

T₃ is essentially deiodination of a T₄ molecule (via iodothyronine deiodinase type I, II, and III), and T₂ is deiodination of a T₃ molecule.

There are two T₂ hormones: 3,5-diiodothyronine and 3,3-diiodothyronine. Both of them are metabolites of T₃ and T₄, but they exhibit very different physiological actions.

T₃ and 3,5-T₂ both reduce body weight, adiposity and [increase] body temperature despite increased food intake. 3,3-T₂ lacks these effects. T₃ and 3,5-T₂ reduce blood glucose levels, whereas 3,3-T₂ worsens glucose tolerance. Neither T₃ nor 3,5-T2 affects markers of insulin sensitization in skeletal muscle or white adipose tissue (WAT), but both reduce hepatic GLUT2 glucose transporter levels and glucose output. T₃ and 3,5-T₂ also induce expression of mitochondrial uncoupling proteins (UCPs) 3 and 1 in skeletal muscle and WAT respectively. [Da Silva Teixeira, et al, Acta Physiol 2016]

According to a review of "Translating pharmacological findings from hypothyroid rodents to euthyroid humans: is there a functional role of endogenous 3,5-T2?" (Pietzner, et al, Thyroid 25.2 (2015): 188-197) in SuppVersity:

While 3,5-T₂ burns fat (especially in the liver) and increases your metabolism, its cousin 3,3-T₂ will do nothing for your BMR/RMR + glucose and fatty acid metabolism and can, on top of that, even impair your glucose metabolism and ... increase the amount of liver fat and food intake.

Considerable research supports 3,5-T₂, which has been shown to possess the following attributes (references for these stats are found below):

• increase hepatic oxygen consumption by about 30%
• act rapidly and directly through activation of the mitochondria
• shows a dose-dependent effect which increased RM and oxidative capacity (greatest response to T₂ was in liver and in brown adipose tissue [BAT], the kind that burns fat)
• T₂ was also shown to have a similar effect to that of T₃ on lipid metabolism with T₂ actually doing a little better in some tissue

Thyroid stimulating hormone (TSH) inhibition is not as severe or as last with 3,5-T₂ vs. T₃:

• TSH inhibition isn't nearly as severe with T₂ as it is with T₃; T₂ is 13% less inhibitory on TSH levels, as compared to T₃
• T₃ and T₂ suppressed TSH to similar levels--it took 15 mcg/100g body weight per day of T₃ to accomplish this, while it took 200 mcg/100g body weight per day of T₂ to accomplish the same thing (it took about 13 times more T₂ to exert the same effect on TSH as T₃)

Bottom Line

3,5-T₂ can:

• reduce body weight and adiposity (fat storage)n despite increased food intake
• reduce blood glucose levels
• reduce hepatic GLUT2 glucose transporter levels and glucose output
• increase body temperature
• induce expression of mitochondrial uncoupling proteins in skeletal muscle (UCP3) and WAT/BAT (UCP1)--UCPs are crucial for fat burning
• increase hepatic oxygen consumption by about 30%
• act rapidly and directly through activation of the mitochondria

3,3-T₂ can:

• impair glucose metabolism
• worsen glucose tolerance
• increase the amount of liver fat and food intake
• not decrease body weight or adiposity

Most doctors are ignorant of the benefits of T₂, despite decades of research. However, there are OTC supplements available that contain this hormone, although most contain both 3,5-T₂ and 3,3-T₂. The only product I have found that favors 3,5-T₂ over 3,3-T₂ is ThyroTwin (175 mcg 3,5-T₂, 25 mcg 3,3-T₂ per capsule).

If you choose to supplement with 3,5-T₂, be sure to maintain adequate protein intake (1.0-1.5 grams per pound of body weight), do weight training 3-4 times a week (preferably full-body workouts), and if you choose to do so, or want to do so, add low-dose testosterone therapy to offset potential muscle loss (inject subcutaneously for better results).

3,5-T₂ is an effective metabolism booster, fat burner, and it may be useful in treating Hashimoto's without resorting to the stronger and possibly more catabolic T₃.

***

Here are a handful of recent articles on 3,5-T₂ (with links):

da Silva Teixeira, S., Filgueira, C., Sieglaff, D. H., Benod, C., Villagomez, R., Minze, L. J., Zhang, A., Webb, P. and Nunes, M. T. (2016), 3,5-diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. Acta Physiologica. doi: 10.1111/apha.12821

Lombardi A, Moreno M, de Lange P, Iossa S, Busiello RA, Goglia F. Regulation of skeletal muscle mitochondrial activity by thyroid hormones: focus on the “old” triiodothyronine and the “emerging” 3,5-diiodothyronine. Frontiers in Physiology. 2015;6:237. doi:10.3389/fphys.2015.00237.

Pietzner M, Lehmphul I, Friedrich N, et al. Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2? Thyroid. 2015;25(2):188-197. doi:10.1089/thy.2014.0262.

Goglia F. The effects of 3,5-diiodothyronine on energy balance. Frontiers in Physiology. 2014;5:528. doi:10.3389/fphys.2014.00528.

Padron AS, Neto RAL, Pantaleão TU, et al. Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid-sensitive tissues. The Journal of Endocrinology. 2014;221(3):415-427. doi:10.1530/JOE-13-0502.

A. Lombardi, P. de Lange, E. Silvestri, R. A. Busiello, A. Lanni, F. Goglia, M. Moreno. 3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement. American Journal of Physiology - Endocrinology and MetabolismPublished 1 March 2009 Vol. 296 no. 3, E497-E502 DOI:10.1152/ajpendo.90642.2008
Goglia F. Biological Effects of 3,5-Diiodothyronine (T2). Biochemistry (Moscow), 70(2), 2005: 164-172. Translated from Biokhimiya, 70(2), 2005: 203-213.

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References for 3,5-T₂ and 3,5-T₂ vs. T₃ (via T-Nation):

• Horst C, et al. "Rapid stimulation of hepatic oxygen consumption by 3,5-di-iodo-L-thyronine." Biochem J 1989 Aug 1;261(3):945-50
• Lanni A, et al. "Calorigenic effect of diiodothyronines in the rat." J Physiol 1996 Aug 1;494 (Pt 3):831-7
• Goglia F, et al. "Action of thyroid hormones at the cellular level: the mitochondrial target." FEBS Lett 1999 Jun 11;452(3):115-20
• Lanni A, et al. "Effect of 3,3'-diiodothyronine and 3,5-diiodothyronine on rat liver oxidative capacity." Molecular and Cellular Endocrinology. Volume 86, Issue 3. 1992
• Lanni A, et al. J. Endocrinol. 136:59-64 1993.
• O'Reilly I, Murphy MP. Acta Endocrinol. 127:542-546 1992.
• Lanni A, et al. "3,5-Diiodo-L-thyronine and 3,5,3'-triiodo-L-thyronine both improve the cold tolerance of hypothyroid rats, but possibly via different mechanisms." Pflugers Arch 1998 Aug;436(3):407-14
• Varghese S, Oommen OV. "Thyroid hormones regulate lipid metabolism in a teleost Anabas testudineus (Bloch)." Comp Biochem Physiol B Biochem Mol Biol 1999 Dec;124(4):445-50
• J. Kvetny. Horm. Metab. Res. 24:322-325, 1992.
• Moreno M, et al. "Effect of 3,5-Diiodo-L-thyronine on thyroid stimulating hormone and growth hormone serum levels in hypothyroid rats." Life Sciences, Volume 62, No.26, pp. 2369-2377, 1998.
• Horst C, et al. "3,5-Di-iodo-L-thyronine suppresses TSH in rats in vivo and in rat pituitary fragments in vitro." J Endocrinol 1995 May;145(2):291-7

Alternative Approaches to Prostate Cancer Prevention

Back in 2013, Dr. Anne E. Cress (Univ. Arizona Cancer Center) was commissioned to write a chapter for the 3rd edition of Fundamentals of Cancer Prevention. Dr. Cress, who besides being my boss in her lab is also my personal training client, knew about my interest in phytonutrients in cancer prevention, so she asked me to write a small section of the chapter on Alternative Approaches to Prostate Cancer Prevention. Below is that section.

It's pretty basic stuff, and not very in-depth--nor is it, by itself, firmly grounded in the molecular mechanisms at play. It has been my plan to update it and expand it into a full-length article. But, since then, there have been many, many grants to write/edit, and three first-author papers I have been assigned (two already published - Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers; The Cohesive Metastasis Phenotype in Human Prostate Cancer). Let's just say it was back-burnered.

I post it here in hope that someone might benefit from the information. And, perhaps, as impetus to get off my arse and write a new version.

Fundamentals of Cancer Prevention (2014); edited by David Alberts, Lisa M. Hess. Springer-Verlag Berlin Heidelberg; Heidelberg Germany. DOI: 10.1007/978-3-642-38983-2

Chapter 16: Prevention of Prostate Cancer, Amit M. Algotar, M. Suzanne Stratton, William L. Harryman, and Anne E. Cress

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16.4 Alternative Approaches to Prostate Cancer Prevention (pgs. 501-504)

The natural health industry has a reputation for making unsubstantiated health claims for various herbs, foods, and spices. However, clinical research offers an avenue to evaluate these claims, offering the hope of finding the next aspirin in terms of health benefits versus risks. A few of these supplements show potential in cancer treatment and prevention, most notably curcumin, and resveratrol, and manipulation of lifestyle factors should also be considered as an alternative approach.

16.4.1 Curcumin

Curcumin is one of the rising stars in the alternative health market and has been touted as a treatment for arthritis via regulation of 5-LOX and COX-2 pathways (Rao 2007), as a cancer prevention agent (Rao 2007; Khan et al. 2008), to support liver health (Vitaglione et al. 2005; Reuter et al. 2008), for life extension (Naik et al. 2004), and for a host of other health issues. Curcumin [1,7-bis(4-hydroxy- 3-methoxyphenyl)-1,6-hepatadiene-3,5-dione] is the primary constituent of turmeric (Curcuma longa), a spice used in cooking and folk medicine throughout Southeast Asia, a region evidencing low incidence for most cancer types (Salvioli et al. 2007). Over the last 20 years, researchers have been assembling a considerable body of evidence that curcumin may be a powerful tool in the fight against cancer—via apoptosis (Vitaglione et al. 2005; Khan et al. 2008) and due to its antitumor and anti-inflammatory properties (Piper et al. 1998; Ravindran et al. 2009)—and in slowing the progression of cancer (Plummer et al. 2001; Aggarwal et al. 2006; Bae et al. 2006). Curcumin induces apoptosis in both androgen-dependent and metastatic hormone refractory prostate cancer cells (Yoysungnoen et al. 2006), as well as demonstrating antimetastatic activity (Dorai et al. 2000; Kuttan et al. 2007).

In addition to its own antioxidant activity (Killian et al. 2012), curcumin increases glutathione S-transferase, which upregulates the creation of glutathione (Rao 2007; Basnet and Skalko-Basnet 2011), the body’s master antioxidant [accordingly, researchers are studying curcumin as a liver detoxification supplement (Naik et al. 2004; Vitaglione et al. 2005)]. Curcumin affects several cell-signaling pathways identified as tumor growth and survival mechanisms for several types of cancer, including prostate cancer (Sharma et al. 2001, 2005). Furthermore, curcumin demonstrates androgen receptor-binding capabilities, downregulating the expression of AR (Dorai et al. 2000; Aggarwal 2008). Finally, curcumin promotes PSA inhibition, while one of its constituent curcuminoids also serves as an AR antagonist (Nakamura et al. 2002; Tsui et al. 2008).

Despite these demonstrated chemopreventive benefits of curcumin, researchers remain unclear about the specific mechanisms of action (Shi et al. 2009). Turmeric contains, in addition to curcumin, several minor fractions such as demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III), and cyclocurcumin (Shen and Ji 2012b). Most commercially available products contain three major curcuminoids: 77 % curcumin, 17 % demethoxycurcumin, and 3 % bisdemethoxycurcumin (Kiuchi et al. 1993). Ravindran et al. propose that the presence of these methoxy groups accounts for curcumin’s anti-inflammatory and antiproliferative activity (Ravindran et al. 2009), while the hydroxyl groups provide the antioxidant activity. One of the ongoing issues with curcumin pharmacology is its minimal in vivo bioavailability, resulting in low serum levels and miniscule presence in tissues (Karunagaran et al. 2005; Anand et al. 2007; Aggarwal and Sung 2009). The low absorption and bioavailability of curcumin led some researchers to propose the mechanism of action is not only in the curcuminoids but also in the metabolites and degradation products (Anand et al. 2007; Aggarwal and Sung 2009; Shen and Ji 2012a). Nonetheless, several labs are seeking to isolate specific curcumin compounds according to which pathways they affect. The goal is to develop alternative delivery systems, leading to better absorption, which includes nanoparticle conjugation (Shen and Ji 2012a), β-cyclodextrin, fibrinogen, liposome, and hydrogel (Shankar and Srivastava 2012).

16.4.2 Resveratrol

The headline proclaims, “Daily dose of red wine compound backed for cancer fight” (Gray 2012), but does the research support these claims? Resveratrol (3, 5, 4′ trihydroxy-trans-stilbene) is a natural phytochemical with cardioprotective, antiinflammatory, and anticancer properties (Jang et al. 1997). There is no definitive research confirming resveratrol as a first-line chemopreventive strategy, but there is growing evidence to support continued research.

