Curcumin: The Super Herbal Supplement That Offers Amazing Health Benefits

Curcumin: The Super Herbal Supplement That Offers Amazing Health Benefits In this first part of this article we will learn much about curcumin (Curcuma longa), from the Indian curry spice turmeric, and its various positive effects on human health. Curcumin is the abundant, yellow, fat-soluble pigment responsible for the various health benefits that many are raving about. Although the use of turmeric is common in cooking, it continues to astonish scientists and health practitioners in terms of its extensive positive effects on human health.

Although there is a lot of information out there, it is essential to know the true facts about curcumin and to know how to take advantage of this powerful spice extract.

Following this in-depth review, we will examine other potential herbal components that will enhance the positive health benefits of this super herbal supplement.

What Are the True Facts About Curcumin?

Curcumin was first isolated in 1815 by German scientists, however the first study on its biological activity as an antibacterial agent was not published until 1949. As recently as 1990 there were less than 100 publications on curcumin. Since then there have been over 9,000 articles published in the scientific literature on the biological effects of curcumin, not limited to antibacterial properties.

The active components of curcumin are unique polyphenols known as curcuminoids extracted from the root of the plant. Polyphenols are micronutrients found abundantly in the human diet, and evidence for their role in the prevention of degenerative diseases has been mounting steadily in research over the last 10 years. Curcuminoids are not specific to turmeric but found in various plants such as the herb ginger which is a relative of turmeric.

What Are the Health Benefits of Curcuminoids? How Can You Benefit From Them?

There is now conclusive scientific evidence that curcumin has the potential to affect multiple human ailments in many positive ways. Thus far, studies have substantially indicated that curcuminoids exert potent effects against infection (strong antimicrobial effects) and many chronic diseases, including inflammatory diseases, obesity, aging, cognitive decline, diabetes, heart disease (both electrical and arteriosclerotic), kidney diseases, lung diseases, depression, anxiety, neurological and autoimmune diseases, and protection against heavy metal toxicity. There is also preliminary evidence of protective effects of these curcuminoids on the development of some cancers.

Curcuminoids have also been shown to enhance the efficacy of and be enhanced by other nutraceuticals, such as resveratrol (another polyphenol, used in part for antioxidant qualities), piperine (the active component of black pepper often used as an anti-inflammatory), catechins (another phenol known for antioxidant qualities, often sourced from green tea), quercetin (a polyphenol found in many fruits and vegetables often used for antihistamine qualities) and genistein (the phytoestrogen found in soy that is sometimes used for nutritional supplementation in persons with prostate and breast cancers).

Curcumin’s Benefits In Specific Situations

CURCUMIN MAY RELIEVE ACUTE PAIN

Curcumin (or more specifically, turmeric) has a historical usage for pain relief following trauma. Studies have shown curcumin to be effective on pain management in patients with osteoarthritis, following gall bladder surgery, other post-operative pain, arthritis pain, as well as for pain in persons with daily symptoms.

CURCUMIN PROVIDES CARDIOVASCULAR SUPPORT

Studies show that regular use of curcumin may help increase blood flow, circulation, decrease blood pressure, protect against cardiac hypertrophy (heart enlargement), inflammation, and thrombosis (abnormal clotting).

One interesting fact is that curcumin appears to significantly reduce the leukocyte adhesion molecules involved in the primary stages of atherosclerosis (these are fatty plaque deposits on the arteries that restrict the blood flow).

Other studies have proven that curcumin may prevent the endothelial (the cells lining our arterial blood vessels) dysfunction associated with high blood glucose and may offer protection from a series of side effects associated with diabetes. Supplementation of curcumin is also associated with an increase in blood flow comparable to physical exercise three times a week.

Daily oral supplementation of curcumin for four weeks in healthy people has resulted in a significant (about 40%) increase in circulating nitric oxide, which may increase blood flow and supplements arterial circulation.

In one human study using curcumin there was a significant decrease in blood pressure in people with inflammation of the kidneys (better known as nephritis). In another study, postmenopausal women were given curcumin daily for eight weeks and its consumption was associated with a decrease in systolic blood pressure.

CURCUMIN IMPROVES SKELETAL MUSCLE MASS

The antioxidant effects of curcumin may block the oxidative damage caused to skeletal muscle and its potency was shown to be greater than vitamin E. Curcumin may block the increase in inflammatory cell signal proteins associated with muscle vascular injury. At the same time, it increases the recovery of skeletal muscle capacity, upregulates the antioxidant defenses in skeletal muscular and improves muscle weight. In skeletal muscle and adipose tissue, insulin promotes glucose uptake into the cells by activating a complex cascade of phosphorylation-dephosphorylation reactions. Skeletal muscle is considered a tissue regulator of glucose metabolism, and curcumin reverses some of the glucose metabolism aberrations in skeletal muscle associated with type II diabetes.

CURCUMIN’S POSITIVE EFFECTS IN NEUROLOGICAL HEALTH

DHA (docosahexaenoic acid, a fatty acid component found in fish oil) is the most abundant omega-3 fatty acid in the brain. DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain. Fifty percent of the weight of a brain cell’s membrane is composed of DHA. Curcumin preserves DHA (a long chain omega-3 fatty acid) content in the brain and elevates the levels of enzymes that are needed for the synthesis of DHA in the liver and brain. Certain cognitive disorders including anxiety, depression and Alzheimer’s have been linked to a dietary deficiency in DHA.

One well known damaging effect common to many neurological conditions is increased glutamate levels--leading to death of neuronal cells. Curcumin has been shown to produce protective effects that guard against glutamate-induced toxicity.

Curcumin ingestion has been noted to reduce the negative effects of stress on brain (neuronal) cell function and spatial memory, decrease anxious behaviors, and improve symptoms of depression. Curcumin seems to be particularly effective in improving severe anxiety in obese females. The potent antidepressant effects of curcumin appear to be related to anti-inflammatory and antioxidant effects as well as modifying hormonal stress response.

Other studies have shown that curcumin may slow the cognitive decline in Alzheimer’s patients. Alzheimer’s is particularly characterized by beta-amyloid accumulation, which leads to a build up of plaques in the brain made up of this specific protein. Curcumin inhibits the formation of beta-amyloid proteins in the brain, and this effect is hypothesized as to why curcumin potentially has the effect of slowing the progression of Alzheimer’s. When curcumin is combined with DHA, they have shown it to be even more effective at reducing this protein through different mechanisms of action.

THE ROLE OF CURCUMIN IN IMMUNITY, OXIDATION AND INFLAMMATION

Curcumin has been shown to sequester free radicals, including superoxide radicals, therefore acting as an antioxidant. Studies indicate moderate doses of curcumin are most effective, and high doses can produce pro-oxidant effects. So, it appears that taking moderate doses of curcumin is best.

As mentioned above, curcumin is associated with reducing a variety of inflammatory signals, most of which are associated with arthritis and inflammation of the joints. The anti-inflammatory effects of curcumin are more potent than indomethacin, a commonly used nonsteroidal anti-inflammatory drug.

Many proinflammatory enzymes are suppressed by curcumin. One of curcumin’s most well-researched effects on inflammation is inhibiting the tumor necrosis factor alpha (TNF-α). TNF-α activates NF-kB, a protein complex that influences the genetic code to produce inflammatory cytokines (cell signal proteins). By inhibiting TNF-α, the process of inflammation is alleviated.

Curcumin has been shown to improve symptoms of osteoarthritis, including total symptom reduction of knee osteoarthritis with improvements in pain, stiffness, and physical functioning.

Curcumin also provides a potent suppressive effect on macrophages, a key cell line in the immune system. The suppressive effects of curcumin on other immune system elements has been researched and it has been concluded that if curcumin is taken at higher doses it may suppress important immune functions.

CURCUMIN, OBESITY AND FAT MASS

Curcumin may be able to improve the breakdown of fats in adipocytes (fat cells) and stop lipid accumulation in fat cells undergoing the processes to become more specialized cells.

Curcumin is known to assist with inflammation, and inflammation appears to play an important role in obesity. Particularly, one cell signal protein known as tumor necrosis factor alpha (TNF-α) has been noted to be decreased with administration of curcumin. TNF-α is a potent activator of inflammation and overactivity of TNF-α in fat cells is highly correlated with metabolic syndrome and obesity.

Curcumin also appears to be associated with an increase in adiponectin production in fat cells. Adiponectin is a protein hormone specific to fat cells which is involved in regulating glucose levels as well as fatty acid breakdown. Adiponectin levels are lower in obese subjects than in lean subjects. It has been suggested that low adiponectin levels play a role in the development of insulin resistance and atherosclerosis.

Leptin is a hormone that helps inhibit hunger. Leptin resistance is common in obesity. Leptin secretion from adipocytes appears to be suppressed with curcumin. The decrease of leptin secretion is related to the increase of lipolysis (dissolving fat). The positive effects of curcumin administration in obese subjects has been shown to lead to a decrease in fat mass and weight.

CURCUMIN’S ANTIVIRAL ACTIVITY

One study found that curcumin was able to suppress replication of the Rift Valley fever virus and its fully virulent form. Further studies are in progress.

CURCUMIN AND HORMONAL BALANCE

Curcumin has been shown to preserve testosterone levels and has protective effects on the testes in the presence of alcohol consumption. In one study, curcumin administration to subjects was shown to preserve testicle structure and testosterone levels despite alcohol consumption. Curcumin has anti-estrogenic activity when administered in moderate doses. High doses appear to be estrogenic.

CURCUMIN’S ANTICANCER EFFECTS

Curcumin can protect DNA from oxidation via chelation of the heavy metal arsenic. One of the mechanisms under investigation for chemoprotective effects of curcumin is the inhibitory effect on pro-inflammatory cytokines, and positive influences on specific enzyme activity that induce cell growth, survival, and can induce cellular death via a mechanism that appears to ‘sensitize’ cancer cells to apoptosis (a form of “programmed” cell death).

Cancers for which there is preliminary evidence of the anti-tumor effects of curcumin include prostate, bladder, breast and non-small cell lung cancer.

