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"F OOD IS THE B EST M EDICINE E NHANCING P OST S URGERY R ECOVERY W ITH D IET B Y A RIEL H ART A thesis Submitted to the Division of Natural Sciences New College of Florida In partial fulfillment of the requirements for the degree of Bachelor of Arts in Natural Sciences Under the sponsorship of Dr. Alfred Beulig Sarasota, Florida May, 2012
ii This thesis is dedicated to my family: My mother, for showing me how to care for people. My father, for encouraging my love of thin king, learning, and hypothesizing. Camile, for sharing everything with me. Monica, for inspiring my love of good food. Zachary, for helping me find my way to New College. And of course my other Ariel, for his endless support and confidence in me I am also truly grateful to my thesis sponsor, Dr. Alfred Beulig, and my committee members, Dr. Paul Scudder and Dr. Katherine Walstrom, for their constructive feedback and support.
iii Table of Contents Dedication .................... ................................................................................... i Table of Contents ....................................................................................................... iii List of Acronyms ......................... .............................................................................. iv Abstract ...................................................................................................................... v I. Introduction ........................ ......................................................................................1 II. The Postoperative Condition ................................................................................... 5 2.1. Post Surgical Stress Response and Immune Re gulation ...................................... 5 2.2. Systemic Inflammation ....................................................................................... 7 2.3. Oxidative Stress and Gastrointestinal Involvement in Pathogenic Inflammatory Syn dromes ........................................................................................................ 10 2.4. Metabolic Changes.............................................................................................. 12 2.5. Wound Healing.. .................................................................................................. 13 III. Fish Oil ................................................................................................................ 14 3.1. Evidence from C linical and Animal Studies for Perioperative Fish Oil Supplementation ................................................................................................ 15 3.2. Fish Oil Mechanism of Action ................................................... ........................ 17 3.3. Application of Fish Oil Supplementation in Surgical Patients: Potential Risks and Benefits ........................................................................................................... 22 IV. Virgin Coconu t Oil (VCO) .................................................................................. 23 4.1. Not All Coconut Oil is Created Equal ................................................................. 24 4.2. Minor Active Components of Coconut Oil .... ..................................................... 25 4.3. Medium Chain Triglycerides .............................................................................. 26 4.4. Proposed Therapeutic Mechanism of Virgin Coconut Oil in Surgical Patients .... ....................................................................................................................... 28 V. Turmeric (Curcumin) ............................................................................................ 31 5.1. Curcumin Targets Multiple Aspects of Inflammatory Pathways ........................ 32 5.2. Epigenetic Regulation ......................................................................................... 33 5.3. Antioxidant Properties of Curcumin .................. ................................................. 33 5.4. Wound Healing .................................................................................................... 35 5.5. Angiogenesis ................................................................ ........................................ 35 5.6. Curcumin Targets Gastrointestinal Inflammation Pathway for Initiation of Inflammatory Syndromes ............................................................................... 36 VI. Conclusion .......... ................................................................................................. 37 Bibliography ............................................................................................................. 39
iv List of Acronyms EFA Ess ential Fatty Acid TLR Toll like receptor AA Arachidonic acid DHA Docosahexenoic acid EPA Eicosapentenoic acid NF kB Nuclear factor kappa B IL Interleukin (e.g. IL 1 is interleukin 1) GI tract Gastrointestinal tract NO Nitric Oxide PMN Pol ymorphonuclear neutrophils COX 2 Cyclooxygenase 2 LOX Lipoxygenase CSCN Canadian Society for Clinical Nutrition ESPEN European Society for Parenteral and Enteral Nutrition VLDL Very low density lipoproteins LDL Low density lipoproteins TNF alph a Tumor necrosis factor alpha DPPH 2,2 diphenyl 1 picrylhydrazyl