Pezzuto’s review of the literature, as well as his own research, suggests that resveratrol shows potential as a carcinogenesis inhibitor (Pezzuto 2008). Kraft et al. suggest resveratrol is a promising chemopreventive agent due to its ability to decrease metabolism of phase-I enzyme genes (CYP2E1 and CYP1A1), which are pro-carcinogenic, and/or by increasing the metabolism of phase-II detoxifying enzymes (Kraft et al. 2009) [glutathione S-transferases, uridine diphosphateglucuronosyltransferases, and quinone reductase enzymes (Hebbar et al. 2005)]. Kai, Samuel, and Levenson examined the ability of resveratrol to enhance p53 acetylation and apoptosis in prostate cancer by inhibiting the MTA1/NuRD complex, which then allows the activation of proapoptotic genes (Kai et al. 2010). The expression of MTA1 protein is higher in androgen-independent metastatic tumors in relation to early-stage localized disease and benign prostatic tissues (Hofer et al. 2004). These authors suggest their research identifies MTA1 as a new target in prostate cancer treatment and prevention.

16.4.3 Lifestyle Factors

Based on the research presented for curcumin and resveratrol, there are a few generalizations that can act as guiding principles for prostate cancer prevention. What follows might be considered an ecological approach in that it takes into account the whole ecology of tumorigenesis in the human body [see also (Pienta et al. 2008) for an ecological approach focused on the environment of the tumor itself], where the body is the ecosystem we seek to manipulate. It seems possible now to create an inhospitable environment for the survival of cancer cells in the body.

Estimations from the World Health Organization (WHO) are that 300 million adults are obese and more than a billion adults are overweight (Faloia et al. 2012). This has implications for prostate cancer. Gong et al. identified a 29 % increased risk for high-grade prostate cancer (Gleason ≥7) and an 18 % decreased risk of low-grade tumors in men with a body mass index ≥30 in comparison to men with body mass index <25 [ n = 10,258, 1,936 prostate cancers] (Gong et al. 2006). The consensus in meta-analyses of the connection between obesity and high-grade prostate cancer supports the findings of Gong and colleagues (Gong et al. 2006; Rodriguez et al. 2007; Wright et al. 2007). Burton et al. have correlated obesity with unusually high levels of adipocyte-derived peptides (adipokines), sex hormones [including estrogen, which may be the initiating driver of prostate adenocarcinoma progression (Singha et al. 2008)], and inflammatory cytokines, with both in vitro and epidemiological studies showing that adipokines influence prostate carcinogenesis (Burton et al. 2010). As suggested by Gong et al., Burton et al. found that testosterone levels are lower in obesity, which may select for more aggressive, androgen-independent tumors. However, there is no connection between moderate and high-normal levels of testosterone and prostate cancer (Stattin et al. 2004).

One of the comorbidities of obesity is low-grade or “smoldering” inflammation (Balkwill et al. 2005), which contributes to various forms of disease, including prostate cancer. COX-2 expression, a pro-inflammatory enzyme and the primary target of nonsteroidal anti-inflammatory drugs (NSAIDs), is highly increased in several cancers, including prostate cancer (Gupta et al. 1999). There is some evidence that aspirin use may offer COX-2-mediated protection against esophageal, lung, stomach, and ovarian cancers (Fosslien 2000). In a follow-up for patients in a vascular event prevention study, with randomized trials of daily aspirin versus control, those in the aspirin group had a 40 % reduction in cancer deaths from the 5-year mark forward and consistent death-rate reductions for certain cancers at the 20-year follow-up (Rothwell et al. 2011). Through a review of the records from the United Kingdom’s five large randomized trials of daily aspirin versus no aspirin (cardiovascular event prevention), all participants who showed incident cancers had a 30–40 % risk reduction for distant metastasis and nearly a 50 % risk reduction for metastatic adenocarcinoma (Rothwell et al. 2012).

The major recommendation for lifestyle factors in prostate cancer prevention is that men need to be more physically active (Orsini et al. 2009), which helps prevent obesity, another risk factor for prostate cancer (Rodriguez et al. 2007; Burton et al. 2010). In addition, men must reduce their reliance on the current Western diet, which is high in processed foods, low in fresh fruit and vegetables (sources of phytonutrients), and nearly void of omega-3 fats (anti-inflammatory) while containing abundant omega-6 fats, including arachidonic acid, a powerful driver of the inflammatory process (Matsuyama and Yoshimura 2008). The research has not revealed the definitive diet, and each person processes food a little differently. Consuming more fresh fruits and vegetables [especially cruciferous vegetables, which offer chemoprevention for the prostate (Beaver et al. 2012)], lean meats (chicken, fish, turkey), and nuts and seeds (walnuts, almonds, pumpkin seeds, hemp seed), as part of a diet also rich in curry, would offer a solid foundation for general health.

References

• Aggarwal B (2008) Prostate cancer and curcumin: add spice to your life. Cancer Biol Ther 7:1436–1440
• Aggarwal B, Sung B (2009) Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 30:85–94
• Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB (2006) Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 69:195–206
• Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818
• Bae MK, Kim S, Jeong JW, Lee YM, Kim HS, Kim SR, Yun I, Bae SK, Kim KW (2006) Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1. Oncol Rep 15: 1557–1562
• Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217
• Basnet P, Skalko-Basnet N (2011) Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules 16:4567–459
• Beaver L, Williams DE, Dashwood RH, Ho E (2012) Chemoprevention of prostate cancer with cruciferous vegetables: role of epigenetics. In: Shankar S, Srivastava RK (eds.) Nutrition, diet and cancer. Springer, New York
• Burton A, Tilling KM, Holly JM, Hamdy FC, Rowlands ME, Donovan JL, Martin RM (2010) Metabolic imbalance and prostate cancer progression. Int J Mol Epidemiol Genet 1(4):248–271
• Dorai T, Gehani N, Katz A (2000) Therapeutic potential of curcumin in human prostate cancer – I. Curcumin induces apoptosis in both Curcumin inhibits AR through Wnt/b-catenin signaling androgen-dependent and androgen-independent prostate cancer cells. Prostate Cancer Prostatic Dis 3:84–93
• Faloia E, Michetti G, De Robertis M, Luconi MP, Furlani G, Boscaro M (2012) Inflammation as a link between obesity and metabolic syndrome. J Nutr Metab 2012:476380
• Fosslien E (2000) Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci 30(1):3–21
• Gong Z, Neuhouser ML, Goodman PJ et al (2006) Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev 15:1977–1983
• Gray N (2012) Daily dose of red wine compound backed for cancer fight. NutraIngredient.com. 15 Dec 2012
• Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H (1999) Over‐expression of cyclooxygenase‐2 in human prostate adenocarcinoma. Prostate 42(1):73–78
• Hebbar V, Shen G, Hu R, Kim BR, Chen C, Korytko PJ, Crowell JA, Levine BS, Kong AN (2005) Toxicogenomics of resveratrol in rat liver. Life Sci 76:2299–2314
• Hofer M, Kuefer R, Varambally S, Li H, Ma J, Shapiro GI, Gschwend JE et al (2004) The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Res 64:825–829
• Jang M, Cai L, Udeani GO, Slowing KV et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275(5297):218–220
• Kai L, Samuel SK, Levenson AS (2010) Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. Int J Cancer 126:1538–1548
• Karunagaran D, Rashmi R, Kumar TR (2005) Induction of apoptosis by curcumin and its implications for cancer therapy. Curr Cancer Drug Targets 5:117–129
• Khan N, Adhami VM, Mukhtar H (2008) Apoptosis by dietary agents for prevention and treatment of cancer. Biochem Pharmacol 76(11):1333–1339
• Killian P, Kronski E, Michalik KM, Barbieri O, Astigiano S, Sommerhoff CP, Pfeffer U, NerlichAG, Bachmeier BE (2012) Curcumin inhibits prostate cancer metastasis in vivo by targeting the infl ammatory cytokines CXCL1 and −2. Carcinogenesis, 33(12):2507–2519. doi: 10.1093/carcin/bgs312
• Kiuchi F, Goto Y, Sugimoto N, Akao N, Kondo K, Tsuda Y (1993) Nematocidal activity of turmeric: synergistic action of curcuminoids. Chem Pharm Bull 41:1640–1643
• Kraft T, Parisotto D, Schempp C, Efferth T (2009) Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit Rev Food Sci Nutr 49(9):782–799
• Kuttan G, Kumar KBH, Guruvayoorappan C, Kuttan R (2007) Antitumor, anti-invasion, and antimetastatic effects of curcumin. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease, a special issue of Adv Exp Med Biol 595: 173–184
• Matsuyama M, Yoshimura R (2008) The target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer. Biologics 2(4):725–732
• Naik R, Mujumdar AM, Ghaskadbi S (2004) Protection of liver cells from ethanol cytotoxicity by curcumin in liver slice culture in vitro. J Ethnopharmacol 95(1):31–37
• Nakamura K, Yasunaga Y, Segawa T, Ko D, Moul JW, Srivastava S et al (2002) Curcumin downregulates AR gene expression and activation in prostate cancer cell lines. Int J Oncol 21:825–830
• Orsini N, Bellocco R, Bottai M, Pagano M, Andersson S-O, Johansson J-E, Giovannucci E, Wolk A (2009) A prospective study of lifetime physical activity and prostate cancer incidence and mortality. Br J Cancer 101:1932–1938
• Pezzuto J (2008) Resveratrol as an inhibitor of carcinogenesis. Pharm Biol 46(7–8):443–573
• Pienta K, McGregor N, Axelrod R, Axelrod DE (2008) Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. Transl Oncol 1(4):158–164
• Piper J, Singhal SS, Salameh MS, Torman RT, Awasthi YC, Awasthi S (1998) Mechanisms of anticarcinogenic properties of curcumin: the effect of curcumin on glutathione linked detoxification enzymes in rat liver. Int J Biochem Cell Biol 30:445–456
• Rao C (2007) Regulation of COX and LOX by curcumin. In: Aggarwal BB, Surh YJ, Shishodia S (eds.) Molecular targets and therapeutic uses of curcumin in health and disease. Springer, New York
• Ravindran J, Sahdeo Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11(3):495–510
• Reuter S, Eifes S, Dicato M, Aggarwal BB, Diederich M (2008) Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem Pharmacol 76(11):1340–1351
• Rodriguez C, Freedland SJ, Deka A, Jacobs EJ, McCullough ML, Patel AV, Thun MJ, Calle EE (2007) Body mass index, weight change, and risk of prostate cancer in the Cancer Prevention Study: II. Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 16(1):63–69
• Rothwell P, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TW (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomized trials. Lancet 377:31–41
• Rothwell P, Wilson M, Price JF, Belch JFF, Meade TW, Mehta Z (2012) Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379:1591–1601
• Salvioli S, Sikora E, Cooper EL, Franceschi C (2007) Curcumin in cell death processes: a challenge for CAM of age-related pathologies. Evid Based Complement Alternat Med 4(2):181–190
• Shankar S, Srivastava RK (2012) Curcumin: structure, biology and clinical applications. In: Shankar S, Srivastava RK (eds.) Nutrition, diet and cancer. Springer, New York
• Sharma RA, Ireson CR, Verschoyle RD, Hill KA, Williams ML, Leuratti C, Manson MM, Marnett LJ, Steward WP, Gescher A (2001) Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin Cancer Res 7:1452–1458
• Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer 41:1955–1968
• Shen L, Ji H-F (2012a) Low stability remedies the low bioavailability of curcumin. Trends Mol Med 18(7):363–364
• Shen L, Ji H-F (2012b) The pharmacology of curcumin: is it the degradation products? Trends Mol Med 18(3):135–192
• Shi Q, Shih CC, Lee KH (2009) Novel anti-prostate cancer curcumin analogues that enhance androgen receptor degradation activity. Anticancer Agents Med Chem 9:904–991
• Singha P, Matanheliab SS, Martin FL (2008) A potential paradox in prostate adenocarcinoma progression: oestrogen as the initiating driver. Eur J Cancer 44:928–936
• Stattin P, Lumme S, Tenkanen L et al (2004) High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int J Cancer 108
• Tsui K, Feng TH, Lin CM, Chang PL, Juang HH (2008) Curcumin blocks the activation of androgen and interlukin-6 on prostate-specific antigen expression in human prostatic carcinoma cells. J Androl 29:661–668
• Vitaglione P, Morisco F, Caporaso N, Fogliano V (2005) Dietary antioxidant compounds and liver health. Crit Rev Food Sci Nutr 44(7–8):575–586
• Wright M, Chang SC, Schatzkin A, Albanes D, Kipnis V, Mouw T, Hurwitz P, Hollenbeck A, Leitzmann MF (2007) Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality. Cancer 109(4):675–684
• Yoysungnoen P, Wirachwong P, Bhattarakosol P, Niimi H, Patumraj S (2006) Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell- implanted nude mice. Clin Hemorheol Microcirc 34:109–115

Omega-3 Fats Stimulate Metabolism of Brown Fat

Brown fat, or more precisely Brown Adipose Tissue (BAT), has long been a target for increasing fat loss and reducing the risk of type-II diabetes. BAT promotes heat production (thermogenesis) in mammals, which is essential for small mammal survival cold environments (and for arousal in hibernators).