ANTI-AGING AND LONGEVITY

Autophagy is the regulated, self-degradative process of the cell that disassembles unnecessary components. The lysosomal pathway is evolutionarily conserved and initiates engulfment, degradation and recycling of cellular contents including long-lived proteins and organelles, thus promoting cell survival. Autophagy is induced by conditions of nutrient deprivation as well as physiological and pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection, obesity, and cancer.

Autophagy appears to be activated by many polyphenols including curcumin, resveratrol, silybin (from milk thistle), quercetin, and catechins (common, but usually known to be a component of the four green tea catechins). Curcumin appears to induce autophagy, and so far this effect of curcumin has been detected in glioma, uterine cancer, oral cancer and leukemic cells.

Beyond the possible roles in longevity, autophagy activation from curcumin is thought to be protective against gliomas, as glioma cells are resistant to apoptosis but readily destroyed by autophagy.

At the same time, Parkinson’s pathology may be attenuated with curcumin via preservation of autophagy.

INTESTINAL, LIVER AND KIDNEY HEALTH

One study noted that, in conjunction with standard therapy for ulcerative colitis, supplementation of curcumin daily offered significant protection against colonic inflammation and improved symptoms of ulcerative colitis for as long as it was used. These effects were seen in both ulcerative colitis and Crohn’s disease, which are two human conditions associated with intestinal inflammation.

In additional data, curcumin appears to be able to reduce high fat and triglyceride diet-induced liver fat accumulation (steatohepatitis or fatty infiltration of the liver) and in at least one human intervention showed that curcumin was able to suppress diabetic kidney disease. These benefits could benefit people with lupus as well. As researched, curcumin exerts this apparent kidney protection via suppressing inflammation and related cytokines or mRNA (messenger RNA) associated with inflammation. Curcumin has also been shown to prevent structural changes in the kidneys and delay the inevitable progression of kidney disease to renal (kidney) failure.

CURCUMIN PROTECTS AGAINST HEAVY METALS

Curcumin acts as a chelating agent and appears to provide other mechanisms of protection against heavy metals, including arsenic and mercury.

Why Not Just Add Turmeric Into Your Diet?
Depending on the type of formulation, the usual doses of curcumin are 2 to 8 grams daily in divided doses, with lower doses needed when more enhanced products are taken. Moderate recommended doses are between 2 and 4 grams daily in divided doses. It would take a lot of turmeric to ingest that much curcumin, and as it turns out, curcumin has very poor absorption in the gut unless it is biochemically altered in one of 4 ways. This only further increases the amount of turmeric necessary to ingest to achieve the desired health benefits.

If any one of the following enhancements is performed on the raw extract, it significantly increases uptake of the active components. Use of more than one of these technologies can even further enhance absorption, and therefore the bio-clinical effects.

1. Formulating the curcumin with the table spice black pepper (piperine).
2. Complexing curcumin with phosphatidylcholine to form phytosomes.
3. Using nanoparticle technology.
4. Converting curcumin to water soluble state using polyvinyl pyrrolidone.

These enhancements increase absorption by 20, 29, 30, and 40-fold respectively.

CURCUMIN’S SAFETY AND TOLERABILITY

To date, over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans. In higher doses, curcumin theoretically has potent immune suppressive effects.

CURCUMIN’S DRUG INTERACTIONS

Curcumin may increase bleeding risks when taken with antiplatelet and anticoagulant drugs, and decreases the efficacy of vinblastine, ciprofloxacin and cotrimoxazole when taken concomitantly. According to the Milton S. Hershey Medical Center, it is highly recommended that if you are currently being treated with any of the following medications, you should not use turmeric or curcumin in medicinal forms without first talking to your health care provider.

1. Blood-thinning medications: curcumin (turmeric) may make the effects of these drugs stronger, raising the risk of bleeding. Blood-thinners include warfarin (Coumadin), clopidogrel (Plavix), and aspirin, among others
2. Drugs that reduce stomach acid: curcumin (turmeric) may interfere with the action of these drugs, increasing the production of stomach acid:
   • Cimetidine
   • Famotidine
   • Ranitidine
   • Esomeprazole
   • Omeprazole
   • Lansoprazole
3. Drugs for diabetes that may lower blood sugar: curcumin (turmeric) may make the effects of these drugs stronger, increasing the risk of hypoglycemia (low blood sugar).

The Rest of the Story:

Curcumin Combined With Other Specific Herbs Provides Additional Incredible Health Benefits
In the first part of this article, we learned many interesting facts about curcumin, and its various positive effects on human health. In this rest of this article, we will review other herbal components that can be combined with curcumin to create synergistic effects that specifically target joint health.

As we outlined above there are several ways that curcumin’s bioavailability can be enhanced to optimize its absorption. Studies suggest that an innovative approach would be combining two of those improvements together to significantly increase absorption of the active components, with these modifications enhancing the absorption as well as the positive biological effects greatly.

Specifically, formulating the curcumin with the table spice black pepper (piperine), complexing curcumin with phosphatidylcholine to form phytosomes, using nanoparticle technology and converting curcumin to a water soluble state using polyvinyl pyrrolidone all significantly improve the bioavailability of curcumin products. It should be noted that treatment of intestinal issues does not require these enhancements. Over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans.

Black Pepper Has Health Benefits? Who Knew!

It turns out that piperine (black pepper extract) enhances the bioavailability of the active constituents of multiple other herbs and even pharmaceuticals. So much so that pharmaceutical researchers are exploring the application of piperine in improving the bioavailability of many pharmaceutical products. Beyond that, piperine has its own independent effects.

An in-depth study of the therapeutic potential of piperine and related derivatives shows that piperine is currently “paving its way to become a privileged scaffold for the development of bioactive compounds with therapeutic application in multiple human diseases.” Piperine derivatives have been shown to modulate the activity of several targets related to neurological disorders, including epilepsy, Parkinson’s disease, depression and pain-related disorders. Further research is in progress.

Based on in vivo and in vitro studies, piperine has been found to have immunomodulatory, anti-asthmatic, anti-carcinogenic, anti-inflammatory, anti-ulcer and anti-amoebic properties. The most far-reaching attribute of piperine has been its inhibitory influence on enzymatic drug biotransforming reactions in the liver. Studies have additionally established the safety of black pepper or its active principle, piperine, in several animal studies. It is recognized as GRAS (generally regarded as safe) by the FDA.

Were the Three Kings Right About the Value of Frankincense?

Frankincense, an ancient remedy, is the extracted gum resin of the plant Boswellia serrata (BS), which is known to be effective in the treatment of inflammatory disorders like arthritis. Many anti-arthritic natural medicine combinations contain BS.

The inflammatory response represents the first-line defense of the body to tissue damage and/or to microbial invasion, and it determines the recruitment of immune cells and some plasma proteins. The final goal of inflammation is healing, elimination of the external or internal inflammation source of injury, and the restoration of homeostasis. Boswellia helps in attaining this restoration status.

A Cochrane systematic review concluded that preparations from BS “show trends of benefits” (when used for the treatment of osteoarthritis) coupled with a low burden of side effects, citing two high-quality and two moderate-quality studies demonstrating superiority compared to placebo in reducing pain and increasing functionality, and a moderate quality study indicating a favorable adverse events profile.

Certainly, a couple of double-blind, randomized, placebo-controlled studies done on patients with knee osteoarthritis (OA) demonstrated that phyto preparations from BS gum resin can reduce pain and increase functionality after only a few days (a week or so at most) with no serious adverse effects. In multiple human clinical trials, BS has been shown to meaningfully improve pain levels in of the knee. Boswellia resins may also be beneficial and proprietary preparations derived from BS have good efficacy. All these products have fewer adverse effects than the chronic use of NSAIDs.

Boswellic acids also show anti-inflammatory properties in a variety of other inflammatory diseases, including rheumatoid arthritis, and asthma. Other human studies have confirmed the safety, tolerability, and efficacy of BS extract in patients with OA. Patients receiving BS as an alternative treatment reported a decrease in knee pain and swelling of the knee joint as well as mitigation of difficulty in performing the activities of daily living, which included an increase in knee flexion and an improvement during a long-distance walk.

To conclude, a randomized, double-blind, placebo controlled, crossover study to evaluate the analgesic activity of BS in healthy volunteers using mechanical pain model revealed that the analgesic activity of single oral dose (125 mg, 2 capsules) of BS compared to placebo significantly increased the pain threshold and pain tolerance force and time compared to placebo. BS has also been studied in combination with ashwagandha and curcumin in OA patients, revealing the positive synergistic effects of the herbs when administered together.

Ashwagandha Holds the Key to Physical and Mental Health

Ashwagandha (Withania somnifera) is a key ayurvedic (from India) adaptogenic herbal remedy that has been used by humans for over 5,000 years to help the body cope with the stress of pain and inflammation.

Adaptogens help the body systems “adapt” to stressful physical, emotional and mental conditions. This also includes responses to inflammation and immune stress. In ayurveda, ashwagandha has been historically characterized as having rejuvenation, longevity and revitalizing properties.

The root extracts of ashwagandha are known to possess analgesic, anti-inflammatory and chondroprotective (cartilage protecting) effects. In multiple studies, ashwagandha showed to be a liver protectant, antioxidant, anti-neuroinflammatory, anti-anxiety, immunomodulatory, anti-angiogenic and it can also function as a sleep aid.

In randomized, placebo-controlled, double-blind studies, ashwagandha has been found to produce positive dose-related responses without evidence of problems with efficacy, safety or tolerability. Supplementation with ashwagandha ameliorates knee pain, resolves anxiety, improves upper and lower body strength, increases muscle mass and strength, supports favorable distribution of body mass, improves cardiorespiratory endurance, improves quality of life, has a beneficial effect in the treatment of OCD and bipolar disorder, and is beneficial for normalizing thyroid indices in patients with subclinical hypothyroidism.

The Secret Gift of Guggul

Guggul is a highly valued ayurvedic medicine made from the resin of the myrrh tree (Commiphora mukul) which is native to India. This gum resin has been in use in ayurvedic medicine for thousands of years. It is also a component of some incense and perfumes. Traditionally, guggul resin has been used for reducing symptoms associated with high cholesterol and heart disease. However, recently it has been found useful in the management of inflammatory and joint disorders. In multiple studies, guggul has been found to have antioxidant, anti-inflammatory, anti-obesity, anti-dyslipidemia, and antihypertensive properties, which can serve for the prevention and treatment of metabolic syndrome.

