Medical Benefits of Curcumin

1. Medical benefits of curcumin
   1. Antioxidant

Studies have shown that curcumin has strong anti-oxidant properties and may thus play a vital role in the prevention and treatment of chronic diseases caused by persistent oxidative stress.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Oxidative stress is defined as an imbalance between the production of free radicals and the protective mechanisms of neutralization with anti-oxidants.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} This imbalance can cause cell damages and disturb normal biomolecular pathways, which can have detrimental impacts on the whole organism.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Cellular oxidative stress can impact genomic stability, damage cell structures, disturb normal enzyme function, and cause severe metabolic dysfunction, all of which are associated with the pathogenesis of many human diseases.^{(Menon, Sudheer, & Sudheer, 2007)} Persistent oxidative stress can result in chronic inflammation, which in turn is believed to cause many chronic diseases including diabetes, cancers, neurological disorders, cardiovascular diseases, and pulmonary diseases.^{(Reuter, Gupta, Chaturvedi, & Aggarwal, 2010)}

On a molecular level, oxidative stress is a surplus of highly reactive oxygen species (ROS) or free radicals. The most important free radicals are hydroxyl radical (OH), superoxide (O₂ ^– ) and hydrogen peroxide (H₂O₂). They are a natural byproduct of cellular metabolic processes and play a vital role in signaling pathways.^{(Menon, Sudheer, & Sudheer, 2007)(Lobo, Patil, Phatak, & Chandra, 2010)} However, a surplus of ROS is caused by disrupted endogenous neutralization processes with the help of anti-oxidants, or by additional free radical formation through external factors such as exposure to radiation, ozone, cigarette smoke, environmental pollutants and industrial chemicals.^{(Lobo, Patil, Phatak, & Chandra, 2010)}

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Curcumin has the ability to neutralize free radicals due to its chemical structure. The anti-oxidant activity of curcumin is likely based on the H-atom abstraction of the phenolic O-H and C-H components.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Research on structural variations of the curcumin molecule support this idea.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} As a hydrogen donor, curcumin acts as a radical scavenger detoxifying ROS and thus counteracting the damaging effects of oxidative stress (Lobo 2010).^{(Lobo, Patil, Phatak, & Chandra, 2010)(Aggarwal, et al., 2006)} Curcumin, therefore, presents itself as a potent compound for the prevention of many human diseases caused by persistent oxidative stress.

 

2. Inflammation

Inflammation is a vital part of the body’s immune response. It is the body’s attempt to heal itself after an injury, defend itself against foreign invaders like microorganism, and repair damaged tissue. Inflammation is often characterized by redness, swelling, warmth, sometimes pain and some immobility. Without inflammation, wounds would intensify, inflammation could increase, and become infectious and in the worst case, it can become deadly. Uncontrolled inflammation however, can be problematic; it plays a role in some chronic diseases and is related to cancer, arthritis, inflammatory bowel disease, and obesity. Conventional anti-inflammatory drugs, including NSAIDS, steroids, and statins are often prescribed for a variety of health issues, but long-term use of these compounds can cause negative side effects.

Over the past several years, in-vitro research has indicated that curcumin can reduce inflammatory response by regulating the production of inflammatory molecules.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)} Numerous mechanisms through which curcumin acts as an anti-inflammatory agent have been proposed.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Its anti-inflammatory effects are thought to be due curcumin’s ability to inhibit Cox-2, LOX, and iNOS induction, block the production of interferon-γ and tumor necrosis factor (TNF), and decrease the release of interleukins by suppressing the activation of transcription factors NF- κB and AP-1.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Curcumin is therefore thought to be a powerful disease preventative agent, since dysregulated TNF production and incorrect regulation of NF- κB have both been linked to a number of inflammatory diseases and cancers.