Brown adipocytes in BAT are packed with mitochondria that contain uncoupling protein-1 (UCP1). UCP1, when activated, short circuits the electrochemical gradient that drives ATP synthesis and thereby stimulates respiratory chain activity. Heat is generated from the combustion of available substrates and is distributed to the rest of the body through the circulation. [Harms and Seale (2013); Brown and beige fat: development, function and therapeutic potential. Nature Medicine; 19:1252–1263]

The infamous Dan Duchaine (aka, The Steroid Guru) is credited with bring DNP (2,4-Dinitrophenol) and then usnic acid to the bodybuilding world. Both of these substances increase UCP1 expression, increasing metabolism dramatically, and causing fat loss. But DNP can be frequently fatal and usnic acid is highly liver toxic for most people.

This new research (as well as some previous studies) demonstrate the omega-3 fats can activate UCP1 without the harmful side effects of the drugs once commonly used in bodybuilding. It may be slower in its action, but omega-3 fats have so many other benefits that it is more than worth the slower results.

Omega-3 fatty acids stimulate brown adipose tissue metabolism

21 November 2016; Universidad de Barcelona

Omega-3 fatty acids are able to stimulate the activation of brown and beige adipose tissues, a discovery that would promote the development of new therapies for obesity and other metabolism diseases, according to a research study published in the journal Nature Communications under the supervision of Professor Francesc Villarroya, from the Department of Biochemistry and Molecular Biomedicine and the Biomedical Research Center Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN) of the Institute of Health Carlos III.

In the new study, carried out in laboratory animal models, the research team noticed that Omega-3 fatty acids (n-3 PUFAS) stimulate the activation of brown and beige adipose tissue through a specific receptor (GPR120), which enables the release of the hormone FGF21 (21 fibroblast growth factor). This hormone, built by the adipocyte, is a molecule that regulates lipid glucose and metabolism and therefore, it is an effective target for the action mechanism of Omega-3.

“This discovery has implications in the understanding of the positive effects of n-3 PUFAS on the control of metabolic diseases and other aspects regarding the treatment for obesity and type 2 diabetes”, says Professor Francesc Villarroya, member of the Institute of Biomedicine of the University of Barcelona (IBUB) and head of the Research Group in Genetics and Molecular Biology of Mitochondrial Proteins and Associated Diseases.

Protection key factors to tackle obesity

The study shows that Omega-3 fatty acids enable the adaptive thermogenesis in mammals’ brown adipose tissue, an essential mechanism for the adaption of the organism to cold environments. With rodents, it has been proved that the brown adipose tissue is able to create warmth and protect from obesity through the activation of energy expenditure.

According to the conclusions of the article published in Nature Communications, the specific receptor GPR120 for the Omega poli-unsaturated fatty acids enables the activation of brown adipose tissue, which is linked –in several scientific studies- to protection from obesity and metabolic diseases such as diabetes or dyslipemia (alterations in lipid metabolism).

The main function of brown adipose tissue is to burn calories and to make physical warmth out of fat (thermogenesis). However, a recent study by this research team has defined that brown adipose tissue also acts as an endocrine organ and can secrete factors that activate fat and carbohydrates metabolism. The most known factors up to now are FGF21, neuregulin 4 and interleukin-6, among other molecules of biological interest.

According to Francesc Villarroya, “these molecules, released by the adipose tissue (brown adipocytes or batokines) have positive metabolic effects. For this reason, they could be used in new therapies for obesity and related metabolic diseases”.

Citation:

Tania Quesada-López, Rubén Cereijo, Jean-Valery Turatsinze, Anna Planavila, Montserrat Cairó, Aleix Gavaldà-Navarro, Marion Peyrou, Ricardo Moure, Roser Iglesias, Marta Giralt, Decio L. Eizirik & Francesc Villarroya. The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes. Nature Communications (2017, Nov); Article number: 13479 (2016).
DOI: 10.1038/ncomms13479

Here is the abstract and introduction to the article, which is Open Access.

Abstract

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.

Introduction

Brown adipose tissue (BAT) is the main site of non-shivering thermogenesis in mammals. It confers a unique mechanism for energy expenditure and heat production in response to cold and provides a protective mechanism against excessive body weight accumulation in response to overfeeding [1,2].The interest in brown fat activity as a mechanism of protection against the obesity and metabolic diseases has been renewed by the recent recognition that adult humans possess active BAT, and its activity is negatively associated with obesity and type II diabetes [3]. Many aspects of the molecular mechanisms underlying the function of BAT are known, but we do not comprehensively understand how BAT activity is controlled and integrated with whole organism metabolism to ensure that metabolic substrates are burned and heat is provided. Recent studies unravelled an additional BAT-related means to control energy expenditure, wherein white adipose tissue (WAT) has the capacity to acquire BAT-like properties via the so-called ‘browning’ process. During this process, sustained thermogenic activation leads to the appearance of the so-called beige or brite adipocytes in WAT depots, which, like classical brown adipocytes, express uncoupling protein-1 (UCP1) and perform uncoupled mitochondrial respiration [4,5]. Several lines of evidence suggest that the browning process is especially relevant in controlling whole-body energy balance [4]. This may reflect its high inducibility in response to environmental factors and the ability of beige cells to use additional, non-UCP1-mediated energy expending mechanisms [6].

Studies aimed at assessing how BAT responds to cold can improve our understanding of the processes that mediate BAT activation. Transcriptomic profiling of BAT from cold-exposed mice can provide a snapshot of how BAT responds to the thermogenic activation and may offer an unbiased look at novel BAT activity-related actors. Recently, RNA sequencing (RNA-seq) has emerged as the best tool for transcriptomic studies, as it does not require a priori knowledge of targets, and shows both high reproducibility and a low frequency of false positives [7,8,9]. Moreover, RNA-seq can identify 25–75% more genes than complementary DNA (cDNA) microarrays, and it allows assessment of both whole genes and splice variants [10,11].

Here we used RNA-seq to analyse the responsiveness of BAT to the cold-induced thermogenic activation. Departing from these data set, we identified a novel pathway through which thermogenic activation of BAT and the browning of WAT occur via the activation of GPR120 (FFAR4). GPR120 is a G-protein-coupled receptor that binds unsaturated long-chain fatty acids and their derivatives [12]. GPR120 is known to contribute to mediating the anti-inflammatory actions of polyunsaturated fatty acids (PUFAs) and in protecting against obesity and type II diabetes [13,14]. Here we identify a novel pathway of thermogenic regulation through that PUFA-mediated GPR120 activation induces BAT activity and WAT browning via the hormonal factor fibroblast growth factor-21 (FGF21).

Alex Hoffmann - Bigger Muscles or Stronger Muscles? Or Both?

This is today's ISSA (International Sports Sciences Association) Newsletter. They offer a basic, one-size-fits-all model for training either for size or for strength, although to his credit, Hoffmann admits that individuals vary in their response to stimuli.

Here are a couple of the basics (followed by an exceptions that combines both goals into a single workout):

So how do muscles get stronger?

How can we use this information to help our clients who want to get stronger, but not bigger? We have to consider the amount of weight lifted, the number of reps, and the rest period.

And how do muscles get bigger?

Now you might be thinking that this is common sense, right? Lifting heavy weights make you stronger, but is this also the best strategy for getting bigger muscles?

The quick answer is no. It is not likely that following the recommendations for increasing muscle strength will lead to optimal muscle hypertrophy.

Of course, there are MANY and varied exceptions to these "rules." One of my favorite training protocols is Chad Waterbury's Anti-Bodybuilding Hypertrophy Program (ABBH Program) - see here for the foundation, then here for The Waterbury Method, then here for the science behind his program design. If you want to lose fat as well, see here.

For me -- my strength, my recovery, my limitations -- the 10x3 program is the most successful size program I have used. In the 2nd iteration, Waterbury combines 10x3 with 4x6, which also makes a nice workout strategy for strength gains (slightly less) and hypertrophy (slightly more) due to the higher overall volume in the program design.

The basic idea of strength is low-rep sets, and the basic idea of hypertrophy is volume, and by combining low-rep sets with moderate volume, lifters can get both outcomes from the same program.

Ben Bruno - Neutral-Grip "Squeeze" Floor Press

Via Ben Bruno at Testosterone Nation, my new favorite chest exercise. It feels a lot easier on my shoulders than any other bench press variation.

If you don't have a rack that works for the trap bar, you'll need around 10" risers under each side to be able to get lift off and re-rack.

Tip: A New Way to Build a Powerful Chest

Chances are, you've never tried this pec-builder before. Check it out.

by Ben Bruno | 10/11/16

For this exercise, you'll need a trap bar, football bar, or Dead-Squat™ Bar.This is a great pressing alternative for people whose shoulders don't tolerate the bench press. And if you tweak the technique and turn it into more of a "squeeze" press, it can also be one hell of a chest blaster.

Neutral-Grip "Squeeze" Floor Press



It's going to look like a regular floor press with a few key differences. The devil is in the details. With the "squeeze" version, you want to set up with your lower back flat on the floor and try to purposely sink your chest down rather than puff it up.

After you un-rack the bar, bend your elbows slightly and flare them out. Then on the descent, rather than think about breaking the bar apart, think about squeezing your arms together, like you're giving someone a hug.

You won't be able to bring your arms together unless you possess superhero strength to bend metal, but the act of trying creates massive tension in the pecs. Keep that slight bend in your elbows and don't come all the way up at the top to keep constant tension on the pecs.

If you're using a Swiss bar or a football bar, use the handles that allow for a slightly wider than shoulder-width grip. If you're doing it right, you'll get a big pump with just the bar.

Research Report: Testosterone vs. aromatase inhibitor in older men with low testosterone: Effects on cardiometabolic parameters

This new study (Oct 28, 2016) assessed the effects of long-term testosterone replacement (TT) and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers in older non-diabetic men with low testosterone levels (≥65 years, mean age 71 ± 3 years, serum total T < 350 ng/dL).

Researchers from the National Institute on Aging and Harvard Medical School examined the effects of testosterone replacement (5 g transdermal testosterone gel) versus an aromatase inhibitor (1 mg Anastrozole), taken daily for one year. There were ten men randomly assigned to each group and the study was double-blinded and placebo-controlled. There nine age- and testosterone level-matched men in the placebo group (age=72 ± 3; serum total T = 302.6 ± 95.1 ng/dL).

Aromatase Inhibitors

Aromatase inhibitors (AI) stop the conversion of testosterone into estradiol by inhibiting aromatase, (CYP19A1, a member of the cytochrome P450 superfamily), the enzyme that synthesizes estrogens from androgens. Estradiol is a strong inhibitor of the pituitary/gonadal axis in men, which makes inhibition of its synthesis through AI a pathway to increase circulating gonadotropins (testosterone precursors).

The same researches reported (Dias, et al, 2015) that a 12-month AI intervention in older men with low testosterone raised serum testosterone levels into the normal range and resulted in improved lean body mass and muscle strength. That study, however, did not examine the long-term effects of AI on glucose homeostasis, insulin sensitivity and cardiovascular risk markers.

Using AIs rather than testosterone replacement in older men is thought to be a way to avoid possible complications with prostate enlargement due to androgen stimulation (higher T levels often result in increased PSA scores). The prostate is less likely to be impacted by endogenous T (produced by reduced estradiol, from AI intervention) than by exogenous T (from T replacement therapy).

The researchers in this study did not mention the prostate issues but, rather, possible cardiometabolic issues of increased androgen (decreased HDL cholesterol and increased triglycerides), both of which can be ameliorated with high DHA-fish oil supplementation and a healthy, low-sugar diet (as well as regular exercise).

The primary outcome in the study was the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), which marks for both the presence and extent of any insulin resistance.

Secondary outcomes included:

• OGIS (oral glucose insulin sensitivity) in response to OGTT (oral glucose tolerance test), essentially a test of insulin sensitivity, which is a good prognostic for metabolic syndrome and diabetes
• fasting lipids, a "lipid panel" that includes cholesterol, triglycerides, and high-density lipoproteins (HDLs) as primary markers, but generally will include low-density lipoproteins (LDLs) and very-low-density lipoproteins (VLDLs)--Type 2 diabetes tends to have high triglycerides levels and low HDL levels
• C-reactive protein (CRP), a marker for inflammation, especially as an indicator of heart disease 
• adipokines, which are cytokines (cell-signaling proteins) secreted by adipose tissue (fat), the most well-known of which are leptin, adiponectin, and interleukin-6 (but there are hundreds)--in obesity, leptin sensitivity is decreased (results in lowered awareness of fullness); adiponectin is reduced in diabetics compared to non-diabetics and weight reduction significantly increases circulating concentrations (so high adiponectin = lower body weight)
• abdominal and mid-thigh fat by computed tomography, as indicators of lowered insulin effectiveness (sensitivity) that causes increased body fat storage

All outcomes were assessed at baseline and 12 months.

TAKEAWAYS

Insulin Function

• At the end of 12 months, neither insulin resistance nor insulin sensitivity were improved.
• Likewise for fasting glucose and insulin levels. 
• Further, the AI group experienced decreased insulin sensitivity in muscle.

Gonadal Hormones

• Testosterone levels in both groups significantly increased from baseline into the target range. 
• Serum estradiol levels significantly increased in the TT group. 
• A reduction in estradiol was seen in the AI group. 
• Serum sex-horomone binding globulin (SHBG) levels did not change in any group. 
• Gonadotropin levels were suppressed in the TT group.
• Gonadotropin levels increased in the AI group. 