From current in vitro and in vivo studies, we have learned that guggul has significant unexplored potential effects in the treatment of inflammation, nervous disorders, hyperlipidemia and associated cardiac disorders such as hypertension and ischemia, skin disorders, cancer and urinary disorders. In several human randomized controlled trials, guggul alone has been found to ameliorate symptoms of knee osteoarthritis. In other studies, the effects of adding other specific herbal ingredients to guggul appeared to synergistically enhance the anti-arthritic effects of each ingredient.

Just To Wrap It Up

Why is the combination of different herbal ingredients commonly used for the management of other problems found in a joint health formula? What benefits did these herbs offer that the three wise men already knew about? Imagine the potency that can be achieved by combining guggul with other ingredients like curcumin, piperine, boswellia, guggul, and ashwagandha. In addition, all these herbal preparations have a long history of tolerability and safety and have an interesting beneficial effect on gut health through positive changes in the gut biome (prebiotic and probiotic effects).

Based on what we’ve explored in this newsletter, it is clear that a multicomponent synergistic herbal formula containing curcumin, boswellia, ashwagandha, black pepper and guggul, that has excellent antioxidant, anti-inflammatory, adaptogenic, gut protecting, and analgesic (pain relieving) actions can improve joint health immediately, and over time support long-term healthy joint structure and function.

About Devin Alaric Mikles, MD, FACP

Devin Alaric Mikles, MD, FACP is the recently retired CEO and Medical Director of Choices Integrative Healthcare of Sedona in Arizona, founded in 1998. He is board certified by the American Board of Internal Medicine and is a Fellow of the American College of Physicians. He was a licensed Homeopathic Physician in the state of Arizona. Dr. Mikles has been strongly committed to the development of integrated healthcare delivery systems since 1980. He has been a leader in public and professional health education in his region. Dr. Mikles was a hospice medical director for 20 years and has a deep commitment to assisting others through the transition from this life. He has been a student of multiple other systems of healing since 1969. His integrative medicine practice held a strong focus on prevention, health risk assessment and management, nutritional and functional medicine, chronic disease management, interdisciplinary patient treatment programs and humanism in medicine. His primary vision and goal through the last 25 years has been to assist in the development of new paradigms of healing for our planet. He has been writing poetry, singing and playing music since he was in grade school and has published many of his poems in print journals and online. He has published many health-related articles online since the 1990’s.