v "F OOD IS THE BEST MEDICINE ": ENHANCING POST SURGERY RECOVERY WITH DIET Ariel Hart New College of Florida, 2012 ABSTRACT The trauma of surgery puts patients into a catabolic phase of stress. In order for a body to heal and rebuild, it needs access to the proper substrates, many of which can be provided in a patient's diet, including proteins, vitamins, essential fatty acids, and calories to fuel the necessary bustle of internal activ ity. In recent years, certain "pharmaconutrients" have been found to improve clinical outcomes as dramatically as treatment with antibiotics or other traditional "drugs". Incorporation of this information into the hospital setting is lagging, however, ev en when it comes to providing sufficient calorie and protein intakes. Studies have demonstrated the prevalence of protein and energy malnutrition in hospitals for decades, but the problem still remains. Recent data show that 40 50% of hospitalized patien ts are malnourished. Although "functional foods" have been popularized among consumers, many nutraceuticals with significant clinical and mechanistic evidence are currently under used in western medicine in those places where they could be most beneficial The hospital is an ideal setting for incorporation of functional foods, since the diets of hospitalized patients are almost completely under the control of doctors and other health professionals. Incorporation of nutritional therapy to prevent protein and calorie malnutrition and essential nutrient deficiencies, and to make use of pharmacologically active food products, has the potential to decrease infection rates, durations of hospital stays, and mortalities, improve clinical
vi outcomes, and even lower costs for the hospital and the patient. Although many foods have been shown to possess anti inflammatory, immune modulating, or healing properties, this thesis focuses on fish oil, coconut oil, and turmeric as promising therapeutic foods for surgical pati ents. ________________________ Professor Alfred Beulig Division of Natural Sciences
1 I. Introduction Food has been used for its healing properties throughout time in many traditional cultures. Grandmothers in Tuscany use chestnut meal polenta boiled in red wine to ameliorate coughing. Tibetans use plant foods like nutmeg, cardamon, clo ve, saffron, and bamboo pith to maintain health and bring happiness. Even in the United States, it is traditional to serve chicken noodle soup to ease discomfort and speed recovery from the common cold. (Pieroni and Price, 2006) Although it is clear that food nourishes the body and is necessary for life, true consideration of food in conventional western medicine has only recently began to expand beyond simply maintaining a healthy weight As Wischmeyer proposes in his 2011 review, "We must unlearn' that nutrition is only about delivering basic substrates that are limited to a role in providing a fuel source for basic metabolism and cell growth." (Wischmeyer, 2011) In fact, based on their clinical effects, both preventing calorie and protein malnutrition a nd providing appropriate pharmacologically active nutrients should be considered equally important aspects of treatment as providing patients with antibiotics or other conventional "drugs". N utrition has been recognized as an important factor in wound hea ling for at least a century (Guo et al., 2010), and n umerous studies throughout the past several decades have shown the hugely detrimental effects of malnutrition on medical outcomes for critically ill patients including surgical patients (McWhirter et al ., 1994; Gallagher Allred et al., 1996; Braunschweig et al., 2000; Correia et al., 2003). At the same time, many of these same studies demonstrate the surprising ly common insufficiency of nutrition in hospitals. Recent data show that 40 50% of hospitalize d patients are malnourished. (Wischmeyer, 2011) Although efforts have been made to increase
2 implementation of clinical nutrition, there still remains a huge disparity betwe en well funded institutions and the average hospital, both in the United States and abroad. Hospital malnutrition can originate from a variety of causes. Often, even if patients are given adequate meals, whether they actually consume adequate nutrients is not monitored. A decrease in nutritional status during hospitalization can resu lt from the patient either not absorbing nutrients sufficiently, or not consuming enough food, which itself may result from lack of appetite, inadequate food provided, or even undesirability of the hospital food (a notoriously common complaint). Clinical nutrition is not simply a matter of providing some standard number of calories and nutrients, but also requires monitoring intakes and making repeated assessments of a patient's status to con firm the efficacy of treatment. It is a common misconception tha t as long as a patient is not initially malnourished, they are not at risk for malnourishment that could severely affect their recovery. Priority is therefore given to assessing initially malnourished patients, but clinically significant malnourishment ca n arise during a patient's hospital stay when their nutritional status is not made a priority. A study from 1988 demonstrated that recent food intake is more important than overall nutritional status for the wound healing response (Windsor, 1988). Since even short term malnutrition can significantly affect healing, it is important to monitor patients for the development of nutrient deficiencies. The idea of "functional foods" is a hot topic in popular nutrition and health media. Although the popular me dia is a notoriously misleading source, "functional foods" are not simply a hippie trend or marketing scheme (although the idea has been taken advantage of for such purposes). Functional foods, which are often discussed as "nutraceuticals" or "pharmaconut rients" in peer reviewed literature, are promising as