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Moreover, it has been found that curcumin is a potent inhibitor of the pro-inflammatory transcription factor signal transducer and activator of transcription 3 (STAT3), a protein that mediates inflammatory response by modulating pro-inflammatory cytokine production.^{(Gupta, Patchva, Koh, & Aggarwal, 2012) (Bharti, Donato, & Aggarwal, 2003)}In addition, Huang et al. have shown that curcumin inhibits phorbol 12-myristate 13-acetate (PMA)-induced inflammation fibroblast cells in mice. ^{(Huang, Lee, & Lin, 1991)} It can also inhibit production of pro-inflammatory cytokines in PMA or lipopolysaccharide-stimulated peripheral blood monocytes and alveolar macrophages. ^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}

There is some evidence that the hydroxyphenyl unit in the curcumin molecule may be responsible for its anti-inflammatory activity. One study specifically identified the presence of a 4-hydroxyphenyl unit as crucial in this role, demonstrating that additional small-sized alkyl or methoxy groups on the adjacent 3- and 5-positions on the phenyl ring can increase anti-inflammatory activity. ^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}These findings can help shape drug development efforts and inform molecule design with maximum anti-inflammatory potential.

Aggarwal et al. claim that the natural anti-inflammatory activity of curcumin is on par with steroidal and non-steroidal drugs such as indomethacin and phenylbutazone.^{(Menon, Sudheer, & Sudheer, 2007)} However, both of those drugs have dangerous side effects when taken long term, while the consumption of curcumin appears to be safe, as discussed in later sections. Because of its well-established anti-inflammatory properties and low toxicity profile, curcumin has the potential to alleviate symptoms associated with chronic inflammation, and can even be used as a prevention method against diseases caused by chronic inflammation like cancer.

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With its strong anti-inflammatory properties, curcumin consumption also exhibits pain-relieving effects. Several studies have evaluated patients’ perception of pain compared across groups who were administered either curcumin products, conventional pain medication, or placebo. Osteoarthritis patients reported similar pain-relieving effects of curcumin, conventional analgesic and NSAIDS, but they experienced lower side effects than NSAIDS.^{(Di Pierro, Rapacioli, Di Maio, Appendino, Franceschi, & Togni, 2013)} Patients receiving curcumin after a laparoscopic cholecystectomy reported significantly lower pain perception two weeks post-operative and needed significantly fewer rescue administrations of conventional analgesic drugs as compared to the placebo group.^{(Agarwal, Tripathi, Agarwal, & Saluja, 2011)} These results show that curcumin can improve pain through its pharmacological actions in patients with chronic pain due to chronic inflammation and acute pain due to minor post-operative procedures.

3. Immune support

Curcumin, known for its therapeutic effects for many health issues, is also recognized as a potent modulator of the immune system. Curcumin has been shown to act as an immune support, due to it immunomodulatory effects on several cells and organs of the immune system.^{(Bose, Panda, Mukherjee, & Sa, 2015)} It has been found that curcumin can modulate the growth and cellular response of various cell types of the immune system (Figure 3). How this agent affects T cells, B cells, macrophages, neutrophils, NK cells, and dendritic cells is discussed below.^{(Jagetia & Aggarwal, 2007)}

Several studies have reported that curcumin can modulate the proliferation and activation of T cells. It has been reported that curcumin reduces the proliferation of T cells induced by compounds like concanavalin A (Con A), phytohemagglutinin (PHA), and phorbol-12-myristate-13-acetate (PMA). It has also been shown to reduce IL2 production via modulation of NFκB pathway. It can both suppress and stimulate the proliferation of T cells depending on the context and dose of administration. Bose et al. summarize how curcumin can specifically block proliferation of HTLV-1infected T cells and primary ATL cells through cell cycle arrests by down-regulating Cyclin D1, Cdk1, and Cdc25C and induction of apoptosis by down-regulating XIAP and surviving.^{(Bose, Panda, Mukherjee, & Sa, 2015)} Another study by Hussain et al. carried out in T cell acute lymphoblastic leukemia showed that curcumin suppresses constitutively activated targets of PI3-kinase (AKT, FOXO and GSK3) in T cells leading to the inhibition of proliferation and induction of caspase-dependent apoptosis.^{(Hussain, et al., 2006)} However, another study suggested that the effect of curcumin on T cells was dose-dependent; low-dose curcumin increased the proliferation of splenic lymphocytes, whereas high-dose curcumin depressed it in mice.^{(Bose, Panda, Mukherjee, & Sa, 2015)}