The decreased insulin sensitivity in the AI group more than offsets the reduced estradiol and increased gonadotropin levels in the AI group.

My suggestion, based on this study (and remember, I am NOT a doctor): Traditional TT models are sufficient and might be improved with a 2x weekly dose of an AI.

Further, the most common methods of TT are somewhat erratic--both intramuscular injections and topical applications are unreliable in terms of providing stable levels of testosterone. On the other hand, newer research suggests subcutaneous injection of testosterone enanthate or cypionate may provide more stable and sustained T levels.

IN DEPTH

Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters

Dias JP, Shardell MD, Carlson OD, Melvin D, Caturegli G, Ferrucci L, Chia CW, Egan JM, Basaria S.

Andrology. 2016 Oct 28. DOI: 10.1111/andr.12284. [Epub ahead of print]

Abstract

Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ≥65 years, mean age 71 ± 3 years with serum total T < 350 ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5 g transdermal testosterone gel (TT) (n = 10), 1 mg anastrozole (n = 10) or placebo (n = 9) daily for 12 months. Homeostatic Model Assessment of insulin resistance (HOMAIR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12 months. After 12 months, absolute changes in HOMA-IR in both treatment arms (TT group: -0.05 ± 0.21); (AI group: 0.15 ± 0.10) were similar to placebo (-0.11 ± 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 ± 0.9 mg/L, p = 0.02) and abdominal subcutaneous fat (-60.34 ± 3.19 cm2 , p = 0.003) and leptin levels (-1.5 ± 1.2 ng/mL, p = 0.04) were significantly lower with AI. Mid-thigh subcutaneous fat was reduced in both treatment arms (TT group: -4.88 ± 1.24 cm2 , p = 0.008); (AI group: -6.05 ± 0.87 cm2 , p = 0.0002). In summary, in this proof-of-concept trial, changes in HOMA-IR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men.

The primary purpose of the study (in layman's terms) was to determine if aromatase inhibition (AI) therapy can be as effective as testosterone replacement therapy in controlling diabetes in older men.

The results are interesting but do not seem to support use of AI over TT in men from this age cohort, while also not ruling it out either.

RESULTS

Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and other glucose homeostasis measures

• At the end of the 12-month intervention, HOMA-IR levels were not significantly altered in any of the three group.
• Oral glucose insulin sensitivity (OGIS) was also not statistically altered by any of the treatment regimens.
• The fasting glucose and insulin levels remained unchanged. 
• The total AUC _{0–120 min} for plasma glucose for the three groups was similar.

[AUC = area under the curve = the shape of the plasma glucose course measured at 0, 30, 60, 90, and 120 min during an oral glucose tolerance test (OGTT), based on consuming 75 grams of glucose.]

• However, on analyzing the total insulin response to the glucose challenge, the total AUC _{0–120 min} for plasma insulin was significantly increased in the AI group at 12 months, compared to baseline (p = 0.04) and was not significantly different in the other groups (p > 0.05). 
• Upon further analysis, this increase was evident in the late post-glucose period, which is the muscle glucose uptake phase of insulin action (AUC Insulin _{40–120 min} = 8707.08 ± 2399.11 post-treatment, compared to pre-treatment: 6390.12 ± 1579.27, p = 0.04). 
• No increase was seen in the early post-glucose phase (AUC insulin _{0–20 min}).

These later results (in bold) are interesting because they suggest that additional insulin was needed at the muscle-uptake stage of glucose metabolism in the AI group, but not in the TT group. The authors:

However, and interestingly, an increase in insulin secretion was observed during the muscle glucose uptake phase (40–120 min) of the OGTT in the AI group, pointing to reduced insulin action and illustrating the importance of studying the whole body response to a metabolic challenge. These findings suggest that estradiol is a modulator of muscle insulin sensitivity and are consistent with some animal studies showing that estrogen receptor-α is important for insulin action (Ribas, et al, 2010). These findings should be confirmed in future trials.

For those men who use AIs in place of TT to maintain normal androgen levels, this might be of concern. At the very least, men taking AIs should be doing due diligence to maintain high peripheral insulin sensitivity. Weight training is the easiest way to do this, as well as maintaining a healthy body fat level. A healthy diet low in fructose (1-2 pieces of whole fruit a day) can support good insulin sensitivity (cut out high-fructose corn syrup, fructose sweeteners, table sugar, fruit juice, fruit smoothies, and dried fruit). Supplemental interventions might include curcumin, resveratrol, and cinnamon.

Additional Results

* Changes in gonadal hormones

In both the intervention groups, testosterone levels significantly increased from baseline into the target range. Serum estradiol levels significantly increased in the TT group while a reduction was seen in the AI group. Serum sex-horomone binding globulin (SHBG) levels did not change during intervention in any of the groups. As expected, gonadotropin levels were suppressed in the TT group, whereas they increased in the AI group.

* Adipocytokines

At 12 months, circulating C-reactive protein (CRP) level was not significantly altered in any of the groups. Circulating leptin levels, however, were significantly decreased in the AI group only compared to baseline (me: possibly suggesting impact of decreased insulin resistance?). In contrast, circulating adiponectin levels significantly decreased only in the TT group (me: paradoxical result?).

* Abdominal and mid-thigh fat

Abdominal subcutaneous fat was significantly decreased in the AI group after 12 months while no changes in abdominal visceral fat was seen in any of the groups (me: the failure of either treatment to reduce visceral fat does not seem to promote heart-healthy outcomes, considering the correlation of visceral fat with diabetes and heart disease--the mechanisms would be interesting to know). Mid-thigh subcutaneous fat significantly decreased in both TT group and AI group compared to placebo.

* Fasting lipid profile and BMI

At 12 months, BMI and waist circumference were not significantly different in any of the groups from baseline measurements. Furthermore, no significant changes were seen in fasting lipids after 12 months.

Health News: Epigenetics, Sedentary Behavior, Overindulgence, Microbiome, and Time-Restricted Feeding

Periodically I will be sharing links to news items related to health and fitness. This is the first installment.

The first and most interesting story here is a validation of prior studies on the epigenetics and parental nutrition prior to conception. We have known this is true in mothers, but this reports shows the same is true in fathers. From the article:

Although the link between a mother's preconception activities and the health of her offspring is well-documented, the effects of paternal diet and lifestyle on his progeny are less so. Researchers studied the offspring of male rodents that were exercised for 12 weeks and found that the fathers' exercise regimen programmed the offspring to be able to burn calories more efficiently, "like [an] energy efficient car which uses less gas to run the same distance" lead author Alexander Murashov said. Instead of a leaner body, however, when fed a high-fat diet the offspring had "increased body weight and adiposity, impaired glucose tolerance and elevated insulin levels," wrote the research team.

We are only beginning to understand the power of epigenetics, but this can be valuable information for anyone who is considering becoming a parent.

Dad’s preconception exercise may increase obesity, insulin resistance risk in offspring

Date: November 4, 2016
Source: American Physiological Society (APS)
Summary: Fathers who exercise regularly before their children are conceived may program their offspring's genes with an increased risk for metabolic disorders, according to new research. The surprising results point to the identification of epigenetic markers that may change the process of diagnosis and management of chronic disease.

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Regular exercisers still face health risks from too much sitting

Sedentary behavior raises disease risk, mortality rates for physically active, too 

Date: November 4, 2016
Source: American Physiological Society (APS)
Summary: People who meet recommended weekly physical activity guidelines are still at risk of developing chronic disease if they spend too much non-exercising time sitting. Researchers found that women sit more as they grow older, raising their risks even more.

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Exercise may shield against the health fallout of a weeklong overindulgence

Date: November 4, 2016
Source: American Physiological Society (APS)
Summary: Previous studies show that as little as one week of overeating can impair glycemic control and insulin sensitivity. Just in time for holiday feasting, a new study finds that exercise can protect fat tissue from changes in inflammation levels and fat metabolism caused by a brief period of eating too many calories.

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Intestinal cells 'remodel' in response to a fatty meal

Date: November 2, 2016
Source: Carnegie Institution for Science
Summary: New light has been shed on how form follows function for intestinal cells responding to high-fat foods that are rich in cholesterol and triglycerides.

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Eating dinner early, or skipping it, may be effective in fighting body fat

Date: November 3, 2016
Source: Obesity Society
Summary: The first human test of early time-restricted feeding found that this meal-timing strategy strategy reduced swings in hunger and altered fat and carb burning patterns, which may help with losing weight. In early time-restricted feeding (eTRF), people eat their last meal by the mid-afternoon and don’t eat again until breakfast the next morning.

Americans View Obesity as Tied with Cancer as Top Health Threat

A new survey of Americans shows that 81% of those polled report believing that obesity is a serious health problem facing the nation, tying with cancer as the most serious issue; and 94% agree that obesity increases a person’s risk of dying early even if they don’t have any other health conditions.

The downside is that only 38% consider obesity itself as a disease.

The data is based on a phone survey of 1,509 adults (including over-samples of African Americans and Hispanics in order to be representative).

However, the survey was conducted by the American Society for Metabolic and Bariatric Surgery (ASMBS) and NORC at the University of Chicago (formerly the National Opinion Research Center). Considering that the ASMBS's purpose might be to generate more business for its member surgeons, we could question the data.

Yet, it's good news that Americans are recognizing that obesity is a major health issues.

The reality is that obesity IS on par with cancer as a top threat to health (especially considering the August 2016 New York Times article stating that obesity is linked to at least 13 different cancers). We have long-suspected that obesity is a major factor in many forms of cancer, and now the research into how cancer develops is supporting that suspicion--especially as obesity causes inflammation and inflammation is linked to the development and growth of nearly every major cancer.

One cancer missing from the NYT list (see below) is prostate cancer, which is well-known to be a lifestyle cancer (meaning that exercise, healthy diet, not smoking, and limited drinking are associated with lower risk of the disease). Being overweight or obese increases the risk of the most aggressive (=deadly) forms of the disease.

I hope the fact that this is a survey of Americans indicates that we are finally waking up to the health risks of obesity. Now if we could only get people to honestly recognize when they are overweight or obese, rather than minimizing their weight and size issues.

Three Things You Should Know about the ASMBS and NORC Survey on Obesity Among American Adults…. 

1) Eighty-one percent report obesity as a serious health problem facing the nation, tying with cancer as the most serious issue.
2) Nearly all (94 percent) agree that obesity increases a person’s risk of dying early even if they don’t have any other health conditions. However, few (38 percent) consider obesity in and of itself as a disease.
3) Despite widespread recognition of its severity, more than one-third of those with obesity have not spoken with a doctor or health professional about their weight.

Here is the press release:

The ASMBS and NORC Survey on Obesity in America

A new study from the American Society for Metabolic and Bariatric Surgery (ASMBS) and NORC at the University of Chicago finds that Americans view obesity as tied with cancer as the most serious health problem facing the country. The vast majority identify obesity as a serious problem, and they rate it as more serious a threat than heart disease and diabetes. However, in spite of their understanding of the seriousness of obesity, few seem to know how to achieve long-term weight loss, overestimating the effectiveness of some treatments and underestimating the effectiveness and safety of others. 

The study reveals that the public’s understanding of the severity of obesity and its associated health risks has evolved in recent years, but stereotypes and misperceptions still affect people's attitudes and actions. A lack of individual willpower is cited as the biggest barrier to weight loss, and a majority of people with obesity attempt to lose weight without the help of medical professionals. This is the case despite widespread public knowledge of the high risk of premature death and other serious health conditions, including heart disease and diabetes, which are associated with obesity. 

The nationally representative survey of 1,509 adults included oversamples of African Americans and Hispanics. It was funded by ASMBS and used AmeriSpeak®, the probability-based panel of NORC at the University of Chicago. Interviews were conducted between August 11 and September 21, 2016, online and using landlines and cell phones. 

Two separate reports detail the findings from the 2016 survey from ASMBS and NORC at the University of Chicago. 

The first report, entitled, Obesity Rises to Top Health Concern for Americans, but Misperceptions Persist, shows that nearly all American adults agree that obesity increases a person’s risk of dying early even if they don’t have any other health conditions. However, few consider obesity in and of itself as a disease. Additionally, the results reveal that a majority of Americans with obesity according to their BMI don’t recognize their clinical condition and consider themselves to be overweight, but not obese. 

The second report, entitled, New Insights into Americans’ Perceptions and Misperceptions of Obesity Treatments, and the Struggles Many Face, finds Americans overestimate the effectiveness of diet and exercise alone for long-term weight loss, and tend to underestimate both the safety and effectiveness of medical and surgical treatments. Yet more than 6 in 10 believe that health insurance should cover obesity treatments such as losing weight with the help of a doctor through diet or exercise, weight loss surgery, one-on-one dietary counseling, prescription medications, and formal exercise programs.

The Many Health Benefits of Turmeric and Curcumin - A Literature Review

[NOTE: This article originally appeared at Integral Options Cafe in November of 2015. I have added a few [new] articles published this first appeared.]

Turmeric (Curcuma longa) is a rhizomatic herbaceous plant belonging to the ginger family, Zingiberaceae. It is native to southwest India (also cultivated in Bangladesh, Pakistan, and most of Southeast Asia), where plants are gathered annually for their rhizomes and propagated from some of those same rhizomes in the following season.