3 both preventative and therapeutic treatments for many conditions that still pose a challenge to modern medicine, including inflammation related disorders like heart disease and Alzheimer's, cancer, and even potentially HIV/AIDS. Functional foods have recently begun to trickle into conventional western medicine. Within the last decade, it has become common for cardiologists to prescribe fish oil (omega 3 fatty acid) supplements to patients at risk for h eart disease, and even more recently turmeric has been prescribed to reduce inflammation in arthritic patients. Even more "functional foods" have made their way into health magazines and websites, encouraging consumers to take their health into their own hands. Most of these healing foods were "discovered" through observing their use in traditional cultures either simply as food, or even as medicine. Research into the clinical effects of omega 3 fatty acids, for example, was famously initiated by epidemiol ogical studies showing the correlation between the fish rich diets of Greenland Eskimos and extremely low rates of heart disease and diabetes. (Friedberg et al., 1998) Fish oil, turmeric, and coconut oil, as well as many other food products, have great th erapeutic potential that currently remains largely unexploited in common Western medicine In general, both nutritive and functional food based nutritional therapies are most often considered for patients receiving enteral or parenteral nutrition. This p opulation includes the most critically ill patients, and may therefore show the most dramatic improvements from treatment. Patients in intensive care worldwide receive only about 50% of calories prescribed by physicians. (Wischmeyer, 2011) This surprising statistic is most likely a direct result of the dogmatic practice of waiting to start post surgical feeding until bowel sounds are heard (Warren et al., 2011), for which there is no solid
4 supporting evidence. In fact, it has been shown that early feeding with a regular diet, as opposed to delayed feeding or feeding of a clear liquid diet, is well tolerated, and even reduces postoperative infectious complications, promotes healing, decreases weight loss and protein catabolism, and shortens hospital length o f stay. (Warren et al., 2011) In addition to the provision of adequate basic nutrients, the benefits of providing appropriate pharmaconutrients to assist surgical patient recovery have begun to be recognized. "Immune enhancing diets" (IEDs), consisting of omega 3 fatty acids, arginine, nucleotides, and antioxidants, have been shown to improve T helper cell counts, and possibly increase NO production, and are associated with a consistently significant decrease in infection rates in patients undergoing elect ive surgery. (Zhu et al., 2010) IEDs have been implemented in some hospitals, mostly in Europe, and are currently recommended by major critical care nutrition societies, but are still underused. Additionally, patients in less critical condition who are ab le to take food by mouth could also benefit from increased nutritional care and perhaps even supplementation with some of the same pharmaconutrients that have been used in critical care patients. The period of recovery following any surgery is a sensitive time more deaths occur from surgery complications than in the operating room itself. To quicken and improve recovery after surgery, the primary goals are to control inflammation, prevent infection, and promote healing. Because surgery, particularly elec tive surgery, can generally be planned for, and conditions surrounding surgery can be regulated in a hospital setting, in theory the ideal practices to improve surgery recovery including nutritional therapy, should be reasonable to implement.
5 II. The Postoperative Condition Although responses to different surgeries vary to a large degree based on severity and type of surgery, there are significant similarities between the majority of surgical patients. Regardless of the type of surgery a patient under goes, the stress response, metabolic changes, immune regulation, inflammation, and wound healing will almost certainly be critical factors affecting recovery. 2.1 Post Surgical Stress Response and Immune Regulation The post surgical stress response is intimately connected with immune regulation and inflammation. Glucocorticoids, which are almost invariably heightened immediately after surgery, simultaneously suppress the adaptive immune response and inflammation, and stimulate the innate immune respons e. (Figure 1) They downregulate expression of proinflammatory cytokines like IL 1, lymphotoxin beta, IL 1 a, IL 8, IFN alpha, IFN beta, and TNF alpha, but upregulate TGF beta3, IL 10, and IL10 R. Many proinflammatory ligands have also been found to be do wnregulated by glucocorticoids, while anti inflammatory soluble mediators tend to be upregulated. (Bornstein et al., 2006) The overall effect of glucocorticoids is therefore antagonistic to inflammation, and a balance between glucocorticoids, inflammation and adaptive immunity is critical for simultaneously preventing pathogenic inflammation and staving off infection. Although otherwise antagonistic, glucocorticoids and proinflammatory cytokines work synergistically to stimulate expression of Toll like receptors (TLRs), specifically TLR 2 and TLR 4 in humans, which detect bacterial and viral infections, and are a critical aspect of innate immunity. (Bornstein et al., 2006) Patients with single nucleotide
6 polymorphisms (SNPs) in TLR 2, for example, seem t o be more susceptible to infection (Lorenz et al., 2000; Woehrle et al., 2008). Normally, when agonized by pathogens, TLRs stimulate expression of proinflammatory cytokines and glucocorticoids to respond to the detected infection. However, long term stimu lation of TLRs is associated with chronic metabolic and inflammatory syndromes, (Wong et al., 2009) and unnecessary over activation of TLRs can potentially harm patients. Since essentially every aspect of the stress and immune response can be either benefi cial or detrimental, depending on the degree of the response, treatment should focus on restoring an effective balance rather than simply maximizing or minimizing one aspect of the response. Figure 1: Bidirectional Regulation between the Stress and Immu ne Responses : Glucocorticoids decrease expression of proinflammatory cytokines, counteracting increases in cytokine expression caused by tissue damage, EFA derived eicosanoids, and/or TLR activation. Glucocorticoids also attenuate the adaptive immune resp onse, but increase the innate immune response through increasing expression of TLRs. These TLRs can be activated by pathogens like bacteria or viruses or by saturated fatty acids, but can also be stimulated by proinflammatory cytokines, and when activated stimulate both glucocorticoid production and proinflammatory cytokine expression.