Curcumin has also been shown to regulate other cells of the immune system. It has been shown to prohibit proliferation of B-cell lymphoma cells via down-regulation of c-MYC, BCL-XL and NFκB activities. It has also been reported to block Epstein Barr Virus (EBV)-induced immortalization of B-cells.^{(Bose, Panda, Mukherjee, & Sa, 2015)}

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Many studies have shown curcumin’s ability to modulate the activation of macrophages. For example, curcumin seems to regulate the immune function of mice in a dose-dependent fashion as curcumin treatment enhanced the phagocytosis of peritoneal macrophages and differentially regulates the proliferation of splenocytes.^{(Jagetia & Aggarwal, 2007)} Curcumin has been shown to promote enhanced phagocytosis of peritoneal macrophages in mice. Curcumin is also effective against natural killer T cell lymphoma cell lines, where it promotes apoptosis by regulating the NFκB pathway and blockage of BCLXL, Cyclin D1 etc. Moreover, Kim et al. reported that curcumin can suppress expression of CD80, CD86 and class-II antigens by dendritic cells.^{(Kim , et al., 2005)} Curcumin also blocked the release of inflammatory cytokines like IL1β, IL6 and TNFα from LPS-stimulated dendritic cells. Curcumin was shown to modulate phosphorylation of MAPK and nuclear translocation of NFκB in dendritic cells.^{(Bose, Panda, Mukherjee, & Sa, 2015)}

Curcumin can also apparently modulate the activation of natural killer (NK) cells. Studies by South and his colleagues in rats showed that curcumin at a dose of 1 and 20 mg/kg body weight could not enhance the IgG levels in the NK cells, whereas a higher dose (40 mg/kg) did elevate IgG levels significantly. More importantly, none of the three doses of curcumin significantly enhanced either delayed-type hypersensitivity or NK cell activity. These observations indicate its potential as an anti-proliferative agent that could play an important and decisive role in cancer chemotherapy.^{(Jagetia & Aggarwal, 2007)}

The effect of curcumin on dendritic cells (DC) has been investigated by Kim et al. ^{(Kim , et al., 2005)}. To offer some background, dendritic cells are professional antigen-presenting cells that play a key role as immune sentinels in the initiation of T-cell responses to microbial pathogens, tumors, and inflammation.^{(Jagetia & Aggarwal, 2007)} Peripheral DCs are generally immature both phenotypically and functionally. They nevertheless have clinical potential as cellular adjuvants in the treatment of chronic infectious diseases and tumors.^{(Jagetia & Aggarwal, 2007)} There is only one report to date on immune modulation of murine DCs using curcumin: Researchers found that curcumin significantly depressed the expression of CD80, CD86, and MHC class II antigens in GM-CSF/IL-4 stimulated DCs without affecting MHC class I antigens.^{(Kim , et al., 2005)} They also found that curcumin efficiently blocked the LPS-induced expression of IL-12 and inflammatory cytokines including IL-1β, IL-6, and TNF-α. Curcumin treatment enhanced the Ag capturing ability of DCs via mannose receptor-mediated endocytosis.^{(Kim , et al., 2005)} However, their Th1 and normal cell-mediated immune response was very poor. Further studies showed that treatment of DCs with curcumin before LPS stimulation completely suppressed the LPS-induced phosphorylation of MAPK and NF-κB nuclear translocation.^{(Kim , et al., 2005)} The direct suppression of these activities by curcumin in DCs may lead to the attenuated Tcell-mediated immune responses by interfering with handling and presentation of antigens by DCs.^{(Jagetia & Aggarwal, 2007)}

4. Vasodilator

Traditional Asian medicine has used turmeric to promote circulation. It has been used for the treatment of syndromes caused by obstruction of blood flow such as arthralgia, psychataxia, and dysmenorrhea. It is believed that the active compounds can enter the spleen to assist digestive function, and the liver to eliminate blood stasis. Relaxation of blood vessels and fibrinolysis of blood are thought to result in the improvement of circulation. Curcumin has been found to act as a vasodilator in animal models, most likely due to methanol-soluble compounds, such as curcumin and essential oil.^{(Sasaki, et al., 2003)}

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5. Anti-bacterial and anti-fungal