When not used fresh (like ginger), the rhizomes are boiled for about 30–45 minutes then dried in hot ovens, after which they are ground into a deep-orange-yellow powder commonly used as a spice in various forms of curries, as a dye, and to impart color to mustard condiments.

One active ingredient in turmeric is curcumin (perhaps the most well-known as a result of the proliferation of curcumin supplements over the last two decades), which has an earthy, mildly bitter, and peppery flavor.

The most important chemical components of turmeric are a group of compounds called curcuminoids, which include curcumin (diferuloylmethane), demethoxycurcumin, and bisdemethoxycurcumin. The best-studied compound is curcumin, which constitutes between 3-6% (on average) of powdered turmeric. In addition, other important volatile oils include turmerone, atlantone, and zingiberene.

In India, turmeric has been used as a remedy for stomach and liver ailments, as well as topically to heal sores, basically for its supposed antimicrobial property.

The active compound curcumin is believed to have a wide range of biological effects including anti-inflammatory, antioxidant, antitumor, antibacterial, and antiviral activities, which have shown a lot of potential for use in clinical medicine.

In this review of the literature on curcumin, I am looking at the anti-inflammatory effects, diabetes prevention, anti-cancer effects, with a section devoted to prostate cancer, treatment and prevention of neurodegenerative disorders, and finally, its use of psychological disorders.

NOTE: One of the well-recognized issues with turmeric/curcumin as a medicine is its poor bioavailability through oral administration. There is considerable effort dedicated to finding a way to make curcumin/turmeric more bioavailable, including lipid delivery systems, self-microemulsifying drug delivery system (SMEDDS), nanoparticulate delivery systems. and many others - see Advanced Drug Delivery Systems of Curcumin for Cancer Chemoprevention for a good overview.

If you choose to take turmeric/curcumin (traditionally, curcumin has been much more widely recognized, but newer research suggests the whole herb has more advantages), look for a product that contains piperine or Bioperine (black pepper extract), which inhibits the enzymes that break down most supplements and medicines in the gut.

Contents:

1. ANTI-INFLAMMATORY EFFECTS OF TURMERIC
2. TREATING AND/OR PREVENTING DIABETES
3. ANTI-CANCER USES FOR CURCUMIN
4. TURMERIC/CURCUMIN and PROSTATE CANCER
5. CURCUMIN FOR NEURODEGENERATIVE DISORDERS
6. CURCUMIN/TURMERIC AND PSYCHOLOGICAL DISORDERS

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First, here is an overview of curcumin's biological actions and components.

[new] Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives – A review
Augustine Amalraj, Anitha Pius, Sreerag Gopi, and Sreeraj Gopi

Journal of Traditional and Complementary Medicine (2016, Jun 15, ePub ahead of print); DOI: 10.1016/j.jtcme.2016.05.005

Abstract: In recent years, several drugs have been developed deriving from traditional products and current drug research is actively investigating the possible therapeutic roles of many Ayruvedic and Traditional Indian medicinal therapies. Among those being investigated is Turmeric. Its most important active ingredient is curcuminoids. Curcuminoids are phenolic compounds commonly used as a spice, pigment and additive also utilized as a therapeutic agent used in several foods. Comprehensive research over the last century has revealed several important functions of curcuminoids. Various preclinical cell culture and animals studies suggest that curcuminoids have extensive biological activity as an antioxidant, neuroprotective, antitumor, anti-inflammatory, anti-acidogenic, radioprotective and arthritis. Different clinical trials also suggest a potential therapeutic role for curcuminoids in numerous chronic diseases such as colon cancer, lung cancer, breast cancer, inflammatory bowel diseases. The aim of this review is to summarize the chemistry, analog, metal complex, formulations of curcuminoids and their biological activities.

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1. ANTI-INFLAMMATORY EFFECTS OF TURMERIC

The ability to reduce inflammation may one of the most widely studied actions of turmeric/curcumin.

[new] Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials
James W. Daily, Mini Yang, and Sunmin Park

Journal of Medicinal Food (2016, Aug); 19(8): 717-729. DOI: 0.1089/jmf.2016.3705.

Abstract: Although turmeric and its curcumin-enriched extracts have been used for treating arthritis, no systematic review and meta-analysis of randomized clinical trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric extracts and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were “turmeric,” “curcuma,” “curcumin,” “arthritis,” and “osteoarthritis.” A pain visual analogue score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported reduction of PVAS (mean difference: −2.04 [−2.85, −1.24]) with turmeric/curcumin in comparison with placebo (P < .00001), whereas meta-analysis of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: −15.36 [−26.9, −3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-analysis of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-analysis. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric extract (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.

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Curcumin: An Anti-Inflammatory Molecule from a Curry Spice on the Path to Cancer Treatment

Purusotam Basnet and Natasa Skalko-Basnet

Molecules (2011); 16: 4567-4598; DOI: 10.3390/molecules16064567

Abstract: Oxidative damage and inflammation have been pointed out in preclinical studies as the root cause of cancer and other chronic diseases such as diabetes, hypertension, Alzheimer’s disease, etc. Epidemiological and clinical studies have suggested that cancer could be prevented or significantly reduced by treatment with anti-oxidant and anti-inflammatory drugs, therefore, curcumin, a principal component of turmeric (a curry spice) showing strong anti-oxidant and anti-inflammatory activities, might be a potential candidate for the prevention and/or treatment of cancer and other chronic diseases. However, curcumin, a highly pleiotropic molecule with an excellent safety profile targeting multiple diseases with strong evidence on the molecular level, could not achieve its optimum therapeutic outcome in past clinical trials, largely due to its low solubility and poor bioavailability. Curcumin can be developed as a therapeutic drug through improvement in formulation properties or delivery systems, enabling its enhanced absorption and cellular uptake. This review mainly focuses on the anti-inflammatory potential of curcumin and recent developments in dosage form and nanoparticulate delivery systems with the possibilities of therapeutic application of curcumin for the prevention and/or treatment of cancer.

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Antioxidant and Anti-Inflammatory Properties of Curcumin 

Venugopal P. Menon and Adluri Ram Sudheer

Chapter: The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease
Volume 595 of the series Advances in Experimental Medicine and Biology; pp 105-125

Abstract: Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food-coloring agent. It is also used as a cosmetic and in some medical preparations. The desirable preventive or putative therapeutic properties of curcumin have also been considered to be associated with its antioxidant and anti-inflammatory properties. Because free-radical-mediated peroxidation of membrane lipids and oxidative damage of DNAand proteins are believed to be associated with a variety of chronic pathological complications such as cancer, atherosclerosis, and neurodegenerative diseases, curcumin is thought to play a vital role against these pathological conditions.

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Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric

Bharat B. Aggarwal, Wei Yuan, Shiyou Li, and Subash C. Gupta

Molecular nutrition & food research (2013); 57: 1529–1542. DOI: 10.1002/mnfr.201200838

Abstract: Turmeric, a dried powder derived from the rhizome of Curcuma longa, has been used for centuries in certain parts of the world and has been linked to numerous biological activities including antioxidant, anti-inflammatory, anticancer, antigrowth, anti-arthritic, anti-atherosclerotic, antidepressant, anti-aging, antidiabetic, antimicrobial, wound healing, andmemory-enhancing activities. One component of turmeric is curcumin, which has been extensively studied, as indicated bymore than 5600 citations,most of which have appeared within the past decade. Recent research has identified numerous chemical entities from turmeric other than curcumin. It is unclear whether all of the activities ascribed to turmeric are due to curcumin or whether other compounds in turmeric can manifest these activities uniquely, additively, or synergistically with curcumin. However, studies have indicated that turmeric oil, present in turmeric, can enhance the bioavailability of curcumin. Studies over the past decade have indicated that curcumin-free turmeric (CFT) components possess numerous biological activities including anti-inflammatory, anticancer, and antidiabetic activities. Elemene derived from turmeric is approved in China for the treatment of cancer. The current review focuses on the anticancer and anti-inflammatory activities exhibited by CFT and by some individual components of turmeric, including turmerin, turmerone, elemene, furanodiene, curdione, bisacurone, cyclocurcumin, calebin A, and germacrone.

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The effect of turmeric (Curcumin) supplementation on cytokine and inflammatory marker responses following 2 hours of endurance cycling

Joseph N Sciberras, Stuart DR Galloway, Anthony Fenech, Godfrey Grech, Claude Farrugia, Deborah Duca, and Janet Mifsud

Journal of the International Society of Sports Nutrition (2015); 12(5). DOI: 10.1186/s12970-014-0066-3

Abstract
Background: Endurance exercise induces IL-6 production from myocytes that is thought to impair intracellular defence mechanisms. Curcumin inhibits NF-κB and activator protein 1, responsible for cytokine transcription, in cell lines. The aim of this study was to investigate the effect of curcumin supplementation on the cytokine and stress responses following 2 h of cycling.
Methods: Eleven male recreational athletes (35.5 ± 5.7 years; Wmax 275 ± 6 W; 87.2 ± 10.3 kg) consuming a low carbohydrate diet of 2.3 ± 0.2 g/kg/day underwent three double blind trials with curcumin supplementation, placebo supplementation, and no supplementation (control) to observe the response of serum interleukins (IL-6, IL1-RA, IL-10), cortisol, c-reactive protein (CRP), and subjective assessment of training stress. Exercise was set at 95% lactate threshold (54 ± 7% Wmax) to ensure that all athletes completed the trial protocol.
Results: The trial protocol elicted a rise in IL-6 and IL1-RA, but not IL-10. The supplementation regimen failed to produce statistically significant results when compared to placebo and control. IL-6 serum concentrations one hour following exercise were (Median (IQR): 2.0 (1.8-3.6) Curcumin; 4.8 (2.1-7.3) Placebo; 3.5 (1.9-7.7) Control). Differences between supplementation and placebo failed to reach statistical significance (p = 0.18) with the median test. Repeated measures ANOVA time-trial interaction was at p = 0.06 between curcumin supplementation and placebo. A positive correlation (p = 0.02) between absolute exercise intensity and 1 h post-exercise for IL-6 concentration was observed. Participants reported “better than usual” scores in the subjective assessment of psychological stress when supplementing with curcumin, indicating that they felt less stressed during training days (p = 0.04) compared to placebo even though there was no difference in RPE during any of the training days or trials.
Conclusion: The limitations of the current regimen and trial involved a number of factors including sample size, mode of exercise, intensity of exercise, and dose of curcumin. Nevertheless these results provide insight for future studies with larger samples, and multiple curcumin dosages to investigate if different curcumin regimens can lead to statistically different interleukin levels when compared to a control and placebo.

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Effect on Pro-inflammatory and Antioxidant Genes and Bioavailable Distribution of Whole Turmeric vs Curcumin: Similar Root but Different Effects

Robert CG Martin, Harini S Aiyer, Daniel Malik, and Yan Li

Food Chemistry Toxicology (2012, Feb); 50(2): 227–231. Published online 2011 Nov 4. DOI: 10.1016/j.fct.2011.10.070

Abstract: Curcuma longa is a perennial member of the Zingiberaceae family, and cultivated mainly in India, and Southeast Asia. The hypothesis for this study is that turmeric will have distinctive effects from curcumin due to the presence of other bioactive compounds. Thirty Eight-week old Sprague-Dawley rats were separated into 3 oral feeding groups. Group 1, standard rat chow, Control diet - AIN 93M, group 2 Curcumin- 700 ppm or 0.7 g/kg diet, and group 3 - Turmeric -14,000 ppm or 14 g/kg diet for a total of 3 weeks. One group of rats were feed all three diets only and another group underwent esophagoduodenal anastomosis to evaluate the effects of bioavailability. Curcumin diet did not increase the transcription of mRNA of TNF-alpha, IL-6, iNOS and COX-2. The average fold change in the mRNAs level was not significant. Whereas turmeric diet increases the levels of IL-6 (1.9 fold, p=0.05) iNOS (4.39 fold, p=0.02), IL-8 (3.11 fold, p=0.04) and COX-2 (2.02 fold, p=0.05), suggesting that turmeric either was more bioavailabile or had more affect on pro-inflammatory genes compare to curcumin diet. We have demonstrated the molecular effects of curcumin and turmeric in the role as an anti-inflammatory therapy. However, significant bioavailable differences do occur and must be considered in further chemopreventative investigative trials the setting of reflux esophagitis, Barrett’s esophagus, and other upper gastrointestinal cancers.