References

1. Kunnumakkara AB, Bordoloi D, Padmavathi G, Monisha J, Roy NK1, Prasad S, Aggarwal BB. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol. 2017 Jun; 174(11):1325-1348. Epub 2016 Oct 21.
2. Gao S, Duan X, Wang X, Dong D, Liu D, Li X, Sun G, Li B. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem Toxicol. 2013; 59:739–47.
3. El-Demerdash FM, Yousef MI, Radwan FM. Ameliorating effect of curcumin on sodium arsenite-induced oxidative damage and lipid peroxidation in different rat organs. Food Chem Toxicol. 2009; 47:249–54.
4. Biswas J, Sinha D, Mukherjee S, Roy S, Siddiqi M, Roy M. Curcumin protects DNA damage in a chronically arsenicexposed population of West Bengal. Hum Exp Toxicol. 2010; 29:513–24.
5. Poojan S, Kumar S, Verma V, Dhasmana A, Lohani M, Verma MK. Disruption of Skin Stem Cell Homeostasis following Transplacental Arsenicosis; Alleviation by Combined Intake of Selenium and Curcumin. PLoS One. 2015; 10:e0142818 6. Bhagwat S, Haytowitz DB, Wasswa-Kintu SI, Holden JM. USDA develops a database for Flavonoids to assess dietary intakes. Procedia Food Science. 2013;2:81–6
6. Romagnolo DF, Selmin OI. Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr. 2012;31:206–38. 3.
7. Peterson JJ, Dwyer JT, Jacques PF, McCullough ML. Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. Nutr Rev. 2012;70:491–508. 4.
8. Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer’s disease: the Kame project. Am J Med. 2006;119:751–9. 5.
9. Laurin D, Masaki KH, Foley DJ, White LR, Launer LJ. Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia aging study. Am J Epidemiol. 2004;159:959–67. 6.
10. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, Barberger-Gateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol. 2007;165:1364–71. 7.
11. Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K, Smith AD. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance1-3. J Nutr. 2009;139:120–7. 8.
12. Root M, Ravine E, Harper A. Flavonol intake and cognitive decline in middle-aged adults. J Med Food. 2015;18:1327– 32. 9.
13. Wengreen HJ, Munger RG, Corcoran CD, Zandi P, Hayden KM, Fotuhi M, Skoog I, Norton MC, Tschanz J, Breitner JCS, Welsh-Bohmer KA. Antioxidant intake and cognitive function of elderly men and women: the Cache County study. J Nutr Health Aging. 2007;11:230–7
14. R.W. Kalpravidh, N. Siritanaratkul, P. Insain, R. Charoensakdi, N. Panichkul, S. Hatairaktham, S. Srichairatanakool, C. Phisalaphong, E. Rachmilewitz, S. Fucharoen, Improvement in oxidative stress and antioxidant parameters in betathalassemia/Hb E patients treated with curcuminoids, Clin. Biochem. 43 (2010) 424–429.
15. Huang, X.-M. Zhong, Z.-Y. Li, C.-R. Feng, A.-J. Pan, and Q.-Q. Mao, “Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in rats,” Neuroscience Letters, vol. 493, no. 3, pp. 145– 148, 2011. [70] S.
16. Kulkarni, M. K. Bhutani, and M. Bishnoi, “Antidepressant activity of curcumin: Involvement of serotonin and dopamine system,” Psychopharmacology, vol. 201, no. 3, pp. 435–442, 2008. [71]
17. Sanmukhani, V. Satodia, J. Trivedi et al., “Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial,” Phytotherapy Research, vol. 28, no. 4, pp. 579– 585, 2014. [72]
18. Sahebkar A, Saboni N, Pirro M, Banach M. Curcumin: An effective adjunct in patients with statin-associated muscle symptoms? J Cachexia Sarcopenia Muscle. 2016;8(1):19-24.
19. Bergman, C. Miodownik, Y. Bersudsky et al., “Curcumin as an add-on to antidepressive treatment: a randomized, doubleblind, placebo-controlled, pilot clinical study,” Clinical Neuropharmacology, vol. 36, no. 3, pp. 73–77, 2013.
20. Pandit S., Kim H., Kim J., Jeon J. Separation of an effective fraction from turmeric against Streptococcus mutans biofilms by the comparison of curcuminoid content and anti-acidogenic activity. Food Chem. 2011;126:1565– 1570. [PubMed: 25213928]
21. Paramasivam M., Poi R., Banerjee H., Bandyopadhyay A. High performance thin layer chromatographic method for quantitative determination of curcuminoids in Curcuma longa germplasm. Food Chem. 2009;113:640–644.
22. Chaturvedi T.P. Uses of turmeric in dentistry: an update. Indian J Dent Res. 2009;20:107–109. [PubMed: 19336870]
23. Mukerjee A., Vishwanatha J.K. Formulation, characterization and evaluation of curcumin-loaded PLGA nanospheres for cancer therapy. Anticancer Res. 2009;29:3867–3875. [PubMed: 19846921]
24. Perko T., Ravber M., Knez Z., Skerget M. Isolation, characterization and formulation of curcuminoids and in vitro release study of the encapsulated particles. J Supercrit Fluids. 2015;103:48–54.
25. Kalpravidh R.W., Siritanaratkul N., Insain P. Improvement in oxidative stress and antioxidant parameters in βthalassemia/Hb E patients treated with curcuminoids. Clin Biochem. 2010;43:424–429. [PubMed: 19900435]
26. Changtam C., de Koning H.P., Ibrahim H., Sajid M.S., Gould M.K., Suksamrarn A. Curcuminoid analogs with potent activity against Trypanosoma and Leishmaniaspecies. Eur J Med Chem. 2010;45:941–956. [PubMed: 20004045]
27. Lim H.S., Park S.H., Ghafoor K., Hwang S.Y., Park J. Quality and antioxidantproperties of bread containing turmeric (Curcuma longa L.) cultivated in SouthKorea. Food Chem. 2011;124:1577–1582.
28. Peret-Almeida L., Cherubino A.P.F., Alves R.J., Dufossé L., Glória M.B.A. Separation and determination of the physico-chemical characteristics of curcumin, demethoxy curcumin and bisdemethoxycurcumin. Food Res Int. 2005;38:1039–1044.
29. Khan M.A., El-Khatib R., Rainsford K.D., Whitehouse M.W. Synthesis and anti-inflammatory properties of some aromatic and heterocyclic aromatic curcuminoids. Bioorg Chem. 2012;40:30–38. [PubMed: 22172598]
30. Yue G.G.L., Chan B.C.L., Hon P. Immunostimulatory activities of polysaccharide extract isolated from Curcuma longa. Int J Biol Macromol. 2010;47:342–347.[PubMed: 20609432]
31. Tapal A., Tiku P.K. Complexation of curcumin with soy protein isolate and its implications on solubility and stability of curcumin. Food Chem. 2012;130:960–965.
32. Panahi Y., Saadat A., Beiraghdar F., Nouzari S.M.H., Jalalian H.R., Sahebkar A. Antioxidant effects of bioavailabilityenhanced curcuminoids in patients with solid tumors: a randomized double-blind placebo-controlled trial. J Funct Foods. 2014;6:615–622.
33. Zhan P.Y., Zeng X.H., Zhang H.M., Li H.H. High-efficient column chromatographic extraction of curcumin from Curcuma longa. Food Chem. 2011;129:700–703.
34. Siviero A., Gallo E., Maggini V. Curcumin, a golden spice with a low bioavailability. J Herb Med. 2015;5:57–70. 36. Mahmood K., Zia K.M., Zuber M., Salman M., Anjum M.N. Recent developments in curcumin and curcumin based polymeric materials for biomedical applications: a review. Int J Biol Macromol. 2015;81:877–890. [PubMed: 26391597]
35. Vogel H., Pelletier J. Curcumin-biological and medicinal properties. J Pharma. 1815;2:50.
36. Milobedeska J., Kostanecki S., Lampe V. Structure of curcumin. Ber Dtsch Chem Ges. 1910;43:2163–2170.
37. Lampe V., Milobedeska J. Studien über curcumin. Ber Dtsch Chem Ges. 1913;46:2235–2240.
38. Anderson A.M., Mitchell M.S., Mohan R.S. Isolation of curcumin from turmeric. J Chem Educ. 2000;77:359–360.
39. Bagchi A. Extraction of curcumin. IOSR J Environ Sci Toxicol Food Technol. 2012;1:1–16.
40. Ravindran P.N., Nirmal Babu K., Sivaraman K. CRC Press, Taylor & Francis Group; 2007. Turmeric, the Genus Curcuma; p. 235.
41. Bernabé-Pineda M., Ramírez-Silva M.T., Romero-Romo M., González-Vergara E., Rojas-Hernández A. Determination of acidity constants of curcumin in aqueous solution and apparent rate constant of its decomposition. Spectrochim Acta A Mol Biomol Spectrosc. 2004;60:1091–1097. [PubMed: 15084328]
42. Dohare P., Varma S., Ray M. Curcuma oil modulates the nitric oxide system response to cerebral ischemia/reperfusion injury. Nitric Oxide. 2008;19:1–11.[PubMed: 18485279]
43. Sahoo D.K., Roy A., Chainy G.B.N. Protective effects of vitamin E and curcumin on l-thyroxine-induced rat testicular oxidative stress. Chem Biol Interact. 2008;176:121–128. [PubMed: 18723006]
44. Chen F., Wang H., Xiang X. Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study. J Surg Res. 2014;192:298–304. [PubMed: 25033705]
45. Lopresti A.L., Maes M., Maker G.L., Hood S.D., Drummond P.D. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368–375. [PubMed: 25046624]
46. de Alcantara G.F.T., Simoes-Neto E., da Cruz G.M.P. Curcumin reverses neurochemical, histological and immunohistochemical alterations in the model of global brain ischemia. J Tradit Complement Med. 2016 [PMCID: PMC5198799]
47. Fanaei H., Khayat S., Kasaeian A., Javadimehr M. Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: a randomized, double-blind, placebo-controlled trial. Neuropeptides. 2016;56:25–31. [PubMed: 26608718]
48. Panahi Y., Hosseini M.S., Khalili N., Naimi E., Majeed M., Sahebkar A. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: a randomized controlled trial and an updated meta-analysis. Clin Nutr. 2015;34:1101–1108. [PubMed: 25618800]
49. Jaisin Y., Thampithak A., Meesarapee B. Curcumin I protects the dopaminergic cell line SH-SY5Y from 6hydroxydopamine-induced neurotoxicity through attenuation of p53-mediated apoptosis. Neurosci Lett. 2011;489:192–196. [PubMed: 21167259]
50. Ferreira N., Santos S.A.O., Domingues M.R.M., Saraiva M.J., Almeida M.R. Dietary curcumin counteracts extracellular transthyretin deposition: insights on the mechanism of amyloid inhibition. Biochim Biophys Acta. 2013;1832:39–45. [PubMed: 23069388]
51. Ahmed T., Gilani A. Inhibitory effect of curcuminoids on acetylcholinesterase activity and attenuation of scopolamineinduced amnesia may explain medicinal use of turmeric in Alzheimer’s disease. Pharmacol Biochem Behav. 2009;91:554–559. [PubMed: 18930076]
52. Villaflores O.B., Chen Y., Chen C., Yeh J., Wu T. Effects of curcumin and demethoxycurcumin on amyloid-β precursor and tau proteins through the internal ribosome entry sites: a potential therapeutic for Alzheimer’s disease. Taiwan J Obstet Gynecol. 2012;51:554–564. [PubMed: 23276558]