Curcumin has also been found to enhance the innate immune functions in another way. Guo et al. discovered that curcumin nearly tripled the expression of a gene that encodes a protein known as cathelicidin antimicrobial peptide (CAMP), which can help combat bacteria, viruses and fungi that have not been previously encountered by the immune system. CAMP is the only known antimicrobial peptide of its kind in humans, and is able to destroy a wide range of bacteria, including that which causes tuberculosis. While curcumin’s effect on CAMP is not as potent as that previously found for vitamin D, the compound may still be of value in improving immune function, in addition to providing anti-inflammatory and antioxidant benefits. The authors conclude that it’s possible that sustained consumption over time may be healthy and help protect against infection, especially in the stomach and intestinal tract. These findings may set the path for new research efforts to investigate the regulation of CAMP gene expression, as there is evidence that curcumin has the potential to do that. Positive research findings could provide another tool to develop medical therapies of curcumin products.^{(Guo, Rosoha, Lowry, Borregaard, & Gombart, 2013)}

2. Review of research on medicinal benefits

Curcumin is a molecule that has several different beneficial effects due to its ability to modulate multiple signaling molecules. ^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}Pre-clinical and clinical studies have shown that curcumin presents anti-oxidant, anti-inflammatory, anti-proliferative, chemopreventative, and cholesterol-lowering characteristics. ^{(Gupta, Patchva, Koh, & Aggarwal, 2012)} More specifically, research shows that curcumin can modulate several different transcription factors, cytokines, growth factors, kinases and other enzymes, and gene regulating apoptosis.^{(Gupta, Patchva, Koh, & Aggarwal, 2012) (Aggarwal, et al., 2006)} Below, we summarize some of the most impactful research results of curcumin and its medicinal benefits known today.

1. Rheumatoid Arthritis and Osteoarthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that may impact many organs and tissues but mainly attacks flexible (synovial) joints. Oxidative stress is thought to make an important contribution to joint damage in RA. ROS is a significant mediator that activates a variety of transcription factors including NF-κB and AP-1, thus regulating the expression of many different genes, including those of growth factors, chemokines, cell cycle regulatory molecules, inflammatory cytokines and anti-inflammatory molecules.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)(Godin, et al., 2014)} Therefore, transcription factors and genes involved in inflammation and anti-oxidation are suspected to play a crucial role in RA, suggesting that the anti-inflammatory effects and anti-oxidant properties of curcumin can play a significant role in the treatment and prevention of RA.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Conventional drug therapy include non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs, immunosuppressive agents, immune and biological agents and botanicals; of those drugs, NSAIDs are most commonly administered.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)(Banji, Pinnapureddy, Banji, Saidulu, & Hayath, 2011)} Curcumin, with anti-inflammatory and anti-oxidant actions, was studied both in vivo and in vitro for the treatment of RA instead of conventional NSAIDS and many pre-clinical studies have shown the biological effects and molecular mechanisms of curcumin. Pre-clinical studies show positive results but those findings have yet to be evaluated for the efficacy of curcumin therapy against RA in humans in large randomized clinical trials.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} A randomized pilot study found that curcumin treatment in patients with active RA lead to the highest percentage of symptom improvement as compared to patients who were given either NSAIDs alone or a combination of NSAIDs and curcumin.^{(Chandran & Goel, 2012)}

Osteoarthritis (OA), sometimes called degenerative joint disease or degenerative arthritis, is the most common chronic condition of the joints, affecting approximately 27 million Americans. OA can affect any joint, but it occurs most often in knees, hips, lower back and neck, small joints of the fingers and the bases of the thumb and big toe.^{(What is Osteoarthritis?, 2011)} There is no cure for this condition, but treatments are available to manage symptoms, such as pain, stiffness and swelling. Conventional medication for these symptoms include analgesics, NSAIDs, corticosteroids, and hyaluronic acid.^{(What is Osteoarthritis?, 2011)} DiPierro evaluated the pain-relieving effect of curcumin products for the treatment of pain in patients with OA.^{(Di Pierro, Rapacioli, Di Maio, Appendino, Franceschi, & Togni, 2013)} Results showed that doses of 400mg of curcumin (in a preparation of 2g of Meriva®) had pain relieving effects comparable with the standard dose of 1g acetaminophen, but lower than that of a therapeutic dose of 100mg nimesulide, an NSAID that is marketed in many countries, including Italy where the study was conducted, but it is not marketed in the US. Regarding side effects however, gastric tolerability of Meriva was significantly better than that of nimesulide and comparable with that of acetaminophen.^{(Di Pierro, Rapacioli, Di Maio, Appendino, Franceschi, & Togni, 2013)}  The authors report that the pain-relieving activity could be due to the general down-regulation of the inflammatory response induced by curcumin. Therefore, Meriva or similar curcumin products, could be used in patients with OA to treat acute pain, while reducing conventional pain-relieving medication and thus limiting gastric side effects.