7 2.2 Systemic Inflammation Inflammation is essential to the immune response, and is a critical factor in all kinds of wound healing, both internal and external. Howeve r, it is also involved in the pathology of many common diseases and conditions, including some like arthritis that involve autoimmune responses, as well as atherosclerosis, allergies, neurodegenerative diseases, and cancer. Although glucocorticoids depres s inflammation, tissue damage inherent to surgery, or the presence of bacterial or viral pathogens, triggers the release of proinflammatory cytokines in order to facilitate healing and fight infection at injured sites. Cytokines normally function as autoc rine or paracrine mediators, but with excessive expression, can enter circulation and cause pathological systemic inflammation, associated with poor outcomes in major trauma and sepsis. (Thomas et al., 2004) The spread of cytokines throughout the body, re ferred to as systemic inflammatory response syndrome (SIRS) can progress to life threatening complications like sepsis, multiple organ failure (MOF), acute respiratory distress syndrome (ARDS), and acute lung injury (ALI). (Miyaoka et al., 2005) The infla mmatory process is regulated by a complex array of pro inflammatory and resolving mediators. Products of the clotting system like plasmin and fibrinopeptides, fibrinolytic system products, kinins (bradykinin), vasoactive amines, substance P, complement sy stem by products, eicosanoids, cell adhesion molecules, cytokines, chemokines, oxygen derived free radicals, and nitric oxide all drive the inflammatory response. Cyclopentenone prostaglandins, lipoxins and resolvins, NF !B, apoptosis mediators (caspases, CD44), and annexin 1 have all been found to be involved in
8 resolution of inflammation. (Gilroy et al., 2004) Many inflammatory mediators have multiple contradictory effects. (Table 1) Table 1: Some Key Mediators of Inflammation and Resolution Mediator D escription Pro inflammatory Anti Inflammatory or Resolving NF kB Transcription Factors Regulates expression of pro inflammatory cytokines and chemokines, and controls expression of anti apoptotic genes With alternative DNA binding p50 p50 homodimer comple xes, involved in repression of pro inflammatory genes and promotion of leukocyte apoptosis Eicosanoids Derived from AA, DHA, or EPA; includes prostaglandins, prostacyclins, thromboxanes, and leukotrienes Cause vasodilation, increase vascular permeability stimulate pro inflammatory cytokines, cause fever Some eicosanoid derived metabolites are pro resolving (see lipoxins and resolvins) Lipoxins Eicosanoid Metabolites N/A Inhibit PMN chemotaxis, PMN adhesion to and transmigration through epithelial cells, and stimulate resolving type monocyte adherence and chemotaxis Resolvins Eicosanoid Metabolites (EPA/DHA derived) N/A Inhibit leukocyte trafficking and pro inflammatory cytokine release Nitric Oxide (NO) Signaling molecule and free radical Activates NF kB, vasodilator, toxic to bacteria Can downregulate inflammatory response in the GI tract and scavenge free radicals Cytokines Protein Signaling Molecules, e.g. interferon, interleukin, and growth factors, secreted by immune cells IL 1, IL 6, IL 8, and T NF alpha can activate neutrophils IL 10, IL 4 down regulate inflammatory response
9 The pro inflammatory mediators have only been described within the last half century, but drugs based on interrupting the synthesis or action these mediators, including ster oids, antihistamines, and non steroidal anti inflammatory drugs (NSAIDs), are already common, and are available both with and without a prescription. (Gilroy et al, 2004) Although the prevalence of these drugs is reflective of their efficacy, they all com e with side effects that can limit their usefulness, particularly in patients with pre existing conditions. The inflammatory response is meant to prevent infection, and is therefore a beneficial event as long as it does not become chronic or amplified beyo nd what is necessary, so naturally limiting it can cause some serious side effects. Steroids can cause osteoporosis and impair wound healing, selective COX 2 inhibitors may lead to an increased risk of thrombosis, and anti TNF therapy can lead to increased rates of infection. Even aspirin, which is recommended in low doses by cardiologists as prophylaxis for heart disease, can contribute to the formation of stomach ulcers. Many patients could therefore benefit from therapies that could either replace or work synergistically with the current standard anti inflammatory drugs, so that dosages of more risky drugs could be lowered or even eliminated. Inflammation resolving mediators, like resolvins, lipoxins, and maresins, are an even more recent discovery than pro inflammatory mediators, and have been described only within the past two decades, but are rich in therapeutic potential. (Serhan et al., 2008)