53. Simon A., Allais D.P., Duroux J.L., Basly J.P., Durand-Fontanier S., Delage C. Inhibitory effect of curcuminoids on MCF-7 cell proliferation and structure-activity relationships. Cancer Lett. 1998;129:111–116. [PubMed: 9714342]
54. Semsri S., Krig S.R., Kotelawala L., Sweeney C.A., Anuchapreeda S. Inhibitory mechanism of pure curcumin on Wilms’ tumor 1 (WT1) gene expression through the PKCα signaling pathway in leukemic K562 cells. FEBS Lett. 2011;585:2235–2242. [PubMed: 21658388]
55. Jiang J., Jin X., Zhang H., Su X., Qiao B., Yuan Y. Identification of antitumor constituents in curcuminoids from Curcuma longa L. based on the composition-activity relationship. J Pharm Biomed Anal. 2012;70:664– 670. [PubMed: 22682511]
56. Xie X., Kong P., Wu J., Li Y., Li Y. Curcumin attenuates lipolysis stimulated by tumor necrosis factor-α or isoproterenol in 3T3-L1 adipocytes. Phytomedicine. 2012;20:3–8. [PubMed: 23083815]
57. Hintzpeter J., Hornung J., Ebert B., Martin H., Maser E. Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase – carbonyl reductase 1. Chem Biol Interact. 2015;234:162–168. [PubMed: 25541467]
58. Jayaprakasha G.K., Rao L.J., Sakariah K.K. Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chem. 2006;98:720–724.
59. Galano A., Álvarez-Diduk R., Ramírez-Silva M.T., Alarcón-Ángeles G., Rojas-Hernández A. Role of the reacting free radicals on the antioxidant mechanism of curcumin. J Chem Phys. 2009;363:13–23.
60. Naik S.R., Thakare V.N., Patil S.R. Protective effect of curcumin on experimentally induced inflammation, hepatotoxicity and cardiotoxicity in rats: evidence of its antioxidant property. Exp Toxicol Pathol. 2011;63:419– 431. [PubMed: 20363603]
61. Dall’Acqua S., Stocchero M., Boschiero I. New findings on the in vivo antioxidant activity of Curcuma longa extract by an integrated 1H NMR and HPLC–MS metabolomic approach. Fitoterapia. 2016;109:125–131. [PubMed: 26712080]
62. Yodkeeree S., Chaiwangyen W., Garbisa S., Limtrakul P. Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA. J Nutr Biochem. 2009;20:87– 95. [PubMed: 18495463] Basile V., Ferrari E., Lazzari S., Belluti S., Pignedoli F., Imbriano C. Curcumin derivatives: molecular basis of their anti-cancer activity. Biochem Pharmacol. 2009;78:1305–1315. [PubMed: 19580791]
63. Yodkeeree S., Ampasavate C., Sung B., Aggarwal B.B., Limtrakul P. Demethoxycurcumin suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur J Pharmacol. 2010;627:8–15. [PubMed: 19818349]
64. Prasad C.P., Rath G., Mathur S., Bhatnagar D., Ralhan R. Expression analysis of maspin in invasive ductal carcinoma of breast and modulation of its expression by curcumin in breast cancer cell lines. Chem Biol Interact. 2010;183:455–461. [PubMed: 19944674]
65. Einbond L.S., Wu H., Kashiwazaki R. Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin. Fitoterapia. 2012;83:1160–1168. [PubMed: 22828666]
66. Lin H., Lin J., Ma J. Demethoxycurcumin induces autophagic and apoptotic responses on breast cancer cells in photodynamic therapy. J Funct Foods. 2015;12:439–449.
67. Ye M., Zhao Y., Li Y. Curcumin reverses cisplatin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1α and caspase-3 mechanisms. Phytomedicine. 2012;19:779–787. [PubMed: 22483553]
68. Hong X.J., Ping Y.H., Dong Z.X., Jing W.H., Liang G., Lan T.C. Autophagy accompanied with bisdemethoxycurcumininduced apoptosis in non-small cell lung cancer cells. Biomed Environ Sci. 2015;28:105–115. [PubMed: 25716561]
69. Hong D., Zeng X., Xu W., Ma J., Tong Y., Chen Y. Altered profiles of gene expression in curcumin-treated rats with experimentally induced myocardial infarction. Pharmacol Res. 2010;61:142–148. [PubMed: 19747544]
70. Bronte E., Coppola G., Miceli R.D., Sucato V., Russo A., Novo S. Role of curcumin in idiopathic pulmonary arterial hypertension treatment: a new therapeutic possibility. Med Hypothes. 2013;81:923–926.
71. Sebastia N., Montoro A., Hervás D. Curcumin and trans-resveratrol exert cell cycle-dependent radioprotective or radiosensitizing effects as elucidated by the PCC and G2-assay. Mutat Res. 2014;766–767:49–55.
72. Patel N., Thakkar V., Moradiya P., Gandhi T., Gohel M. Optimization of curcumin loaded vaginal in-situ hydrogel by box-behnken statistical design for contraception. J Drug Deliv Sci Tec. 2015;29:55–69.
73. Reddy P.S., Begum N., Mutha S., Bakshi V. Beneficial effect of Curcumin in Letrozole induced polycystic ovary syndrome. Asian Pac J Reprod. 2016;5:116–122.
74. Akinyemi A.J., Adedara I.A., Thome G.R. Dietary supplementation of ginger and turmeric improves reproductive function in hypertensive male rats. Toxicol Rep. 2015;2:1357–1366.
75. Hartojo W., Silvers A.L., Thomas D.G. Curcumin promotes apoptosis, increases chemosensitivity, and inhibits nuclear factor κB in esophageal adenocarcinoma. Transl Oncol. 2010;3:99–108. [PubMed: 20360934]
76. Chen D., Shien J., Tiley L. Curcumin inhibits influenza virus infection and haemagglutination activity. Food Chem. 2010;119:1346–1351.
77. Zhang D., Luo J., Yan D., Jin C., Dong X., Xiao X. Effects of two curcuminoids on Candida albicans. Chin Herb Med. 2012;4:205–212. Yue G.G., Kwok H., Lee J.K. Novel anti-angiogenic effects of aromatic turmerone, essential oil isolated from spice turmeric. J Funct Foods. 2015;15:243–253.
78. Yue G.G., Jiang L., Kwok H. Turmeric ethanolic extract possesses stronger inhibitory activities on colon tumour growth than curcumin – the importance of turmerones. J Funct Foods. 2016;22:565–577.
79. Yue G.G.L., Chan B.C.L., Hon P. Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa. Food Chem Toxicol. 2010;48:2011–2020. [PubMed: 20438793]
80. Kim A.N., Jeon W., Lee J.J., Kim B. Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bisdemethoxycurcumin in LPS-stimulated macrophages. Free Radic Biol Med. 2010;49:323–331. [PubMed: 20430097]
81. Yang Y., Wu X., Wei Z. Oral curcumin has anti-arthritic efficacy through somatostatin generation via cAMP/PKA and Ca2+/CaMKII signaling pathways in the small intestine. Pharmacol Res. 2015;95–96:71–81.
82. Aqeel Y., Iqbal J., Siddiqui R., Gilani A.H., Khan N.A. Anti-Acanthamoebic properties of resveratrol and demethoxycurcumin. Exp Parasitol. 2012;132:519–523.[PubMed: 23010569] 87. Vieira I.L., de Souza D.C., da Silva Coelho L., Chen L.C., Guillo L.A. In vitro mutagenicity and blood compatibility of paclitaxel and curcumin in poly (DL-lactide-co-glicolide) films. Toxicol In Vitro. 2013;27:198–203. [PubMed: 23108037]
83. Naik R.S., Mujumdar A.M., Ghaskadbi S. Protection of liver cells from ethanol cytotoxicity by curcumin in liver slice culture in vitro. J Ethnopharmacol. 2004;95:31–37. [PubMed: 15374604]
84. Molina-Jijón E., Tapia E., Zazueta C. Curcumin prevents Cr (VI)-induced renal oxidant damage by a mitochondrial pathway. Free Radic Biol Med. 2011;51:1543–1557. [PubMed: 21839166]
85. Balaji B., Balakrishnan B., Perumalla S., Karande A.A., Chakravarty A.R. Photoactivated cytotoxicity of ferrocenylterpyridine oxovanadium (IV) complexes of curcuminoids. Eur J Med Chem. 2014;85:458–467. [PubMed: 25113874] 91. Lei X., Su W., Li P. Ruthenium(II) arene complexes of curcuminoids: synthesis, X-ray diffraction structure and cytotoxicity. Polyhedron. 2014;81:614–618.
86. Goswami T.K., Gadadhar S., Gole B., Karande A.A., Chakravarty A.R. Photocytotoxicity of copper (II) complexes of curcumin and N-ferrocenylmethyl-L-amino acids. Eur J Med Chem. 2013;63:800–810. [PubMed: 23584543]
87. Vajragupta O., Boonchoong P., Watanabe H., Tohda M., Kummasud N., Sumanont Y. Manganese complexes of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity. Free Radic Biol Med. 2003;35:1632–1644. [PubMed: 14680686]
88. Ferrari E., Benassi R., Sacchi S., Pignedoli F., Asti M., Saladini M. Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications. J Inorg Biochem. 2014;139:38–48. [PubMed: 24968097]
89. Barik A., Mishra B., Kunwa A. Comparative study of copper(II)-curcumin complexes as superoxide dismutase mimics and free radical scavengers. Eur J Med Chem. 2007;42:431–439. [PubMed: 17240482]
90. Mohammadi K., Thompson K.H., Patrick B.O. Synthesis and characterization of dual function vanadyl, gallium and indium curcumin complexes for medicinal applications. J Inorg Biochem. 2005;99:2217–2225. [PubMed: 16171869]
91. Sarkar T., Butcher R.J., Banerjee S., Mukherjee S., Hussain A. Visible light-induced cytotoxicity of a dinuclear iron (III) complex of curcumin with low-micromolar IC50 value in cancer cells. Inorg Chim Acta. 2016;439:8–17.
92. Thompson K.H., Bohmerle K., Polishchuk E. Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone. J Inorg Biochem. 2004;98:2063–2070. [PubMed: 15541495]
93. Chandrasekar T., Pravin N., Raman N. Biosensitive metal chelates from curcumin analogues: DNA unwinding and anti-microbial evaluation. Inorg Chem Commun. 2014;43:45–50.
94. Bansal S.S., Kausar H., Vadhanam M.V., Ravoori S., Gupta R.C. Controlled systemic delivery by polymeric implants enhances tissue and plasma curcumin levels compared with oral administration. Eur J Pharm Biopharm. 2012;80:571–577. [PubMed: 22227368]
95. Li M., Cui J., Ngadi M.O., Ma Y. Absorption mechanism of whey-protein-delivered curcumin using Caco-2 cell monolayers. Food Chem. 2015;180:48–54.[PubMed: 25766800]Chopra D., Ray L., Dwivedi A. Photoprotective efficiency of PLGA-curcumin nanoparticles versus curcumin through the involvement of ERK/AKT pathway under ambient UV-R exposure in HaCaT cell line. Biomaterials. 2016;84:25–41. [PubMed: 26803409]
96. Manju S., Sreenivasan K. Gold nanoparticles generated and stabilized by water soluble curcumin-polymer conjugate: blood compatibility evaluation and targeted drug delivery onto cancer cells. J Colloid Interf. 2012;368:144– 151.