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2. Alzheimer’s/Neurodegenerative Diseases

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, usually affecting people ages 65 years and older. The pathogenesis of AD involves aggregation of Aβ (especially Aβ1–42) into fibrils, formation of amyloid plaques, and deposition of these plaques into the brain. These plaques are believed to cause the loss of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease.^{(Gupta, Patchva, & Aggarwal, Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials, 2013)}

Extensive research shows that age-dependent neurodegeneration is associated with decreased levels of anti-oxidants and increased oxidative damage to proteins, DNA, and lipids; thus making curcumin with its anti-oxidant potential a promising preventative substance against neurodegenerative diseases.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of AD indicate a direct effect of curcumin in decreasing the amyloid pathology of AD.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005)}

Pre-clinical studies of AD indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005)} Additional support for this theory is derived from epidemiological studies in India, a country with one of the lowest prevalence rates of AD in the world and where turmeric consumption is widespread.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005) (Chandra, et al., 2001)} Though there are many potential explanations for this observation (i.e. a study limitation known as ecologic fallacy) a preventative role of curcumin is a possibility.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005)}

Findings from animal studies provide evidence that curcumin can ameliorate the pathology and cognitive deficits in animal models of AD but leaves the mechanism for this activity open to question.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005)} Ringman et al. performed subsequent fluorescence studies showing that curcumin binds to amyloid plaques in human AD and Tg2576 transgenic mouse brain tissue in-vitro. Furthermore, curcumin was found to bind to amyloid plaques when such mice were either fed curcumin or curcumin injected in the carotid artery.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005)} This demonstrates that curcumin crosses the blood-brain barrier in these mice, and direct binding to plaques may be important in its antiamyloid activity. Animal studies therefore are highly suggestive of efficacy against AD pathology via multiple possible mechanisms. Further study of curcumin in the treatment or prevention of AD in humans is warranted.^{(Ringman, Frautschy, Cole, Materman, & Cummings, 2005)}

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3. Cancer

Recent pre-clinical studies have found that curcumin has a dose-dependent chemopreventive effect in several types of tumors, including colon, pancreatic, duodenal, stomach, esophageal and oral carcinogenesis.^{(Maheshwari, Singh, Gaddipati, & Srimal, 2006)(Kanai, 2014)} Protective effects against breast cancer have also been reported.^{(Aggarwal, et al., 2006)}

With respect to breast cancer, the overexpression of the gene HER2/neu is responsible for almost 30% of breast cancer cases in women; moreover both HER2 and EGF receptors stimulate proliferation of breast cancer cells. Curcumin can suppress the growth of breast cancer cells as it has been found to downregulate the activity of epithelial growth factor receptor (EGFR) and HER2/neu and to deplete the cells of HER2/neu protein.^{(Aggarwal, et al., 2006)}

Curcumin has anticancer effects both alone and in combination with other anticancer drugs (e.g. gemcitabine, 5-fluorouracil, and oxaliplatin), and it has been shown to modulate a variety of molecular targets in preclinical models, with more than 30 molecular targets identified to date. Of these various molecules, NF-kB is thought to be one of the primary targets of curcumin activity. ^{(Kanai, 2014)} Curcumin may also act as an anti-cancer agent through the suppression of NF- κB activation.^{(Aggarwal, et al., 2006)} NF- κB is a nuclear transcription factor required for the expression of genes involved in cell proliferation, cell invasion, metastasis, angiogenesis, and resistance to chemotherapy.^{(Aggarwal, et al., 2006)(Baldwin, 2001)} This factor is activated in response to inflammatory stimuli, carcinogens, tumor promoters, and hypoxia, which is frequently encountered in tumor tissues.^{(Aggarwal, et al., 2006)}