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Anti-inflammatory and Anti-oxidant Properties of Curcuma longa (Turmeric) Versus Zingiber officinale (Ginger) Rhizomes in Rat Adjuvant-Induced Arthritis 

Gamal Ramadan, Mohammed Ali Al-Kahtani, and Wael Mohamed El-Sayed

Inflammation (2011, Aug); 34(4): 291-301. DOI: 10.1007/s10753-010-9278-0

Abstract: Anti-inflammatory and Anti-oxidant Properties of Curcuma longa (Turmeric) Versus Zingiber officinale (Ginger) Rhizomes in Rat Adjuvant-Induced Arthritis Gamal Ramadan,1,2,3 Mohammed Ali Al-Kahtani,1 and Wael Mohamed El-Sayed1,2 Abstract—Turmeric (rich in curcuminoids) and ginger (rich in gingerols and shogaols) rhizomes have been widely used as dietary spices and to treat different diseases in Ayurveda/Chinese medicine since antiquity. Here, we compared the anti-inflammatory/anti-oxidant activity of these two plants in rat adjuvant-induced arthritis (AIA). Both plants (at dose 200 mg/kg body weight) signi- ficantly suppressed (but with different degrees) the incidence and severity of arthritis by increasing/ decreasing the production of anti-inflammatory/pro-inflammatory cytokines, respectively, and activating the anti-oxidant defence system. The anti-arthritic activity of turmeric exceeded that of ginger and indomethacin (a non-steroidal anti-inflammatory drug), especially when the treatment started from the day of arthritis induction. The percentage of disease recovery was 4.6–8.3% and 10.2% more in turmeric compared with ginger and indomethacin (P<0.05), respectively. The present study proves the anti-inflammatory/anti-oxidant activity of turmeric over ginger and indomethacin, which may have beneficial effects against rheumatoid arthritis onset/progression as shown in AIA rat model.

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2. TREATING AND/OR PREVENTING DIABETES

One of the lesser known uses of turmeric/curcumin is in the treatment and prevention of diabetes.

Curcuminoids and Sesquiterpenoids in Turmeric (Curcuma longa L.) Suppress an Increase in Blood Glucose Level in Type 2 Diabetic KK-Ay Mice 

Tozo Nishoyama, Tatsumasa Mae, Hideyuki Kishida, Misuzu Tsukagawa, Yoshihiro Mimaki, Minpei Kuroda, Yutaka Sashida, Kazuma Takahashi, Teruo Kawada, Kaku Nakagawa, and Mikio Kitahara

Journal of Agricultural Food Chemistry (2005); 53(4): 959−963. DOI: 10.1021/jf0483873

Abstract: Turmeric, the rhizome of Curcuma longa L., has a wide range of effects on human health. The chemistry includes curcuminoids and sesquiterpenoids as components, which are known to have antioxidative, anticarcinogenic, and antiinflammatory activities. In this study, we investigated the effects of three turmeric extracts on blood glucose levels in type 2 diabetic KK-Ay mice (6 weeks old, n ) 5/group). These turmeric extracts were obtained by ethanol extraction (E-ext) to yield both curcuminoids and sesquiterpenoids, hexane extraction (H-ext) to yield sesquiterpenoids, and ethanol extraction from hexane-extraction residue (HE-ext) to yield curcuminoids. The control group was fed a basal diet, while the other groups were fed a diet containing 0.1 or 0.5 g of H-ext or HE-ext/100 g of diet or 0.2 or 1.0 g of E-ext/100 g of diet for 4 weeks. Although blood glucose levels in the control group significantly increased (P < 0.01) after 4 weeks, feeding of 0.2 or 1.0 g of E-ext, 0.5 g of H-ext, and 0.5 g of HE-ext/100 g of diet suppressed the significant increase in blood glucose levels. Furthermore, E-ext stimulated human adipocyte differentiation, and these turmeric extracts had human peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand-binding activity in a GAL4- PPAR-γ chimera assay. Also, curcumin, demethoxycurcumin, bisdemethoxycurcumin, and arturmerone had PPAR-γ ligand-binding activity. These results indicate that both curcuminoids and sesquiterpenoids in turmeric exhibit hypoglycemic effects via PPAR-γ activation as one of the mechanisms, and suggest that E-ext including curcuminoids and sesquiterpenoids has the additive or synergistic effects of both components.

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Turmerin, the antioxidant protein from turmeric (Curcuma longa) exhibits antihyperglycaemic effects 

P.C. Lekshmi, Ranjith Arimboor, K.G. Raghu & A. Nirmala Menon

Natural Product Research (2012); 26(17): 1654-1658. DOI: 10.1080/14786419.2011.589386

Abstract: A wide range of proteinaceous inhibitors are present in plants to protect themselves from hydrolytic enzymes. In this study, turmerin, a water-soluble peptide in turmeric rhizomes, was evaluated for its inhibitory potential against glucosidase and its antioxidant (AO) capacity. Turmerin inhibited -amylase and -glucosidase activities with IC50 values 31 and 192 mg mL1, respectively. Under the experimental conditions, those values for a standard glucosidase inhibitor, acarbose, were 81 and 296 mg mL1, respectively. The AO capacity of turmerin was evaluated using in vitro assay systems. Turmerin showed good DPPH (IC50 ¼ 29 mg mL1 ) and superoxide (IC50 ¼ 48 mg mL1) and moderate ABTS (IC50 ¼ 83 mg mL1 ) radical scavenging and Fe(II) chelation (IC50 ¼ 101 mg mL1) capacities. The inhibitory potential showed by turmerin against enzymes linked to type 2 diabetes, as well as its moderate AO capacity, could rationalise the traditional usage of turmeric rhizome preparations against diabetes.

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Oral supplementation of turmeric attenuates proteinuria, transforming growth factor-b and interleukin-8 levels in patients with overt type 2 diabetic nephropathy: A randomized, double-blind and placebo-controlled study

Parviz Khajehdehi, Maryam Pakfetrat, Katayoun Javidnia, Fariborz Azadi, Leila Malekmakan, Mahshid Hashemi Nasab & Gholamreza Dehghanzadeh

Scandinavian Journal of Urology and Nephrology (2011); 45: 365–370. DOI: 10.3109/00365599.2011.585622

Abstract
Objective. End-stage renal disease (ESRD) due to type 2 diabetic nephropathy is a very common condition which is increasing in prevalence, and is associated with high global levels of mortality and morbidity. Both proteinuria and transforming growth factor-b (TGF-b) may contribute to the development of ESRD in patients with diabetic nephropathy. Experimental studies indicate that turmeric improves diabetic nephropathy by suppressing TGF-b. Therefore, this study investigated the effects of turmeric on serum and urinary TGF-b, interleukin-8 (IL-8) and tumour necrosis factor-a (TNF-a), as well as proteinuria, in patients with overt type 2 diabetic nephropathy.
Material and methods. A randomized, double-blind and placebocontrolled study was carried out in the Diabetes Clinic of the Outpatient Department of Shiraz University of Medical Sciences on 40 patients with overt type 2 diabetic nephropathy, randomized into a trial group (n = 20) and a control group (n = 20). Each patient in the trial group received one capsule with each meal containing 500 mg turmeric, of which 22.1 mg was the active ingredient curcumin (three capsules daily) for 2 months. The control group received three capsules identical in colour and size containing starch for the same 2 months.
Results. Serum levels of TGF-b and IL-8 and urinary protein excretion and IL-8 decreased significantly comparing the pre- and post-turmeric supplementation values. No adverse effects related to turmeric supplementation were observed during the trial.
Conclusion. Short-term turmeric supplementation can attenuate proteinuria, TGF-b and IL-8 in patients with overt type 2 diabetic nephropathy and can be administered as a safe adjuvant therapy for these patients.

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Curcumin, the Active Principle of Turmeric (Curcuma longa), Amerliorates Diabetic Nephropathy in Rats 

Sameer Sharma, Shrinivas K Kulkarni and Kanwaljit Chopra

Clinical and Experimental Pharmacology and Physiology (2006); 33(10): 940–945. DOI: 10.1111/j.1440-1681.2006.04468.x

Summary

1. Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti-oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats.

2. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti-oxidant enzymes superoxide dismutase and catalase.

3. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age-matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats.

4. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin.

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3. ANTI-CANCER USES FOR CURCUMIN

There has likely been more money invested in how curcumin/turmeric can combat various kinds of cancer than in any other research area. With good reason., as many of these studies show. I'm going to begin with some general studies, then move to the more specific, with a subjection here just for prostate cancer.

[new] Curcumin induces apoptosis by inhibiting sarco/endoplasmic reticulum Ca2+ ATPase activity in ovarian cancer cells

Jeong-ah Seo, Boyun Kim, Danny N. Dhanasekaran, Benjamin K. Tsang, and Yong Sang Song

Cancer Letters (2016, Feb 1); 371(1): 30-37. DOI: 10.1016/j.canlet.2015.11.021

Abstract: Aberrant increase in the expression levels of sarco/endoplasmic reticulum calcium ATPase (SERCA), which regulates Ca(2+) homeostasis, has been observed in ovarian cancers. In this study, we demonstrated that curcumin increases cytosolic Ca(2+) concentration through inhibition of SERCA activity, causing apoptosis in ovarian cancer cells but not in normal cells, including peripheral blood mononuclear cells (PBMCs) and ovarian surface epithelial cells (OSE). Curcumin induced apoptosis in ovarian cancer cells in a concentration- and time-dependent manner. Cytosolic Ca(2+) flux was evident after the curcumin treatment (15 µM). Treatment with Ca(2+) chelator reduced curcumin-induced apoptosis, confirming the possible involvement of increased cytosolic Ca(2+) concentration in this response. Basal mRNA and protein levels of SERCA2 were significantly higher in ovarian cancer cells than in OSE. SERCA activity was suppressed by curcumin, with no effect on protein expression. Forced expression of the SERCA2b gene in ovarian cancer cells prevented curcumin-induced cytosolic Ca(2+) elevation and subsequent apoptosis, supporting an important role of SERCA in curcumin-induced apoptosis of ovarian cancer cells. Taken together, inhibition of SERCA activity by curcumin disrupts the Ca(2+) homeostasis and thereby promotes apoptosis in ovarian cancer cells.

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[new] Turmeric ethanolic extract possesses stronger inhibitory activities on colon tumour growth than curcumin – The importance of turmerones

Grace Gar-Lee Yue, Lei Jiang, Hin-Fai Kwok, Julia Kin-Ming Lee, Kar-Man Chan, Kwok-Pui Fung,
Ping-Chung Leung, and Clara Bik-San Lau

Journal of Functional Foods (2016, Apr); 22: 565–577. DOI: 10.1016/j.jff.2016.02.011

Highlights

• Turmerones enhanced anti-proliferative effects of curcumin in colon cancer cells.
• Turmerones augmented anti-angiogenic activities of curcumin in endothelial cells.
• Turmeric extract exerted superior in vivo anti-tumour effects against curcumin alone.
• Turmeric extract might serve as potential adjuvant therapy for colorectal cancer.

Abstract: The active ingredient curcuminoid (including curcumin, demethoxycurcumin and bisdemethoxycurcumin) from the Asian medicinal and culinary herb turmeric possesses anti-tumour effects, but poor oral absorption in the intestine impedes its widespread clinical application. Our previous study showed that turmerones increased the accumulation of curcumin inside colonic cells. The present study demonstrates the enhanced anti-proliferative and anti-angiogenic activities of curcumin in the presence of turmerones in human colon cancer cells and endothelial cells, respectively. Furthermore, in HT29 tumour xenograft-bearing mice fed with curcumin alone or turmeric ethanolic extract (in which the concentration of curcumin was kept the same), the tumour burden of turmeric extract-fed mice was the lowest, suggesting turmeric extract provided better anti-tumour activities than the same amount of curcumin alone did. The superior anti-tumour effects of turmeric extract, which contains curcumin, turmerones and other constituents, were verified in tumour-bearing mice, indicating the potential use of turmeric for colorectal cancer adjuvant therapy.

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How Curcumin Protects Against Cancer

J. Everett Borger

Life Extension Magazine (2011, Mar)

Abstract: 
According to the American Cancer Society [1], one out of every three women in the United
States risks developing some form of cancer over the course of their lives. For men, that
number rises to one in two. Since cancer is an age-related disease, the risk of diagnosis
increases the longer one lives, making it the second leading cause of death in this country [2,3].

These data underscore a stark reality. When it comes to cancer prevention, the medical
establishment and drug company profiteers remain grossly negligent in protecting the public.
The result is countless avoidable cancer deaths each year. There is an urgent need to provide
aging individuals with validated interventions to target cancer’s multiple causative factors before they take hold.

Among the most compelling and underrecognized of these is curcumin. In contrast to mainstream oncology’s focus on single agent toxic treatments, curcumin has emerged as a potent multimodal cancer-preventing agent, with 240 published studies appearing in the global scientific literature in the past year alone.

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Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively?

Jayaraj Ravindran, Sahdeo Prasad, and Bharat B. Aggarwal

The AAPS Journal (2009, Sep); 11(3): 495-510. DOI: 10.1208/s12248-009-9128-x

Abstract: Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.

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Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of I B Kinase and Akt Activation

Sita Aggarwal, Haruyo Ichikawa, Yasunari Takada, Santosh K. Sandur, Shishir Shishodia,
and Bharat B. Aggarwal

Molecular Pharmacology (2006); 69(1): 195–206. DOI: 10.1124/mol.105.017400

Abstract: Curcumin (diferuloylmethane), an anti-inflammatory agent used in traditional medicine, has been shown to suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis through a mechanism not fully understood. Because several genes that mediate these processes are regulated by nuclear factor- B (NF- B), we have postulated that curcumin mediates its activity by modulating NF- B activation. Indeed, our laboratory has shown previously that curcumin can suppress NF- B activation induced by a variety of agents (J Biol Chem 270:24995–50000, 1995) . In the present study, we investigated the mechanism by which curcumin manifests its effect on NF- B and NF- B-regulated gene expression. Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF)-induced NF- B activation. Curcumin inhibited TNF-induced NF- B-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF- B reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF- B-inducing kinase, I B kinase complex (IKK), and the p65 subunit of NF- B. Such TNFinduced NF- B-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-xL, Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1 -converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin. COX-2 promoter activity induced by TNF was abrogated by curcumin. We found that curcumin suppressed TNFinduced nuclear translocation of p65, which corresponded with the sequential suppression of I B kinase activity, I B phosphorylation, I B degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Curcumin also inhibited TNF-induced Akt activation and its association with IKK. Glutathione and dithiothreitol reversed the effect of curcumin on TNF-induced NF- B activation. Overall, our results indicated that curcumin inhibits NF- B activation and NF- B-regulated gene expression through inhibition of IKK and Akt activation.