97. Pereira A.G.B., Fajardo A.R., Nocchi S., Nakamura C.V., Rubira A.F., Muniz E.C. Starch-based microspheres for sustained-release of curcumin: preparation and cytotoxic effect on tumor cells. Carbohydr Polym. 2013;98:711– 720. [PubMed: 23987403]
98. Hasan M., Belhaj N., Benachour H. Liposome encapsulation of curcumin: physico-chemical characterizations and effects on MCF7 cancer cell proliferation. Int J Pharm. 2014;461:519–528. [PubMed: 24355620]
99. Yang L., Gao S., Asghar S. Hyaluronic acid/chitosan nanoparticles for delivery of curcuminoid and its in vitro evaluation in glioma cells. Int J Biol Macromol. 2015;72:1391–1401. [PubMed: 25450553]
100. Mulik R.S., Mönkkönen J., Juvonen R.O., Mahadik K.R., Paradkar A.R. Transferrin mediated solid lipid nanoparticles containing curcumin: enhanced in vitro anticancer activity by induction of apoptosis. Int J Pharm. 2010;398:190–203. [PubMed: 20655375]
101. Ganta S., Devalapally H., Amiji M. Curcumin enhances oral bioavailability and anti-tumor therapeutic efficacy of paclitaxel upon administration in nanoemulsion formulation. J Pharm Sci. 2010;99:4630–4641. [PubMed: 20845461]
102. Plyduang T., Lomlim L., Yuenyongsawad S., Wiwattanapatapee R. Carboxymethylcellulose–tetrahydrocurcumin conjugates for colon-specific delivery of a novel anti-cancer agent, 4-amino tetrahydrocurcumin. Eur J Pharm Biopharm. 2014;88:351–360. [PubMed: 24859389]
103. Subramanian S.B., Francis A.P., Devasena T. Chitosan-starch nanocomposite particles as a drug carrier for the delivery of bis-desmethoxy curcumin analog. Carbohydr Polym. 2014;114:170–178. [PubMed: 25263878]
104. Gopi S., George R., Sriraam V.T. Cell culture study on the effects of “cureit” – a novel bio available curcumin on hyaluronidase inhibition – anti aging effects. Int J Curr Res. 2014;6:8473–8474.
105. Gopi S., George R., Jude S., Sriraam V.T. Cell culture study on the cytotoxic effects of “Cureit” – a novel bio available curcumin-anti cancer effects. J Chem Pharm Res. 2014;6:96–100.
106. Gopi S., George R., Sriraam V.T. Cell culture study on the effect of bio available curcumin – “cureit” on elastase inhibition activity. Br Biomed Bull. 2014;2:545–549.
107. Patil S., Choudhary B., Rathore A., Roy K., Mahadik K. Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells. Phytomedicine. 2015;22:1103–1111. [PubMed: 26547533]
108. Suwannateep N., Wanichwecharungruang S., Haag S.F. Encapsulated curcumin results in prolonged curcumin activity in vitro and radical scavenging activity ex vivo on skin after UVB-irradiation. Eur J Pharm Biopharm. 2012;82:485–490. [PubMed: 22954772]
109. Malik P., Ameta R.K., Singh M. Preparation and characterization of bionanoemulsions for improving and modulating the antioxidant efficacy of natural phenolic antioxidant curcumin. Chem Biol Interact. 2014;222:77– 86. [PubMed: 25110318]
110. Portes E., Gardrat C., Castellan A., Coma V. Environmentally friendly films based on chitosan and tetrahydrocurcuminoid derivatives exhibiting antibacterial and antioxidative properties. Carbohydr Polym. 2009;76:578–584.
111. Tovsen M.L., Bruzell E., Ferrari E. Antibacterial phototoxic effects of synthetic asymmetric and glycosylated curcuminoids in aqueous formulations studies on curcumin and curcuminoids. LIV. J Photochem Photobiol B. 2014;140:150–156. [PubMed: 25129700]
112. Kakkar V., Kaur I.P. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol. 2011;49:2906– 2913. [PubMed: 21889563]
113. Kakkar V., Muppu S.K., Chopra K., Kaur I.P. Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur J Pharm Biopharm. 2013;85:339–345. [PubMed: 23454202]
114. Puglia C., Frasca G., Musumeci T. Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice. Eur J Pharm Biopharm. 2012;81:288–293. [PubMed: 22504443]
115. Mayadevi M., Sherin D.R., Keerthi V.S., Rajasekharan K.N., Omkumar R.V. Curcumin is an inhibitor of calcium/calmodulin dependent protein kinase II. Bioorg Med Chem. 2012;20:6040–6047. [PubMed: 22989913]
116. Takikawa M., Kurimoto Y., Tsuda T. Curcumin stimulates glucagon-like peptide-1 secretion in GLUTag cells via Ca2+/calmodulin-dependent kinase II activation. Biochem Biophys Res Commun. 2013;435:165–170. [PubMed: 23660191]
117. Arunkhamkaew S., Athipornchai A., Apiratikul N., Suksamrarn A., Ajavakom V. Novel racemic tetrahydrocurcuminoid dihydropyrimidinone analogues as potent acetylcholinesterase inhibitors. Bioorg Med Chem Lett. 2013;23:2880–2882. [PubMed: 23583510]
118. Campos C.A., Gianino J.B., Bailey B.J. Design, synthesis, and evaluation of curcumin-derived arylheptanoids for glioblastoma and neuroblastoma cytotoxicity. Bioorg Med Chem Lett. 2013;23:6874–6878. [PubMed: 24183537]
119. Hagl S., Kocher A., Schiborr C., Kolesova N., Frank J., Eckert G.P. Curcumin micelles improve mitochondrial function in neuronal PC12 cells and brains of NMRI mice – impact on bioavailability. Neurochem Int. 2015;89:234– 242. [PubMed: 26254982]
120. Kim T., Davis J., Zhang A.J., He X., Mathews S.T. Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. Biochem Biophys Res Commun. 2009;388:377–382. [PubMed: 19665995]
121. Nayak A.P., Tiyaboonchai W., Patankar S., Madhusudhan B., Souto E.B. Curcuminoids-loaded lipid nanoparticles: novel approach towards malaria treatment. Colloids Surf B. 2010;81:263–273.
122. Ferrari E., Lazzari S., Marverti G., Pignedoli F., Spagnolo F., Saladini M. Synthesis, cytotoxic and combined cDDP activity of new stable curcumin derivatives. Bioorg Med Chem. 2009;17:3043–3052. [PubMed: 19329324]
123. Zhang Q., Zhong Y., Yan L., Sun X., Gong T., Zhang Z. Synthesis and preliminary evaluation of curcumin analogues as cytotoxic agents. Bioorg Med Chem Lett. 2011;21:1010–1014. [PubMed: 21215629]
124. Shi Q., Wada K., Ohkoshi E. Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens. Bioorg Med Chem. 2012;20:4020– 4031. [PubMed: 22672984]
125. Caprioglio D., Torretta S., Ferrari M. Triazole-curcuminoids: a new class of derivatives for ‘tuning’ curcumin bioactivities? Bioorg Med Chem. 2016;24:140–152.[PubMed: 26705144]
126. Claramunt R.M., Bouissane L., Cabildo M.P. Synthesis and biological evaluation of curcuminoid pyrazoles as new therapeutic agents in inflammatory bowel disease: effect on matrix metalloproteinases. Bioorg Med Chem. 2009;17:1290–1296. [PubMed: 19128977]
127. Tham C.L., Lie C.Y., Lam K.W. A synthetic curcuminoid derivative inhibits nitric oxide and proinflammatory cytokine synthesis. Eur J Pharmacol. 2010;628:247–254. [PubMed: 19958764]
128. Nieto C.I., Cabildo M.P., Cornago M.P. Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1Hpyrazoles derived from hemicurcuminoids. J Mol Struct. 2015;1100:518–529.
129. Sribalan R., Kirubavathi M., Banuppriya G., Padmini V. Synthesis and biological evaluation of new symmetric curcumin derivatives. Bioorg Med Chem Lett. 2015;25:4282–4286. [PubMed: 26264500]
130. Banuppriya G., Sribalan R., Padmini V., Shanmugaiah V. Biological evaluation and molecular docking studies of new curcuminoid derivatives: synthesis and characterization. Bioorg Med Chem Lett. 2016;26:1655–1659. [PubMed: 26944612]
131. Changtam C., Hongmanee P., Suksamrarn A. Isoxazole analogs of curcuminoids with highly potent multidrugresistant antimycobacterial activity. Eur J Med Chem. 2010;45:4446–4457. [PubMed: 20691508]
132. Lal J., Gupta S.K., Thavaselvam D., Agarwal D.D. Biological activity, design, synthesis and structure activity relationship of some novel derivatives of curcumin containing sulfonamides. Eur J Med Chem. 2013;64:579– 588. [PubMed: 23685942]
133. Sanabria-Rios D.J., Rivera-Torres Y., Rosario J. Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria. Bioorg Med Chem Lett. 2015;25:5067– 5071. [PubMed: 26483137]
134. Hahm E., Cheon G., Lee J., Kim B., Park C., Yang C. New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex. Cancer Lett. 2002;184:89–96. [PubMed: 12104052]
135. Adams B.K., Ferstl E.M., Davis M.C. Synthesis and biological evaluation of novel curcumin analogs as anticancer and anti-angiogenesis agents. Bioorg Med Chem. 2004;12:3871–3883. [PubMed: 15210154]
136. Youssef D., Nichols C.E., Cameron T.S., Balzarini J., Clercqd E.D., Jha A. Design, synthesis, and cytostatic activity of novel cyclic curcumin analogues. Bioorg Med Chem Lett. 2007;17:5624–5629. [PubMed: 17768050]
137. Wei X., Du Z., Zheng X., Cui X., Conney A.H., Zhang K. Synthesis and evaluation of curcumin-related compounds for anticancer activity. Eur J Med Chem. 2012;53:235–245. [PubMed: 22551677]
138. Sanabria-Rios D.J., Rivera-Torres Y., Rosario J. Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity. Bioorg Med Chem Lett. 2015;25:2174–2180. [PubMed: 25881826]
139. Youssef K.M., Ezzo A.M., El-Sayed M.I., Hazzaa A.A., EL-Medany A.H., Arafa M. Chemopreventive effects of curcumin analogs in DMH-Induced colon cancer in albino rats model. Future J Pharm Sci. 2015;1:57–72.
140. Leow P., Bahety P., Boon C.P. Functionalized curcumin analogs as potent modulator of the Wnt/β-catenin signaling pathway. Eur J Med Chem. 2014;71:67–80.[PubMed: 24275249]
141. Venkateswarlu S., Ramachandra M.S., Subbaraju G.V. Synthesis and biological evaluation of polyhydroxycurcuminoids. Bioorg Med Chem. 2005;13:6374–6380.[PubMed: 16112582]
142. Chen C., Johnston T.D., Jeon H. An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells. Int J Pharm. 2009;366:133–139. [PubMed: 18840516]
143. Parvathy K.S., Negi P.S., Srinivas P. Curcumin–amino acid conjugates: synthesis, antioxidant and antimutagenic attributes. Food Chem. 2010;120:523–530.
144. Li P., Liu Z. Ferrocenyl-substituted curcumin: can it influence antioxidant ability to protect DNA? Eur J Med Chem. 2011;46:1821–1826. [PubMed: 21388716]
145. Sahu P.K., Sahu P.K., Sahu P.L., Agarwal D.D. Structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives. Bioorg Med Chem Lett. 2016;26:1342–1347. [PubMed: 26810315]