In vivo and in vitro studies have demonstrated curcumin’s ability to inhibit carcinogenesis at three stages: tumor promotion, angiogenesis and tumor growth. Curcumin suppresses mitogen-induced proliferation of blood mononuclear cells, inhibits neutrophil activation and mixed lymphocyte reaction and also inhibits both serum-induced and platelet derived growth factor (PDGF)-dependent mitogenesis of smooth muscle cells. It has also been reported to be a partial inhibitor of protein kinase. ^{(Maheshwari, Singh, Gaddipati, & Srimal, 2006)}

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The molecular basis of anti-carcinogenic and chemopreventive effects of curcumin is attributed to its effect on several targets including transcription factors, growth regulators, adhesion molecules, apoptotic genes, angiogenesis regulators and cellular signaling molecules. Curcumin has been shown to down regulate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1β and inhibit the activation of transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), which regulate the genes for pro-inflammatory mediators and protective antioxidant genes. Curcumin inhibited NF-κB activation by blocking phosphorylation of I-κB through inactivation of I-κB kinase complex. Suppression of AP-1 was due to a direct interaction of curcumin with AP-1 binding to its DNA binding motif and also due to inhibition of c-Jun and c-fos, components of AP-1. It is also reported to suppress the activity of a number of enzymes such as cytochrome P450 and COX-2. Other studies have identified reduction in radiation induced DNA damage in rat lymphocytes and its anti-mutagenic potential. ^{(Maheshwari, Singh, Gaddipati, & Srimal, 2006)}   [Where science gets heavy let’s add an image or ALSO dumb it down]

Understanding curcumin’s effect on NF- κB activation is critical because NF- κB is involved in so many of the activities that curcumin is known to block. NF- κB plays a pivotal role in cells of the immune system because it is rapidly activated by a wide variety of pathogenic signals and functions as a potent and pleiotropic transcriptional activator. Intervention in NF- κB activation may be beneficial in suppressing toxic/septic shock, and radiation damage, thus making curcumin a potent anti-carcinogenic agent. Singh et al showed that curcumin completely blocked the TNF-dependent activation of NF- κB.^{(Singh & Aggarwal, 1995)} The activation induced by various other agents including phorbol ester and H2O2 was also inhibited by curcumin. As has been shown with other inhibitors, the effect of curcumin was not due to the chemical modification of NF- κB proteins. More specifically, the inhibition of NF- κB activation was accompanied by the inhibition of p65 translocation to the nucleus and of I-κBa degradation. Identifying how curcumin blocks the activation of NF- κB requires an understanding of the mechanism by which various inducers activate this important transcription factor. The role of different TNF-activated signals including acidic and neutral sphingomyelinase-generated ceramides, proteases, serine/threonine protein kinase, protein tyrosine kinase, protein tyrosine phosphatase, and superoxide radicals in the activation of NF- κB have been implicated. Whether these signals are generated by TNF sequentially or independently of each other, however, is not understood. Overall the authors conclude that because of its very low pharmacological toxicity and its ability to modulate activation of NF-kB by various agents, curcumin has a high potential for use in modulating expression of genes regulated by NF- κB, explaining its beneficial anti-carcinogenic effects.^{(Singh & Aggarwal, 1995)}

In conclusion, there is plenty of evidence that curcumin has the potential to act preventative against a number of different cancers. The other pertinent feature of both turmeric and curcumin is that despite being consumed daily for centuries in Asian countries, it has not been shown to cause any toxicity. ^{(Maheshwari, Singh, Gaddipati, & Srimal, 2006)} It may thus be a useful product for the long-term use in cancer prevention.