10 2.3 Oxidative Stress and Gastrointestinal Involvement in Pathogenic Infl ammatory Syndromes The gastrointestinal tract is sensitive to surgical stress from any type of surgery. Shunting of blood to vital organs during physiological stress results in decreased mucosal blood flow in the gastrointestinal tract. Hypoperfusion comp romises the integrity of the mucosal barrier first by suppressing production of mucus and limiting the ability to remove back diffusing protons, and then through oxidative stress resulting from reperfusion. When hypoxic conditions are reversed by reperfus ion, reactive oxygen species like superoxide and hydrogen peroxide are generated by xanthine oxidase, activated neutrophils, and dysfunctional mitochondria (which often become dysfunctional through oxidative stress). These ROS lead to overgrowth and incre ased hydrophobicity and virulence of bacteria, and alter membrane and surfactant glycosylation, allowing bacteria that would normally be sequestered in the gut lumen to adhere to the mucosal epithelium and translocate into circulation. (Thomas et al., 2004 ) (Figure 2)
11 Figure 2: (from Thomas et al., 2004) Surgical stress often results in generation of reactive oxygen species, which can alter the luminal bacterial population, bacterial hydrophobicity, and glycosylation of the brush border membrane and surfa ctants. Together, these alterations can cause an increase in bacterial adherence to the mucosal epithelium, and therefore an increase in bacterial translocation. (BBM brush border membrane) The spread of bacteria to other areas of the body from the gut is thought to initiate sepsis and/or multiple organ failure. Superoxide and hydroxyl radicals also compromise the structure and function of the brush border membrane (BBM) by inducing membrane lipid peroxidation, and provoking activation and translocation of phospholipase A 2 (PLA 2 ) onto the BBM. In the brush border membrane, PLA 2 leads to phospholipid degradation and generation of arachidonic acid, which can be used to produce proinflammatory mediators that can then reach other organs through systemic cir culation via the lymphatics. Together with cytokines released in response to oxidative stress and tissue damage (which induce neutrophil recruitment and activation of transcriptional factors like NF kB and activator
12 protein 1 that further amplify the infla mmatory response and tissue damage), t he circulating AA derived eicosanoids result in sequestration of neutrophils in the lungs or other organs and most likely cause the oxidative stress and damage associated with inflammatory syndromes like acute respirat ory distress syndrome (ARDS) and multiple organ failure (MOF). ( Thomas et al., 2004) 2.4 Metabolic Changes Insulin resistance, and a diabetes like state of hyperglycemia, typically develops after elective surgery, and can even last five days or more, dep ending on the level of trauma caused by the surgery. Since postoperative reduction in insulin sensitivity has been associated with longer hospital stays, reducing post operative insulin resistance is a potential target for clinical improvement. (Thorell et al., 1999) Postoperative insulin resistance can be partially attenuated by foregoing the common practice of pre surgical fasting and instead feeding patients carbohydrate rich drinks preoperatively (Awad et al., 2010). However, glucocorticoid and cytokin e regulated metabolic changes still occur even in preoperatively fed patients. More invasive types of surgery and greater intraoperative blood loss, which would both typically lead to greater levels of glucocorticoids and cytokines, are therefore both inde pendently correlated with increased post operative insulin resistance. (Thorell et al., 1999) Gluconeogenesis occurs as a complication of diabetes (Naskar et al., 2011), and similarly goes hand in hand with hyperglycemia and insulin resistance in surgical patients. Glycogenolysis and gluconeogensis are enhanced by high postoperative levels of catecholamines, glucocorticoids, and cytokines. Skeletal muscle is catabolized to provide an endogenous