146. Qiu X., Liu Z., Shao W. Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors. Bioorg Med Chem. 2008;16:8035–8041.[PubMed: 18678491] 153. Han Y., Shin D., Lee Y. 2-Hydroxycurcuminoid induces apoptosis of human tumor cells through the reactive oxygen species–mitochondria pathway. Bioorg Med Chem Lett. 2011;21:747–751. [PubMed: 21183341]
147. Yuan X., Li H., Bai H. Synthesis of novel curcumin analogues for inhibition of 11β-hydroxysteroid dehydrogenase type 1 with anti-diabetic properties. Eur J Med Chem. 2014;77:223–230. [PubMed: 24642565]
148. Park C., Ahn C.M., Oh S. Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin mimics as dual antagonist of L-type Ca2+ channel and endothelin A/B2 receptor. Bioorg Med Chem. 2015;23:6673–6682. [PubMed: 26386817]
149. Srinivasan M., Sudheer A.R., Rajasekaran K.N., Menon V.P. Effect of curcumin analog on γ-radiation-induced cellular changes in primary culture of isolated rat hepatocytes in vitro. Chem Biol Interact. 2008;176:1–8. [PubMed: 18597748]
150. Baldwin P.R., Reeves A.Z., Powell K.R. Monocarbonyl analogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis. Eur J Med Chem. 2015;92:693–699. [PubMed: 25618016]
151. Devasena T., Rajasekaran K.N., Gunasekaran G., Viswanathan P., Menon V.P. Anticarcinogenic effect of bis-1,7(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione a curcumin analog on DMH-induced colon cancer model. Pharmacol Res. 2003;47:133–140. [PubMed: 12543061]
152. Shishu, Kaur I.P. Antimutagenicity of curcumin and related compounds against genotoxic heterocyclic amines from cooked food: the structural requirement. Food Chem. 2008;111:573–579.
153. Lin C., Lin H., Chen H., Yu M., Lee M. Stability and characterisation of phospholipid-based curcuminencapsulated microemulsions. Food Chem. 2009;116:923–928.
154. Ponnusamy S., Zinjarde S., Bhargava S., Rajamohanan P.R., RaviKumar A. Discovering bisdemethoxycurcumin from Curcuma longa rhizome as a potent small molecule inhibitor of human pancreatic a-amylase, a target for type-2 diabetes. Food Chem. 2012;135:2638–2642. [PubMed: 22980852]
155. Martins R.M., Pereira S.V., Siqueira S., Salomao W.F., Freitas L.A.P. Curcuminoid content and antioxidant activity in spray dried microparticles containing turmeric extract. Food Res Int. 2013;50:657–663.
156. Bergonzi M.C., Hamdouch R., Mazzacuva F., Isacchi B., Bilia A.R. Optimization, characterization and in vitro evaluation of curcumin microemulsions. LWT. 2014;59:148–155.
157. Fu S., Augustin M.A., Shen Z., Ng K., Sanguansri L., Ajlouni S. Bioaccessibility of curcuminoids in buttermilk in simulated gastrointestinal digestion models. Food Chem. 2015;179:52–59. [PubMed: 25722138]
158. Laokuldilok N., Thakeow P., Kopermsub P., Utama-ang N. Optimisation of microencapsulation of turmeric extract for masking flavor. Food Chem. 2016;194:695–704. [PubMed: 26471609]
159. Borrin T.R., Georges E.L., Moraes I.C.F., Pinho S.C. Curcumin-loaded nanoemulsions produced by the emulsion inversion point (EIP) method: an evaluation of process parameters and physicochemical stability. J Food Eng. 2016;169:1–9.
160. Hewlings SJ, Kalman DS. Curcumin: A Review of Its’ Effects on Human Health. Foods. 2017;6(10):92. Published 2017 Oct 22. doi:10.3390/foods6100092.
162. Mazzanti G, Di Giacomo S. Curcumin and Resveratrol in the Management of Cognitive Disorders: What is the Clinical Evidence? Molecules. 2016;21(9):1243. Published 2016 Sep 17. doi:10.3390/molecules21091243.
163. Kim Y, Clifton P. Curcumin, Cardiometabolic Health and Dementia. Int J Environ Res Public Health. 2018;15(10):2093. Published 2018 Sep 24. doi:10.3390/ijerph15102093.
164. Siviero A., Gallo E., Maggini V. Curcumin, a golden spice with a low bioavailability. J Herb Med. 2015;5:57–70.
165. Han HK. The effects of black pepper on the intestinal absorption and hepatic metabolism of drugs. Expert Opin Drug Metab Toxicol. 2011 Jun;7(6):721-9. doi: 10.1517/17425255.2011.570332. Epub 2011 Mar 24.
166. Dudhatra GB, Mody SK, Awale MM, et al. A comprehensive review on pharmacotherapeutics of herbal bioenhancers. ScientificWorldJournal. 2012;2012:637953.
167. Kesarwani K, Gupta R, Mukerjee A. Bioavailability enhancers of herbal origin: an overview. Asian Pac J Trop Biomed. 2013;3(4):253-66.
168. Atal CK, Zutshi U, Rao PG. Scientific evidence on the role of Ayurvedic herbals on bioavailability of drugs. J Ethnopharmacol. 1981 Sep;4(2):229-32.
169. Atal S, Atal S, Vyas S, Phadnis P. Bio-enhancing Effect of Piperine with Metformin on Lowering Blood Glucose Level in Alloxan Induced Diabetic Mice. Pharmacognosy Res. 2016;8(1):56-60.
170. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998 May;64(4):353-6. PMID: 9619120 DOI: 10.1055/s-2006-957450.
171. Chavarria D, Silva T, et al. Lessons from black pepper: piperine and derivatives thereof, Expert Opinion on Therapeutic Patents, (2016) 26:2, 245-264, DOI: 10.1517/13543776.2016.1118057.
172. Peterson CT, Vaughn AR, Sharma V, et al. Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. J Evid Based Integr Med. 2018;23:2515690X18790725.
173. Panahi Y, Khalili N, Hosseini MS, Abbasinazari M, Sahebkar A. Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: results of a randomized controlled trial. Complement Ther Med. 2014 Oct;22(5):851-7. doi: 10.1016/j.ctim.2014.07.006. Epub 2014 Jul 22.
174. Monograph, Black Pepper. Natural Medicines Comprehensive Database. Accessed online 3.13.2019. NMCD
175. Dragos D, Gilca M, Gaman L, et al. Phytomedicine in Joint Disorders. Nutrients. 2017;9(1):70. Published 2017 Jan 16. doi:10.3390/nu9010070.
176. Beghelli D et al. Antioxidant and Ex Vivo Immune System Regulatory Properties of Boswellia serrata Extracts. Oxid Med Cell Longev. 2017;2017:7468064.
177. Ernst E. Frankincense: systematic review. BMJ. 2008;337:a2813. Published 2008 Dec 17. doi:10.1136/bmj.a2813.
178. Catanzaro D et al. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage. PLoS One. 2015;10(5):e0125375. Published 2015 May 8. doi:10.1371/journal.pone.0125375.
179. Siddiqui MK. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011;73(3):255-61.
180. Cameron M, Chrubasik S. Oral herbal therapies for treating osteoarthritis. Cochrane Database Syst Rev.2014;5(5):CD002947. Published 2014 May 22. doi:10.1002/14651858.CD002947.pub2.
181. Grover AK, Samson SE. Benefits of antioxidant supplements for knee osteoarthritis: rationale and reality. Nutr J. 2016;15:1. Published 2016 Jan 5. doi:10.1186/s12937-015-0115-z.
182. Nieman DC, Shanely RA, Luo B, Dew D, Meaney MP, Sha W. A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial. Nutr J. 2013;12(1):154. Published 2013 Nov 25. doi:10.1186/1475 2891-12-154.
183. Sengupta K, Alluri KV, Satish AR, et al. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10(4):R85.
184. Sengupta K, Krishnaraju AV, Vishal AA, et al. Comparative efficacy and tolerability of 5-Loxin and AflapinAgainst osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci. 2010;7(6):366-77. Published 2010 Nov 1.
185. Lampl C, Haider B, Schweiger C. Long-term efficacy of Boswellia serrata in 4 patients with chronic cluster headache. J Headache Pain. 2013;14(Suppl 1):P37.
186. Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis. Br J Sports Med. 2018 Feb;52(3):167-175. doi: 10.1136/bjsports-2016-097333. Epub 2017 Oct 10.
187. Nieman DC, Shanely RA, Luo B, Dew D, Meaney MP, Sha W. A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial. Nutr J. 2013;12(1):154. Published 2013 Nov 25. doi:10.1186/1475-2891-12-154.
188. Kimmatkar N, Thawani V, Hingorani L, Khiyani R.Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – A randomized double blind placebo controlled trial. Phytomedicine 10(1), 2003, Pages 3-7, ISSN 0944-7113. https://doi.org/10.1078/094471103321648593.
189. Kunnumakkara AB, Banik K, Bordoloi D, et al. Googling the Guggul (Commiphora and Boswellia) for Prevention of Chronic Diseases. Front Pharmacol. 2018;9:686. Published 2018 Aug 6. doi:10.3389/fphar.2018.00686.
190. Togni S, Maramaldi G, Di Pierro F, Biondi M. A cosmeceutical formulation based on boswellic acids for the treatment of erythematous eczema and psoriasis. Clin Cosmet Investig Dermatol. 2014;7:321-7. Published 2014 Nov 11. doi:10.2147/CCID.S69240.
191. Vishal AA, Mishra A, Raychaudhuri SP. A double blind, randomized, placebo controlled clinical study evaluates the early efficacy of aflapin in subjects with osteoarthritis of knee. Int J Med Sci. 2011;8(7):615-22.
192. Prabhabathi K et al. A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model. Indian J Pharmacol. 2014;46(5):475-9.
193. Kulkarni RR, Patki PS, Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol 1991;33:91-95.
194. Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R. A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of withania somnifera. Indian J Psychiatry. 2000 Jul;42(3):295-301.
195. Choudhary B, Shetty A, Langade DG. Efficacy of Ashwagandha (Withania somnifera [L.] Dunal) in improving cardiorespiratory endurance in healthy athletic adults. Ayu. 2015 Jan-Mar;36(1):63-8. doi: 10.4103/0974-8520.169002.
196. Chandran U, Patwardhan B. Network ethnopharmacological evaluation of the immunomodulatory activity of Withania somnifera. J Ethnopharmacol. 2017 Feb 2;197:250-256. doi: 10.1016/j.jep.2016.07.080. Epub 2016 Jul 31.
197. Gannon JM, Forrest PE, Roy Chengappa KN. Subtle changes in thyroid indices during a placebocontrolled study of an extract of Withania somnifera in persons with bipolar disorder. J Ayurveda Integr Med. 2014 Oct-Dec;5(4):241-5. doi: 10.4103/0975-9476.146566.
198. Gautam A, Wadhwa R, Thakur MK. Assessment of Cholinergic Properties of Ashwagandha LeafExtract in the Amnesic Mouse Brain. Ann Neurosci. 2016 Jul;23(2):68-75. doi: 10.1159/000443573. Epub 2016 Jul 7.
199. Gupta M, Kaur G. Aqueous extract from the Withania somnifera leaves as a potential antineuroinflammatory agent: a mechanistic study. J Neuroinflammation. 2016 Aug 22;13(1):193. doi: 10.1186/s12974-016-0650-3.