4. Diabetes Mellitus Type 2

Diabetes mellitus (DM) is a chronic metabolic disease in which a person has high concentrations of blood sugar. The high blood sugar in turn produces symptoms of polyuria, polydipsia, and polyphagia. Other than DM type 1 and gestational diabetes, DM Type 2 (DMT2) results from the body’s inability to use insulin properly (insulin resistant). Extensive research over the past several years has indicated that pro-inflammatory cytokines and oxidative stress play a role in the pathogenesis of DMT2. Because of its anti-inflammatory properties, as discussed in previous chapters, curcumin represents a promising therapeutic option for DMT2. Curcumin’s ability to decrease blood sugar levels in human patients was first reported in 1972 and has since been investigated in numerous trials with positive results suggestive of curcumin having beneficial effects even in a pre-diabetic population.^{(Gupta, Patchva, & Aggarwal, Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials, 2013)}

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5. Cardiovascular disease

Cardiovascular Diseases (CVDs), including heart disease, vascular disease and atherosclerosis, are a critical current global health threat. Epidemiological and clinical trials have shown strongly consistent relationships between the inflammatory markers and risk of cardiovascular diseases.^{(Libby, 2006)} It is widely studied that the key mechanisms in the development of CVDs are inflammation and oxidative stress, activation of pro-inflammatory cytokines, chronic transmural inflammation and C reactive protein (CRP).^{(Wongcharoen & Phrommintikul, 2009)} Thus cytokines, other bioactive molecules, and cells that are characteristic of inflammation are believed to be involved in atherogenesis, a disorder that can ultimately lead to CVDs. Abundant evidence suggests that curcumin mediates its effects against CVDs through diverse mechanisms such as oxidative stress, inflammation and cell death.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Curcumin thus has the potential to protect against cardiac hypertrophy and fibrosis through its anti-inflammatory effects as described in previous chapters. Also, reports by DiSilvestro et al. showed that a low dose of a curcumin-lipid preparation can produce a variety of potentially health promoting effects in healthy middle aged people, including cardiovascular health.^{(DiSilvestro, Joseph, Zhao, & Bomser, 2012)}

6. Digestive disorders – Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leucocyte infiltration, and upregulation of proinflammatory cytokines. Pre-clinical research with animal models suggest that curcumin has protective effects on digestive disorders with great potential as a treatment method for IBD. ^{(Ukil, Maity, Karmakar, Datta, Vedasiromoni, & Das, 2003)} Ukil et al. recently investigated the protective effects of curcumin on mice models. Reports showed that curcumin could prevent and improve experimental colitis in murine models with inflammatory bowel disease (IBD) and could be a potential target for the patients with IBD. ^{(Aggarwal, et al., 2006)(Jian , Mai, Wang, Zhang, Luo, & Fang, 2005)}

As shown in vivo in humans and rats, curcumin can ameliorate inflammatory bowel disease by reducing inflammatory cytokine levels, blunting NO and O2 production, and suppressing NF-κB activation in colon epithelium.^{(Jagetia & Aggarwal, 2007)}

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Intestinal lesions were associated with neutrophil infiltration, increased serine protease activity (may be involved in the degradation of colonic tissue), and high levels of malondialdehyde. Dose–response studies revealed that pretreatment of mice with curcumin at 50 mg/kg daily i.g. for 10 days significantly ameliorated diarrhea and the disruption of colonic architecture. Higher doses (100 and 300 mg/kg) had comparable effects. In curcumin-pretreated mice, there was a significant reduction in the degree of both neutrophil infiltration and LPO in the inflamed colon as well as decreased serine protease activity. Curcumin also reduced the levels of NO and O2– associated with the favorable expression of Th1 and Th2 cytokines and inducible NO synthase. Consistent with these observations, NF-κB activation in colonic mucosa was suppressed in the curcumin-treated mice. These findings suggested that curcumin exerts beneficial effects in experimental colitis and may, therefore, be useful in the treatment of IBD. Salh et al. also showed that curcumin is able to attenuate colitis in the dinitrobenzene (DNB) sulfonic acid-induced murine model of colitis.^{(Salh, et al., 2003)} When given before the induction of colitis, it reduced macroscopic damage scores and NF-κB activation, reduced myeloperoxidase activity, and attenuated the DNB-induced message for IL-1β. Western blotting analysis revealed a reproducible DNB-induced activation of p38 MAPK in intestinal lysates detected by a phosphospecific antibody. This signal was significantly attenuated by curcumin. Furthermore, the above workers showed that the immunohistochemical signal is dramatically attenuated at the level of the mucosa by curcumin. Thus they concluded that curcumin attenuates experimental colitis through a mechanism that also inhibits the activation of NF-κB and effects a reduction in the activity of p38 MAPK. They proposed that this agent may have therapeutic implications for human IBD.^{(Aggarwal, et al., 2006)}