13 supply of amino acid substrates to meet high demands for synt hesis of cells and proteinaceous mediators, and gluconeogenesis. (Grimble, 1998) Intense and/or prolonged catabolism, however, leads to immunosuppression, erosion of lean body mass, delayed wound healing, and fatigue, and is therefore associated with prol onged convalescence and increased morbidity. (Donatelli et al., 2006) Increased free fatty acid and triglyceride concentrations attached to VLDL and LDL also follows administration of IL 1 and TNF alpha, due to enhanced lipolysis in adipose tissue and inc reased hepatic lipogenesis. (Grimble, 1998) Although similar lipid profiles seen in diabetic patients are risk factors for cardiovascular disease, effects of these short term changes in lipid parameters have not been studied in surgical patients. 2.5 Wo und Healing Another consideration in post surgical recovery is healing of surgical wounds. Not only are improperly healed wounds unattractive, delayed wound healing prolongs susceptibility to infection. At the same time, an infected wound is unable to h eal until the infection is quenched. If the infection overwhelms the patient's immune response and continues to provoke inflammation, wounds can become chronic, and tissue damage can spread rather than decrease over time. Various factors contribute to wo und healing, including the inflammatory response itself, collagen deposition and re epithelialization. (Guo et al., 2010)
14 III. Fish Oil Since Bang and Dyerberg associated fish oil consumption with lower rates of cardiovascular disease in the 1970s (J acobsen, 2010), studies on the beneficial effects of fish oil have mushroomed into a significant body of research. Fish oil is the classic functional food success story with research sparked by traditional diet or medicine validating health claims and r evealing abundant functional potential. In the last several decades, docosahexenoic acid (DHA) and eicosapentenoic acid (EPA), the omega 3 fatty acids in fish oil, have been found to be involved in inflammatory and immune regulation, and therefore show po tential in the prevention and even treatment of many conditions, including depression, cardiovascular disease, neurodegenerative disorders, arthritis, and other inflammation related conditions. Fish oil capsules have become a popular over the counter supp lement, as many of the proven and potential benefits of omega 3's have reached the public through popular media, and at the same time, use of fish oil supplements has been legitimized by their relatively recent acceptance among cardiologists, who now routi nely prescribe omega 3 fatty acid supplements for patients at risk for heart disease. Within the past decade, significant research on the use of fish oil in lipid emulsions as a part of enteral and parenteral nutrition for critically ill patients, includi ng surgical patients, has led to recommendations by the European Society for Parenteral and Enteral Nutrition (ESPEN) and the Canadian Society for Clinical Nutrition (CSCN) to include fish oil in lipid emulsions. Although the official position of the Amer ican Society for Parenteral and Enteral Nutrition (ASPEN) also favors the use of omega 3 fatty acids in lipid emulsions (as expressed in a 2012 "Position Paper" by Vanek et al.), there is still lingering skepticism about the safety and efficacy of fish oil for
15 critically ill patients, and consequently new fish oil containing lipid emulsions are not yet available in the United States. 3.1 Evidence from Clinical and Animal Studies for Perioperative Fish Oil Supplementation Most international societies fo r critical care nutrition, including the ESPEN and CSCN, agree that the use of fish oil in enteral and parenteral lipid emulsion formulas is safe and beneficial for the majority of critical care patients. (Wischmeyer, 2011) The initial introduction of soyb ean oil based intravenous fat emulsions in 1961 was a significant improvement from previously used dextrose only parenteral formulas, which could cause hepatic steatosis, respiratory insufficiency, and hyperglycemia induced compromised immune function. Ho wever, after the discovery that 100% soybean oil lipid emulsions (high in omega 6 fatty acids) actually amplify the stress response, as indicated by high post operative serum interleukin 6 (IL 6) and C reactive protein, and depress immune function, as demo nstrated by decreased stimulated lymphocyte proliferation (Bernabe Garcia et al., 2011), the need for alternative oil based emulsions became clear. Not only has replacement of soybean oil with fish oil been shown to attenuate the inflammatory and immune d epressing effects of the former, it has also been shown to have additional immune enhancing and anti inflammatory effects. Although safety has been confirmed and efficacy shown in a plethora of studies, an inconsistency in study design, and lack of clear safe and effective dosages for specific conditions, have been cited to explain why soybean oil only lipid emulsions are still the only lipid emulsion formulas available in the United States. (Vanek et al., 2012)