200. Jahanbakhsh SP, Manteghi AA, Emami SA, Mahyari S, Gholampour B, Mohammadpour AH, Sahebkar A. Evaluation of the efficacy of Withania somnifera (Ashwagandha) root extract in patients with obsessive-compulsive disorder: A randomized double-blind placebo-controlled trial. Complement Ther Med. 2016 Aug;27:25-9. doi: 10.1016/j.ctim.2016.03.018. Epub 2016 Apr 9.
201. Jansen RL, Brogan B, Whitworth AJ, Okello EJ. Effects of five Ayurvedic herbs on locomotor behaviour in a Drosophila melanogaster Parkinson’s disease model. Phytother Res. 2014 Dec;28(12):1789-95. doi: 10.1002/ptr.5199. Epub 2014 Aug 4.
202. Kaushik MK, Kaul SC, Wadhwa R, Yanagisawa M, Urade Y. Triethylene glycol, an active component of Ashwagandha (Withania somnifera) leaves, is responsible for sleep induction. PLoS One. 2017 Feb 16;12(2):e0172508. doi: 10.1371/journal.pone.0172508. eCollection 2017.
203. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK. Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One. 2011;6(11):e27265. doi: 10.1371/journal.pone.0027265. Epub 2011 Nov 11.
204. Kumar G, Patnaik R. Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study. Med Hypotheses. 2016 Jul;92:35-43. doi: 10.1016/j.mehy.2016.04.034. Epub 2016 Apr 20.
205. Patel SB, Rao NJ, Hingorani LL. Safety assessment of Withania somnifera extract standardized for Withaferin A: Acute and sub-acute toxicity study. J Ayurveda Integr Med. 2016 Mar;7(1):30-7. doi: 10.1016/j.jaim.2015.08.001. Epub 2016 May 24.
206. Pathak-Gandhi N, Vaidya AD. Management of Parkinson’s disease in Ayurveda: Medicinal plants and adjuvant measures. J Ethnopharmacol. 2017 Feb 2;197:46-51. doi: 10.1016/j.jep.2016.08.020. Epub 2016 Aug 17.
207. Pratte MA, Nanavati KB, Young V, Morley CP. An alternative treatment for anxiety: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withania somnifera). J Altern Complement Med. 2014 Dec;20(12):901-8. doi: 10.1089/acm.2014.0177.
208. Ramakanth GS, Uday Kumar C, Kishan PV, Usharani P. A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina somnifera extracts in knee joint pain. J Ayurveda Integr Med. 2016 Jul - Sep;7(3):151-157. doi10.1016/j.jaim.2016.05.003. Epub 2016 Sep 16.
209. Ramakanth GS, Uday Kumar C, Kishan PV, Usharani P. A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina somnifera extracts in knee joint pain. J Ayurveda Integr Med. 2016 Jul - Sep;7(3):151-157. doi: 10.1016/j.jaim.2016.05.003. Epub 2016 Sep 16.
210. Saha S, Islam MK, Shilpi JA, Hasan S. Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera’s key metabolite Withaferin A. In Silico Pharmacol. 2013 Jul 29;1:11. doi: 10.1186/2193-9616-1-11. eCollection 2013.
211. Saikat Sen, Raja Chakraborty. Revival, modernization and integration of Indian traditional herbal medicine in clinical practice: Importance, challenges and future. J Tradit Complement Med. 2017 Apr; 7(2): 234–244. Published online 2016 Jun 28. doi: 10.1016/j.jtcme.2016.05.006 PMCID: PMC5388083.
212. Samadi Noshahr Z, Shahraki MR, Ahmadvand H, Nourabadi D, Nakhaei A. Protective effects of Withania somnifera root on inflammatory markers and insulin resistance in fructose-fed rats. Rep Biochem Mol Biol. 2015 Apr;3(2):62-7.
213. Sandhu JS, Shah B, Shenoy S, Chauhan S, Lavekar GS, Padhi MM. Effects of Withania somnifera (Ashwagandha) and Terminalia arjuna (Arjuna) on physical performance and cardiorespiratory endurance in healthy young adults. Int J Ayurveda Res. 2010 Jul;1(3):144-9. doi: 10.4103/09747788.72485.
214. Sarbishegi M, Heidari Z, Mahmoudzadeh-Sagheb H, Valizadeh M, Doostkami M. Neuroprotective effects of Withania coagulans root extract on CA1 hippocampus following cerebral ischemia in rats. Avicenna J Phytomed. 2016 Jul-Aug;6(4):399-409.
215. Saykally JN, Hatic H, Keeley KL, Jain SC, Ravindranath V, Citron BA. Withania somnifera Extract Protects Model Neurons from In Vitro Traumatic Injury. Cell Transplant. 2017 Jul;26(7):1193-1201. doi: 10.1177/0963689717714320.
216. Sharma AK, Basu I, Singh S. Efficacy and Safety of Ashwagandha Root Extract in Subclinical Hypothyroid Patients: A Double-Blind, Randomized Placebo-Controlled Trial. J Altern Complement Med. 2018 Mar;24(3):243-248. doi: 10.1089/acm.2017.0183. Epub 2017 Aug 22.
217. Shenoy S, Chaskar U, Sandhu JS, Paadhi MM. Effects of eight-week supplementation of Ashwagandha on cardiorespiratory endurance in elite Indian cyclists. J Ayurveda Integr Med. 2012 Oct;3(4):209-14. doi: 10.4103/0975-9476.104444.
218. Shukla SD, Bhatnagar M, Khurana S. Critical evaluation of ayurvedic plants for stimulating intrinsic antioxidant response. Front Neurosci. 2012 Jul 26;6:112. doi: 10.3389/fnins.2012.00112. eCollection 2012.
219. Singh G, Tiwari M, Singh SP, Singh S, Trivedi PK, Misra P. Silencing of sterol glycosyltransferases modulates the withanolide biosynthesis and leads to compromised basal immunity of Withania somnifera. Sci Rep. 2016 May 5;6:25562. doi:10.1038/srep25562.
220. Srivastav S, Fatima M, Mondal AC. Important medicinal herbs in Parkinson’s disease pharmacotherapy. Biomed Pharmacother. 2017 Aug;92:856-863. doi: 10.1016/j.biopha.2017.05.137. Epub 2017 Jun 6.
221. Srivastava P, Yadav RS. Efficacy of Natural Compounds in Neurodegenerative Disorders. Adv Neurobiol. 2016;12:107-23. doi: 10.1007/978-3-319-28383-8_7.
222. Vedi M, Rasool M, Sabina EP. Amelioration of bromobenzene hepatotoxicity by Withania somnifera pretreatment: Role of mitochondrial oxidative stress. oxicol Rep. 2014 Aug 27;1:629-638. doi: 10.1016/j.toxrep.2014.08.009. eCollection 2014.
223. Wankhede S, Langade D, Joshi K, Sinha SR, Bhattacharyya S. Examining the effect of Withania somnifera supplementation on muscle strength and recovery: a randomized controlled trial. J Int Soc Sports Nutr. 2015 Nov 25;12:43. doi: 10.1186/s12970-015-0104-9. eCollection 2015.
224. Ziegenfuss TN, Kedia AW, Sandrock JE, Raub BJ, Kerksick CM, Lopez HL. Effects of an Aqueous Extract of Withania somnifera on Strength Training Adaptations and Recovery: The STAR Trial. Nutrients. 2018 Nov 20;10(11). pii: E1807. doi: 10.3390/nu10111807.
225. Santana-Gálvez J, Cisneros-Zevallos L, Jacobo-Velázquez DA. Chlorogenic Acid: Recent Advances on Its Dual Role as a Food Additive and a Nutraceutical against Metabolic Syndrome. Molecules. 2017;22(3):358. Published 2017 Feb 26. doi:10.3390/molecules22030358.
226. Shokoohi R, Kianbakht S, Faramarzi M, et al. Effects of an Herbal Combination on Glycemic Control and Lipid Profile in Diabetic Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Evid Based Complementary Altern Med. 2017;22(4):798-804.
227. Das S, Datta A, Bagchi C, Chakraborty S, Mitra A, Tripathi SK. A Comparative Study of LipidLowering Effects of Guggul and Atorvastatin Monotherapy in Comparison to Their Combination in High Cholesterol Diet-Induced Hyperlipidemia in Rabbits. J Diet Suppl. 2016;13(5):495-504. doi: 10.3109/19390211.2015.1118654. Epub 2016 Jan 6.
228. Yamada T, Sugimoto K. Guggulsterone and Its Role in Chronic Diseases. Adv Exp Med Biol. 2016;929:329-361.
229. Shishodia S, Harikumar KB, Dass S, Ramawat KG, Aggarwal BB. The guggul for chronic diseases: ancient medicine, modern targets. Anticancer Res. 2008 Nov-Dec;28(6A):3647-64.
230. Nuzzo D, Amato A, Picone P, et al. A Natural Dietary Supplement with a Combination of Nutrients Prevents Neurodegeneration Induced by a High Fat Diet in Mice. Nutrients. 2018;10(9):1130. Published 2018 Aug 21. doi:10.3390/nu10091130. 71. Farooqui AA, Farooqui T, Madan A, Ong JH, Ong WY. Ayurvedic Medicine for the Treatment of Dementia: Mechanistic Aspects. Evid Based Complement Alternat Med. 2018;2018:2481076. Published 2018 May 15. doi:10.1155/2018/2481076.
231. Kamble , Sathaye S, Shah DP. Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process. Indian J Pharm Sci. 2008 May-Jun;70(3):368-72. doi: 10.4103/0250-474X.43005.
232. Chopra A, Saluja M, Kianifard T, Chitre D, Venugopalan A. Long term effectiveness of RA-1 as a monotherapy and in combination with disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis. J Ayurveda Integr Med. 2018;9(3):201-208.
233. Shah R, Gulati V, Palombo EA. Pharmacological properties of guggulsterones, the major active components of gum guggul. Phytother Res. 2012 Nov;26(11):1594-605. doi: 10.1002/ptr.4647. Epub 2012 Mar 3.
234. Sarup P, Bala S, Kamboj S. Pharmacology and Phytochemistry of Oleo-Gum Resin of Commiphora wightii (Guggulu). Scientifica (Cairo). 2015;2015:138039.
235. Sharma AV, Dudhamal TS, Gupta SK, Mahanta V. Clinical study of Agnikarma and Panchatikta Guggulu in the management of Sandhivata (osteoarthritis of knee joint). Ayu. 2016;37(1):38-44.
236. Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011 May;73(3):255-61. doi: 10.4103/0250-474X.93507.
237. Peterson CT, Vaughn AR, Sharma V, Chopra D, Mills PJ, Peterson SN, Sivamani RK. Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. J Evid Based Integr Med. 2018 JanDec;23:2515690X18790725. doi: 10.1177/2515690X18790725.
238. Ho TJ, Jiang SJ, Lin GH, et al. The In Vitro and In Vivo Wound Healing Properties of the Chinese Herbal Medicine “Jinchuang Ointment”. Evid Based Complement Alternat Med. 2016;2016:1654056.
239. Choudhary M, Kumar V, Malhotra H, Singh S. Medicinal plants with potential anti-arthritic activity. J Intercult Ethnopharmacol. 2015;4(2):147-79.
240. Grover AK, Samson SE. Benefits of antioxidant supplements for knee osteoarthritis: rationale and reality. Nutr J. 2016;15:1. Published 2016 Jan 5. doi:10.1186/s12937-015-0115-z.
241. Attiq A, Jalil J, Husain K, Ahmad W. Raging the War Against Inflammation With Natural Products. Front Pharmacol. 2018;9:976. Published 2018 Sep 7. doi:10.3389/fphar.2018.00976.
242. Gujral M., Sareen K., Tangri K., Amma M., Roy A. (1960). Antiarthritic and anti-inflammatory activity of gum guggul (Balsamodendron mukul Hook). Indian J. Physiol. Pharmacol. 4:267. [PubMed] 84. Sharma MR, Mehta CS, Shukla DJ, Patel KB, Patel MV, Gupta SN. Multimodal Ayurvedic management for Sandhigatavata (Osteoarthritis of knee joints). Ayu. 2013;34(1):49-55.