 

7. Obesity

Obesity affects more than 30% of the US population and a major risk factor for a number of health issues, including type 2 diabetes, cardiovascular diseases, and cancers. Research shows that obesity is a pro-inflammatory disease; thus, to reduce the health burden of obesity and its associated health issues, the use of anti-inflammatory prevention methods can be paramount. Curcumin exhibits its activity against obesity by anti-inflammatory and antioxidant mechanisms. Curcumin as a potential treatment for obesity and obesity-related metabolic diseases has been shown extensively through suppressing the pro-inflammatory NF-κB, signal transducer and activators of STAT3, and Wnt/β-catenin, as discussed in previous chapters.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} By suppressing those molecules and modulating the respective pathways, curcumin may have the potential to prevent both obesity and obesity related health issues.

3. Discussion, Conclusion and Future Direction

As most diseases affecting the majority of our population are associated with chronic inflammation, such as cancer, diabetes, arthritis, and even Alzheimer’s, it is crucial to find safe and efficacious anti-inflammatory agents with minimal side effects that can be used as preventative as well as treatment measures. Today in modern medicine, steroids and nonsteroidal anti-inflammatory drugs (NSAIDS) are the most commonly used anti-inflammatory agents. However, there are numerous side effects associated with these products, especially when used long-term.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)} Considering the disease burden of our population suffering from conditions caused by disrupted inflammatory processes and the side effects of conventional anti-inflammatory treatment, there is great need for new efficacious anti-inflammatory substances that can safely be consumed over long periods of time. Products containing curcumin pose a promising solution for such alternative treatment and prevention methods. Traditional medical practices recently started to include the use of turmeric and curcumin on a wide variety of health issues and show positive effects. Based on pre-clinical studies and early phase in-human trials, there is evidence that curcumin is safe and expected to be effective against chronic inflammation and cancer. However, larger scale clinical trials are needed to obtain a more comprehensive efficacy and safety profile of curcumin compounds.

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Since ancient times, turmeric has been used in a wide range of inflammatory, neoplastic and other conditions. In recent years, the molecular basis for turmeric and its active ingredient curcumin’s efficacy has been extensively investigated. Many cellular and molecular targets have been identified and many questions still remain. In complex multifactorial illnesses such as systemic inflammatory diseases and cancer, an agent that acts at a number of different cellular levels offers perhaps a better chance of effective prophylaxis or treatment. Its non-toxicity and good tolerability in human subjects, in combination with strong promising results from cell line, animal and early human clinical studies, support the ongoing research and development of curcumin as a preventive and disease-modifying agent.^{(Epstein, Sanderson, & MacDonald, 2010)}

Based on promising preclinical results, several research groups have progressed to testing the anticancer effects of curcumin in clinical trials; however, the poor bioavailability of this agent has been the major challenge for its clinical application. This problem has been solved by the development of highly bioavailable forms of curcumin supplements that include other curcuminoids or additional adjuvants, and higher plasma curcumin levels can now be achieved without increased toxicity in patients with pancreatic cancer.^{(Kanai, 2014)}

Future research efforts should focus on even better formulation of curcumin products or novel routes of administration.^{(Hsu & Cheng, 2007)} Pre-clinical and early phase human studies show positive results.  Modern western science needs to perform larger scale studies to confirm the medicinal benefits of curcumin that ancient Ayurvedic science has already known and applied for thousands of years. Future research efforts should focus on not only the ideal formulation and efficacy of curcumin and piperine, but also investigate the effects of non-curcumin turmeric compounds and their interaction with curcumin. Ultimately, we are interested to provide the ideal formulation of curcumin supplements that can easily be taken on a daily basis without the risk of any adverse reactions, and with maximum benefit for our health. To optimize bioavailability and maximize biochemical processes is our fundamental research goal.

There are plenty of results that are published, the issue is many are not consistent.  The existing clinical trials have not studied apples to apples with truly equivalent combinations and thus more clinical trials must be undertaken to truly understand the best composition.

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