16 Immune enhancing effects of fish oil have be en confirmed by various clinical and animal studies. One study found that rats fed diets rich in omega 3 fatty acids showed a significant decrease in immunosuppression after tumor excision surgery as compared to rodents fed omega 6 fatty acid rich diets. Syngeneic melanoma cells had been implanted in the rats' footpads and allowed to grow into tumors of a particular size before being excised. Fish oil's beneficial effect on post surgical immunosuppression prevented metastasis, which typically follows surgi cal removal of primary tumors, by increasing scavenging T cell activity, and therefore greatly enhanced recurrence free survival. (Goldfarb et al., 2011) Similarly promising results were found when Larsen et al. used a lipid emulsion containing 10% fish oi l to feed infants undergoing open heart surgery. This study found that, compared with infants fed n 6 polyunsaturated fatty acids alone, the fish oil fed infants had reduced levels of TNF and shortened hospital stays. (Larsen et al, 2011) A double blinded randomized controlled trial by Farquharson et al. found that cardiac surgery patients who ingested fish oil from 3 weeks prior to 6 days after surgery spent significantly less time in the intensive care unit post surgery. (Farquharson et al., 2011) A 2011 prospective randomized double blind placebo controlled clinical trial of 28 patients with severe sepsis at a hospital in Taiwan found that treatment with a 10% fish oil lipid emulsion was safe and reduced clinical severity of sepsis based on Acute Physiology and Chronic Health Evaluation (APACHE) II and III, and Simplified Acute Physiology (SAP) scores (Khor et al., 2011). A recent review by Bernabe Garcia et al. observed that results f rom studies of fish oil supplementation in abdominal surgery patients varied from not significant to suggesting beneficial effects on infection, length of stay in intensive care, length of hospital stay, and mortality, but that this variation likely
17 result ed from inconsistencies between studies in periods of ingestion and quantities of fish oil. (Bernabe Garcia et al., 2011) These varied results highlight the importance of determining optimal dosages and timing of omega 3 fatty acid consumption for clinical use. An even more recent study by Han et al. found that supplementation with parenteral omega 3 fatty acids was both safe and potentially improved immune function and reduced hyperinflammatory response in patients after major surgery. (Han et al., 2012) Omega 3 fatty acid supplementation has also been found to be effective when paired with arginine, nucleotide, and antioxidant supplementation in "immune enhancing diets" (IEDs). (Wischmeyer, 2011) 3.2 Fish Oil Mechanism of Action Increased intake of th e n 3 polyunsaturated fatty acids in fish oil increases the proportion of n 3 fatty acids in the plasma membrane and in the lipid membranes surrounding organelles like the golgi apparatus and mitochondria. (Shaikh et al., 2012) This alteration of lipid mem brane composition has myriad effects, many of which are just beginning to be elucidated. The omega 3 fatty acids in fish oil shift eicosanoid production towards less pro inflammatory mediators, affect signaling pathways by disrupting the organization of t he plasma membrane, produce resolving mediators, and decrease leukocyte chemotaxis, expression of adhesion molecules, and production of reactive oxygen species (ROS) and inflammatory cytokines. The net result is a significant decrease in pathological infl ammation, but simultaneous maintenance and promotion of beneficial immune function. The most well described mechanism of fish oil is the alteration of eicosanoid synthesis. In inflammatory cell membranes, 20 carbon polyunsaturated fatty acids
18 (PUFAs), in cluding the omega 3 fatty acid EPA and the omega 6 PUFA arachidonic acid (AA), serve as substrates for eicosanoid synthesis. Normally, AA is available in higher proportions than other 20 carbon PUFAs, and therefore acts as the primary substrate for eicosa noid synthesis. When the dietary ratio of omega 3:omega 6 fatty acid increases, however, this ratio is reflected in inflammatory cell membranes. Omega 3 fatty acids replace omega 6 fatty acids, particularly AA, in inflammatory cell membranes, and therefo re make AA less available for eicosanoid synthesis. (Calder, 2006) EPA also competes with AA for the cyclooxygenase (COX) and lipooxygenase (LOX) enzymes that convert these essential fatty acids into eicosanoid inflammatory mediators. (Figure 3) Although E PA is used to synthesize similar mediators to those synthesized from AA, many EPA derived mediators have been shown to be significantly less potent than their AA derived counterparts. (Calder, 2006)