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Chemopreventive activity of turmeric essential oil and possible mechanisms of action.

Liju VB, Jeena K, Kuttan R.

Asian Pacific Journal of Cancer Prevention (2014); 15(16): 6575-6580.

Abstract: This study aimed to evaluate the antimutagenic and anticarcinogenic activity of turmeric essential oil as well as to establish biochemical mechanisms of action. Antimutagenicity testing was accomplished using strains and known mutagens with and without microsomal activation. Anticarcinogenic activity was assessed by topical application of 7, 12-dimethylbenz[a]anthracene (DMBA) as initiator and 1% croton oil as promoter for the induction of skin papillomas in mice. Inhibition of p450 enzymes by TEO was studied using various resorufins and aminopyrene as substrate. Turmeric essential oil (TEO) showed significant antimutagenic activity (p<0.001) against direct acting mutagens such as sodium azide (NaN3), 4-nitro-O-phenylenediamine (NPD) and N-methyl- N-nitro N'nitrosoguanine (MNNG). TEO was found to have significant antimutagenic effect (>90%) against mutagen needing metabolic activation such as 2-acetamidoflourene (2-AAF). The study also revealed that TEO significantly inhibited (p<0.001) the mutagenicity induced by tobacco extract to Salmonella TA 102 strain. DMBA and croton oil induced papilloma development in mice was found to be delayed and prevented significantly by TEO application. Moreover TEO significantly (P<0.001) inhibited isoforms of cytochrome p450 (CYP1A1, CYP1A2, CYP2B1/2, CYP2A, CYP2B and CYP3A) enzymes in vitro, which are involved in the activation of carcinogens. Results indicated that TEO is antimutagenic and anticarcinogenic and inhibition of enzymes (p450) involved in the activation of carcinogen is one of its mechanisms of action.

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Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis

Ji H. Kim, Subash C. Gupta, Byoungduck Park, Vivek R. Yadav, and Bharat B. Aggarwal

Molecular Nutrition & Food Research (2012, Mar); 56(3): 454–465. Published online 2011 Dec 7. DOI: 10.1002/mnfr.201100270

Abstract

Scope: The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products.

Methods and results: Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis.

Conclusion: Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways.

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Bioactivity of Turmeric-Derived Curcuminoids and Related Metabolites in Breast Cancer

Laura E. Wright, Jen B. Frye, Bhavana Gorti, Barbara N. Timmermann, and Janet L. Funk

Current Pharmaceutical Design (2013); 19(34): 6218–6225. 

Abstract: While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurally-related metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10–16μg/mL) and secretion of osteolytic PTHrP (IC50=2–3μg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58 μM), demethoxycurcumin was without effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22–31μM) to the same degree as the curcuminoid mixture (IC50=16 μM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti-cancer effects.

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Curcumin Inhibition of Integrin (α6β4)-Dependent Breast Cancer Cell Motility and Invasion

Hong Im Kim, Huang Huang, Satish Cheepala, Shile Huang, and Jun Chung

Cancer Prevention Research (2008); 1: 385-391. Published online October 6, 2008. DOI: 10.1158/1940-6207.CAPR-08-0087

Abstract: Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. However, the mechanism by which curcumin inhibits cancer cell functions such as cell growth, survival, and cell motility is largely unknown. We explored whether curcumin affects the function of integrin α6β4, a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced α6β4-dependent breast cancer cell motility and invasion in a concentration-dependent manner without affecting apoptosis in MDA-MB-435/β4 (β4-integrin transfectants) and MDA-MB-231 breast cancer cell lines. Further, curcumin selectively reduced the basal phosphorylation of β4 integrin (Y1494), which has been reported to be essential in mediating α6β4-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked α6β4-dependent Akt activation and expression of the cell motility–promoting factor ENPP2 in MDA-MB-435/β4 cell line. A multimodality approach using curcumin in combination with other pharmacologic inhibitors of α6β4 signaling pathways showed an additive effect to block breast cancer cell motility and invasion. Taken together, these findings show that curcumin inhibits breast cancer cell motility and invasion by directly inhibiting the function of α6β4 integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that over-express α6β4.

[NOTE: This specific integrin is what CressLabs at the University of Arizona Comprehensive Cancer Center has been working on for the last 30 years in relation to prostate cancer. All integrins are comprised of an alpha unit and a beta unit, making 24 known combinations in humans. Integrins function as transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions. The α3, α6, and α7 subunits are laminin-binding integrins, which pair with either β1 or β4 to form heterodimers. The β4 subunit is unique in that it only pairs with the α6 subunit, but has recently been shown to have 5 variations: β4A. β4B, β4C (the "normal form" of β4, and the most widely studied), β4D, and β4E (a vary unique and relatively unknown form only recently investigated at the CressLab.]

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Curcumin Combined with Turmerones, Essential Oil Components of Turmeric, Abolishes Inflammation-Associated Mouse Colon Carcinogenesis

Akira Murakami, Ikuyo Furukawa, Shingo Miyamoto, Takuji Tanaka, and Hajime Ohigash

BioFactors (2013, Mar/Apr); 39(2): 221–232. DOI: 10.1002/biof.1054

Abstract: Curcumin (CUR), a yellow pigment in turmeric, has marked potential for preventing colon cancer. We recently reported that ar-turmerone (ATM) suppressed nitric oxide (NO) generation in macrophages. In the present study, we explored the molecular mechanisms by which ATM attenuates NO generation and examined the anti-carcinogenesis activity of turmerones (TUR, a mixture of 5 sesquiterpenes including ATM). Both CUR and ATM inhibited lipopolysaccharide (LPS)-induced expression of inducible forms of both nitric oxide synthase and cyclooxygenase (iNOS and COX-2, respectively). A chase experiment using actinomycin D revealed that ATM accelerated the decay of iNOS and COX-2 mRNA, suggesting a post-transcriptional mechanism. ATM prevented LPS-induced translocation of HuR, an AU-rich element-binding protein that determines mRNA stability of certain inflammatory genes. In a colitis model, oral administration of TUR significantly suppressed 2% dextran sulfate sodium (DSS)-induced shortening of the large bowel by 52–58%. We also evaluated the chemopreventive effects of oral feeding of TUR, CUR, and their combinations using a model of dimethylhydradine-initiated and DSS-promoted mouse colon carcinogenesis. At the low dose, TUR markedly suppressed adenoma multiplicity by 73%, while CUR at both doses suppressed adenocarcinoma multiplicity by 63–69%. Interestingly, the combination of CUR and TUR at both low and high doses abolished tumor formation. Collectively, our results led to our hypothesis that TUR is a novel candidate for colon cancer prevention. Furthermore, we consider that its use in combination with CUR may become a powerful method for prevention of inflammation-associated colon carcinogenesis.

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4. TURMERIC/CURCUMIN and PROSTATE CANCER

Chemopreventive potential of curcumin in prostate cancer

Marie-Helene Teiten, Francois Gaascht, Serge Eifes, Mario Dicato, Marc Diederich

Genes & Nutrition (2010); 5(1): 61–74. DOI 10.1007/s12263-009-0152-3

Abstract: The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention in order to prevent or eradicate prostate malignancies. We present here an overview of the chemopreventive potential of curcumin (diferuloylmethane), a well-known natural compound that exhibits therapeutic promise for prostate cancer. In fact, it interferes with prostate cancer proliferation and metastasis development through the down-regulation of androgen receptor and epidermal growth factor receptor, but also through the induction of cell cycle arrest. It regulates the inflammatory response through the inhibition of pro-inflammatory mediators and the NF-jB signaling pathway. These results are consistent with this compound’s ability to up-induce pro-apoptotic proteins and to down-regulate the anti-apoptotic counterparts. Alone or in combination with TRAIL-mediated immunotherapy or radiotherapy, curcumin is also reported to be a good inducer of prostate cancer cell death by apoptosis. Curcumin appears thus as a non-toxic alternative for prostate cancer prevention, treatment or co-treatment.

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Curcumin Attenuates β-catenin Signaling in Prostate Cancer Cells through Activation of Protein Kinase D1

Vasudha Sundram, Subhash C. Chauhan, Mara Ebeling, Meena Jaggi

PLoS ONE (2012, Apr): 7(4); e35368. DOI: 10.1371/journal.pone.0035368

Abstract: Prostate cancer is the most commonly diagnosed cancer affecting 1 in 6 males in the US. Understanding the molecular basis of prostate cancer progression can serve as a tool for early diagnosis and development of novel treatment strategies for this disease. Protein Kinase D1 (PKD1) is a multifunctional kinase that is highly expressed in normal prostate. The decreased expression of PKD1 has been associated with the progression of prostate cancer. Therefore, synthetic or natural products that regulate this signaling pathway can serve as novel therapeutic modalities for prostate cancer prevention and treatment. Curcumin, the active ingredient of turmeric, has shown anti-cancer properties via modulation of a number of different molecular pathways. Herein, we have demonstrated that curcumin activates PKD1, resulting in changes in β-catenin signaling by inhibiting nuclear β-catenin transcription activity and enhancing the levels of membrane β-catenin in prostate cancer cells. Modulation of these cellular events by curcumin correlated with decreased cell proliferation, colony formation and cell motility and enhanced cell-cell aggregation in prostate cancer cells. In addition, we have also revealed that inhibition of cell motility by curcumin is mediated by decreasing the levels of active cofilin, a downstream target of PKD1. The potent anti-cancer effects of curcumin in vitro were also reflected in a prostate cancer xenograft mouse model. The in vivo inhibition of tumor growth also correlated with enhanced membrane localization of β-catenin. Overall, our findings herein have revealed a novel molecular mechanism of curcumin action via the activation of PKD1 in prostate cancer cells.

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Therapeutic potential of curcumin in human prostate cancer--I: Curcumin induces apoptosis in both androgen-dependent and androgen-independent prostate cancer cells

T Dorai, N Gehani & A Katz

Prostate Cancer and Prostatic Diseases (2000); 3(2): 84-93. DOI: 10.1038/sj.pcan.4500399

Abstract: In an effort to find an alternative nontoxic means of inducing the apoptosis potential in both androgen-dependent and hormone refractory prostate cancer cells, attention was focused on curcumin (turmeric), traditionally used in medicine and cuisine in India and other south-east Asian countries. The results indicate that curcumin is a novel and potent inducer of apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. This was accomplished by down-regulating apoptosis suppressor proteins and other crucial proteins such as the androgen receptor. It is concluded that curcumin may provide an alternative, nontoxic modality by which the clinician may prevent the progression of prostate cancer to its hormone refractory state or to treat advanced prostate cancer by forcing them to undergo apoptosis.

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Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2

Peter H. Killian, Emanuel Kronski, Katharina M. Michalik, Ottavia Barbieri, Simonetta Astigiano,
Christian P. Sommerhoff, Ulrich Pfeffer, Andreas G. Nerlich, and Beatrice E. Bachmeier

Carcinogenesis (2012); 33(12): 2507-2519. DOI: 10.1093/carcin/bgs312

Abstract: In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase (IKKβ, leading to stabilization of the inhibitor of NFκB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of curcumin with the synthetic IKKβ inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and down regulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFκB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo.

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The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo

JH Hong, KS Ahn, E Bae, SS Jeon, and HY Choi

Prostate Cancer and Prostatic Diseases (2006); 9(2): 147–152. DOI: 10.1038/sj.pcan.4500856

Abstract: Curcumin has become a focus of interest with regard to its antitumor effects in prostate cancer; however, the effects of this agent on invasion and metastasis remain less well understood. Matrix metalloproteinases (MMPs) are important prerequisite for tumor invasion and metastasis. In this study, we evaluated the effects of curcumin on prostate cancer cells (DU-145) invasion in both in vitro and in vivo. We utilized zymography and ELISA in order to determine the MMP-2 and MMP-9 activity. Matrigel invasion assay was performed to assess cellular invasion. We developed a xenograft model to examine tumorigenicity. Curcumin treatment resulted not only in a significant reduction in the expression of MMP-2 and MMP-9, but also effected the inhibition of invasive ability in vitro. Curcumin was shown to induce a marked reduction of tumor volume, MMP-2, and MMP-9 activity in the tumor-bearing site. The metastatic nodules in vivo were significantly fewer in the curcumin treated group than untreated group. Curcumin appears to constitute a potential agent for the prevention of cancer progression, or at least of the initial phase of metastasis, in prostate cancer.

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Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor 

Young Hwa Soung and Jun Chung

Molecular Cancer Therapeuitics (2011); 10(5): 883-891. Published Online First March 9, 2011. DOI: 10.1158/1535-7163.MCT-10-1053

Abstract: The functional interaction between integrin α6β4 and growth factor receptors has been implicated in key signaling pathways important for cancer cell function. However, few attempts have been made to selectively target this interaction for therapeutic intervention. Previous studies showed that curcumin, a yellow pigment isolated from turmeric, inhibits integrin α6β4 signaling important for breast carcinoma cell motility and invasion, but the mechanism is not currently known. To address this issue, we tested the hypothesis that curcumin inhibits the functional interaction between α6β4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between α6β4 and EGFR, and blocks a6b4/EGFR-dependent functions of carcinoma cells expressing the signaling competent form of a6b4. We further showed that curcumin inhibits EGF-dependent mobilization of α6β4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents α6β4 distribution to lipid rafts where functional interactions between α6β4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits α6β4 signaling and functions by altering intracellular localization of α6β4, thus preventing its association with signaling receptors such as EGFR.

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5. CURCUMIN FOR NEURODEGENERATIVE DISORDERS

Probably the second largest research investment in turmeric/curcumin has been in the field of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington’s disease, and others.

Potential Therapeutic Effects of Curcumin, the Anti-inflammatory Agent, Against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases

Bharat B. Aggarwal and Kuzhuvelil B. Harikumar

International Journal of Biochemistry & Cell Biology (2009); 41(1): 40–59. Published online 2008 Jul 9. DOI: 10.1016/j.biocel.2008.06.010

Abstract: Although safe in most cases, ancient treatments are ignored because neither their active component nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research performed within the past two decades has shown that this activity of turmeric is due to curcumin (diferuloylmethane). This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various proinflammatory chronic diseases. These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further.

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The effect of curcumin (turmeric) on Alzheimer's disease: An overview

Shrikant Mishra and Kalpana Palanivelu

Annals of Indian Academic Neurology (2008, Jan-Mar); 11(1): 13–19. DOI: 10.4103/0972-2327.40220

Abstract: This paper discusses the effects of curcumin on patients with Alzheimer's disease (AD). Curcumin (Turmeric), an ancient Indian herb used in curry powder, has been extensively studied in modern medicine and Indian systems of medicine for the treatment of various medical conditions, including cystic fibrosis, haemorrhoids, gastric ulcer, colon cancer, breast cancer, atherosclerosis, liver diseases and arthritis. It has been used in various types of treatments for dementia and traumatic brain injury. Curcumin also has a potential role in the prevention and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD. A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer's disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. This paper reviews the various mechanisms of actions of curcumin in AD and pathology.

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Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia

Nozomi Hishikawa, Yoriko Takahashi, Yoshinobu Amakusa, Yuhei Tanno, Yoshitake Tuji and Hisayoshi Niwa

AYU (An International Quarterly Journal of Research in Ayurveda) (2012, Oct/Nov); 33(4): 499-504.

Abstract: We describe here three patients with the Alzheimer's Disease (AD) whose behavioral symptoms were improved remarkably as a result of the turmeric treatment, which is the traditional Indian medicine. Their cognitive decline and Behavioral and Psychological Symptoms of Dementia (BPSD) were very severe. All three patients exhibited irritability, agitation, anxiety, and apathy, two patients suffer from urinary incontinence and wonderings. They were prescribed turmeric powder capsules and started recovering from these symptoms without any adverse reaction in the clinical symptom and laboratory data. After 12 weeks of the treatment, total score of the Neuro-Psychiatric Inventory-brief questionnaire decreased significantly in both acuity of symptoms and burden of caregivers. In one case, the Mini-Mental State Examination (MMSE) score was up five points, from 12/30 to 17/30. In the other two cases, no significant change was seen in the MMSE; however, they came to recognize their family within 1 year treatment. All cases have been taking turmeric for more than 1 year, re-exacerbation of BPSD was not seen. The present cases suggest a significant improvement of the behavioral symptoms in the AD with the turmeric treatment, leading to probable benefit of the use of turmeric in individuals with the AD with BPSD.

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The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse

Giselle P. Lim, Teresa Chu, Fusheng Yang, Walter Beech, Sally A. Frautschy, and Greg M. Cole

The Journal of Neuroscience (2001, Nov); 21(21): 8370-8377.

Abstract: Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1β, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble β-amyloid (Aβ), soluble Aβ, and plaque burden were significantly decreased by 43–50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

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Curcumin and neurodegenerative diseases: A perspective

Darvesh AS, Carroll RT, Bishayee A, Novotny NA, Geldenhuys WJ, Van der Schyf CJ

Expert Opinion on Investigational Drugs (2012, Aug); 21(8): 1123-40. DOI: 10.1517/13543784.2012.693479

Abstract
Introduction: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD).

Areas Covered: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed.

Expert Opinion: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.

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Curcumin: A potential neuroprotective agent in Parkinson's disease

Mythri RB & Bharath MM

Current Pharmaceutical Design (2012); 18(1): 91-99. DOI: 10.2174/138161212798918995

Abstract: Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD.

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6. CURCUMIN/TURMERIC AND PSYCHOLOGICAL DISORDERS

This is one of the newer areas of research into the benefits of curcumin/turmeric. The majority of the studies seem to be focused on its potential as a natural antidepressant.

Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats

Ying Xu, Baoshan Ku, Li Cui, Xuejun Li, Philip A. Barish, Thomas C. Foster, William O. Ogle

Brain Research (2007, Aug); 1162(8): 9–18. DOI: 10.1016/j.brainres.2007.05.071

Abstract: Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. As the active component of curcuma longa, curcumin possesses many therapeutic properties; we have previously described its antidepressant activity in our earlier studies using the chronic unpredictable stress model of depression in rats. Recent studies show that stress-induced damage to hippocampal neurons may contribute to the phathophysiology of depression. The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT1A mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT1A receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin.

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Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study 

Adrian L Lopresti, Michael Maes, Garth L Maker, Sean D Hood, Peter D Drummond

Journal of Affective Disorders (2014, Jun); 167: 368-375. DOI: 10.1016/j.jad.2014.06.001

Abstract

Background: Curcumin, the principal curcuminoid derived from the spice turmeric, influences several biological mechanisms associated with major depression, namely those associated with monoaminergic activity, immune-inflammatory and oxidative and nitrosative stress pathways, hypothalamus-pituitary-adrenal (HPA) axis activity and neuroprogression. We hypothesised that curcumin would be effective for the treatment of depressive symptoms in individuals with major depressive disorder.
Methods: In a randomised, double-blind, placebo-controlled study, 56 individuals with major depressive disorder were treated with curcumin (500 mg twice daily) or placebo for 8 weeks. The primary measure was the Inventory of Depressive Symptomatology self-rated version (IDS-SR30). Secondary outcomes included IDS-SR30 factor scores and the Spielberger State-Trait Anxiety Inventory (STAI).
Results: From baseline to week 4, both curcumin and placebo were associated with improvements in IDS-SR30 total score and most secondary outcome measures. From weeks 4 to 8, curcumin was significantly more effective than placebo in improving several mood-related symptoms, demonstrated by a significant group x time interaction for IDS-SR30 total score (F1, 53=4.22, p=.045) and IDS-SR30 mood score (F1, 53=6.51, p=.014), and a non-significant trend for STAI trait score (F1, 48=2.86, p=.097). Greater efficacy from curcumin treatment was identified in a subgroup of individuals with atypical depression.
Conclusions: Partial support is provided for the antidepressant effects of curcumin in people with major depressive disorder, evidenced by benefits occurring 4 to 8 weeks after treatment.
Limitations: Investigations with larger sample sizes, over extended treatment periods, and with varying curcumin dosages are required.

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Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB 

Ying Xu, Baoshan Ku, Lu Tie, Haiyan Yao, Wengao Jiang, Xing Ma, Xuejun Li

Brain Research (2006, Nov); 1122(1): 56–64. DOI: 10.1016/j.brainres.2006.09.009

Abstract: Curcuma longa is a major constituent of the traditional Chinese medicine Xiaoyao-san, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and its antidepressant effects were described in our prior studies in mouse models of behavioral despair. We hypothesized that curcumin may also alleviate stress-induced depressive-like behaviors and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Thus in present study we assessed whether curcumin treatment (2.5, 5 and 10 mg/kg, p.o.) affects behavior in a chronic unpredictable stress model of depression in rats and examined what its molecular targets may be. We found that subjecting animals to the chronic stress protocol for 20 days resulted in performance deficits in the shuttle-box task and several physiological effects, such as an abnormal adrenal gland weight to body weight (AG/B) ratio and increased thickness of the adrenal cortex as well as elevated serum corticosterone levels and reduced glucocorticoid receptor (GR) mRNA expression. These changes were reversed by chronic curcumin administration (5 or 10 mg/kg, p.o.). In addition, we also found that the chronic stress procedure induced a down-regulation of brain-derived neurotrophic factor (BDNF) protein levels and reduced the ratio of phosphorylated cAMP response element-binding protein (pCREB) to CREB levels (pCREB/CREB) in the hippocampus and frontal cortex of stressed rats. Furthermore, these stress-induced decreases in BDNF and pCREB/CREB were also blocked by chronic curcumin administration (5 or 10 mg/kg, p.o.). These results provide compelling evidence that the behavioral effects of curcumin in chronically stressed animals, and by extension humans, may be related to their modulating effects on the HPA axis and neurotrophin factor expressions.

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Is there a role for curcumin in the treatment of bipolar disorder?

Elisa Brietzke, Rodrigo B. Mansur, Andre Zugman, André F. Carvalho, Danielle S. Macêdo, Danielle S. Cha, Vanessa C. Abílio, and Roger S. McIntyre

Medical Hypotheses (2013, May); 80(5): 606–612. DOI: 10.1016/j.mehy.2013.02.001

Abstract: Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa), a plant commonly used in Indian and Chinese traditional medicine to treat rheumatism, cough, inflammation and wounds. Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.
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An Overview of Curcumin in Neurological Disorders

S. K. Kulkarni and A. Dhir

Indian Journal Pharmaceutical Sciences (2010, Mar-Apr); 72(2): 149–154. DOI: 10.4103/0250-474X.65012

Abstract: Curcumin, the principal curcuminoid found in spice turmeric, has recently been studied for its active role in the treatment of various central nervous system disorders. Curcumin demonstrates neuroprotective action in Alzheimer's disease, tardive dyskinesia, major depression, epilepsy, and other related neurodegenerative and neuropsychiatric disorders. The mechanism of its neuroprotective action is not completely understood. However, it has been hypothesized to act majorly through its anti-inflammatory and antioxidant properties. Also, it is a potent inhibitor of reactive astrocyte expression and thus prevents cell death. Curcumin also modulates various neurotransmitter levels in the brain. The present review attempts to discuss some of the potential protective role of curcumin in animal models of major depression, tardive dyskinesia and diabetic neuropathy. These studies call for well planned clinical studies on curcumin for its potential use in neurological disorders.

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Multiple antidepressant potential modes of action of curcumin: A review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating and neuroprotective effects

Lopresti, A.L., Hood, S.D., and Drummond, P.D.

Journal of Psychopharmacology (2012, Dec); 26(12): 1512-1524. DOI: 10.1177/0269881112458732

Abstract: Curcumin is the principal curcuminoid of the popular Indian spice turmeric and has attracted increasing attention for the treatment of a range of conditions. Research into its potential as a treatment for depression is still in its infancy, although several potential antidepressant mechanisms of action have been identified. Research completed to date on the multiple effects of curcumin is reviewed in this paper, with a specific emphasis on the biological systems that are compromised in depression. The antidepressant effects of curcumin in animal models of depression are summarised, and its influence on neurotransmitters such as serotonin and dopamine is detailed. The effects of curcumin in moderating hypothalamus-pituitary-adrenal disturbances, lowering inflammation and protecting against oxidative stress, mitochondrial damage, neuroprogression and intestinal hyperpermeability, all of which are compromised in major depressive disorder, are also summarised. With increasing interest in natural treatments for depression, and efforts to enhance current treatment outcomes, curcumin is presented as a promising novel, adjunctive or stand-alone natural antidepressant.

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The CB1 Receptor-Mediated Endocannabinoid Signaling and NGF: The Novel Targets of Curcumin

Parichehr Hassanzadeh & Anna Hassanzadeh

Neurochemical Research (2012, May); 37(5): 1112-1120. DOI: 10.1007/s11064-012-0716-2

Abstract: Increasing interest has recently been attracted towards the identification of natural compounds including those with antidepressant properties. Curcumin has shown promising antidepressant effect, however, its molecular target(s) have not been well defined. Based on the interaction between the neurotrophins and endocannabinoid system as well as their contribution to the emotional reactivity and antidepressant action, here we show that 4-week treatment with curcumin, similar to the classical antidepressant amitriptyline, results in the sustained elevation of brain nerve growth factor (NGF) and endocannabinoids in dose-dependent and brain region-specific fashion. Pretreatment with cannabinoid CB1 receptor neutral antagonist AM4113, but not the CB2 antagonist SR144528, prevents the enhancement of brain NGF contents. AM4113 exerts no effect by itself. Our findings by presenting the CB1 receptor-mediated endocannabinoid signaling and NGF as novel targets for curcumin, suggest that more attention should be focused on the therapeutic potential of herbal medicines including curcumin.

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Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes

Mohit Kumar Bhutani, Mahendra Bishnoi, and Shrinivas K. Kulkarni

Pharmacology Biochemistry and Behavior (2009, Mar); 92(1): 39–43. DOI: 10.1016/j.pbb.2008.10.007

Abstract: Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.