19 Figure 3: (Adapted f rom Calder, 2006) EPA and AA are converted into eicosanoids via the same enzymes. The eicosanoids produced from EPA, however, are significantly less pro inflammatory. COX, Cyclooxygenase; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic a cid; HPEPE, hydroperoxyeicosapentaenoic acid; HPETE, hydroxyperoxyeicosatetraenoic acid; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane. AA products are shown in red and EPA products are shown in blue EPA and DHA are also substr ates for the generation of resolvins and protectins, which are involved in the resolution of inflammation. (Shaikh, 2012) Termination of inflammation was once thought to be a passive process, involving the spontaneous break down of pro inflammatory mediato rs, but within the last two decades the discovery of active endogenous chemical resolving mediators has significantly changed this picture, and given rise to an area of great therapeutic potential for the myriad common chronic inflammatory disorders. (Kasu ga et al., 2008) EPA and DHA can decrease leukocyte chemotaxis, expression of adhesion molecules, production of reactive oxygen species (ROS), and inflammatory cytokine production (Yates et al., 2011), most likely indirectly, Arachidonic acid (AA) or Eicosapentaenoic Acid (EPA) COX 15 LOX 12 LOX 5 LOX PGG 2 PGG 3 15 HPETE 15 HPEPE 5 HPETE 5 HPEPE 12 HPETE 12 HPEPE PGH 2 PGH 3 15 HETE 15 HEPE LTA 4 LTA 5 12 HETE 12 HEPE LTC 4 LTC 5 5 HETE 5 HEPE LTD 4 LTD 5 LTE 4 LTE 5 LTB 4 LTB 5 Lipoxin A 4 PGD 2 PGD 3 TXA 2 TXA 3 PGI 2 PGI 3 PGE 2 PGE 3 PGF 2 PGF 3
20 through their pro resolving pr oducts. Resolvin D1, derived from DHA, for example, stops neutrophil chemotaxis. (Kasuga et al., 2008) EPA and DHA have been shown to disrupt membrane organization. Most studies on the effects of omega 3 fatty acids on lipid membranes have used DHA, which consists of a 22 carbon chain with 6 double bonds. DHA transitions between multiple conformations, including bent structures in which the terminal methyl approaches the head group region of the phospholipid, making it incompatible with highly ordered sat urated acyl chains and cholesterol in lipid rafts. (Figure 4) Disruption of lipid rafts can affect the localization and function of membrane proteins, and therefore lead to inflammation regulating changes in cell signaling and transcription. (Shaikh, 2012 ) For example, Wong et al found that DHA prevented incorporation of inflammation stimulating toll like receptors (TLRs) into lipid rafts, thereby inhibiting TLR activation (Wong et al., 2009). Figure 4: These different conformations of DHA were obtained with molecular dynamic simulations. The kinked conformations caused by DHA's 6 double bonds render it incompatible with ordered saturated acyl chains and cholesterol. (From Shaikh, 2012) Dietary omega 3 fatty acids also appear to decrease expression of arginase 1, an enzyme which breaks down arginine and contributes to arginine deficiency after physical
21 injury. (Bansal et al., 2005) Since arginine deficiency is associated with suppression of T lymphocyte function and NO production (Zhu et al., 2010), n 3 fatty acid consumption in surgical patients could also improve clinical outcomes through restoring these aspects of immune function. Omega 3 fatty acid emulsions have been shown to be effective, particularly when paired with arginine supplementation in i mmune enhancing diets (IEDs) to further counteract disease induced arginine deficiency. (Wischmeyer, 2011) Most studies to date have not discriminated between DHA and EPA, but in reality their effects are not precisely the same. DHA is particularly involv ed in brain development and function, and is distributed primarily in the retina, sperm, cerebral cortex, spleen, and blood cells, whereas EPA is found in muscle, liver, spleen, and red blood cells. (Kasuga et al., 2008) Functional differences may account for some inconsistencies between studies using equal EPA+DHA concentrations, but different proportions of the two fatty acids. For example, a dose response study by Schmidt et al suggested that maximum inhibition of leukocyte chemotaxis occurred at an int ake of about 1.3 g EPA+DHA/d, while a study by Healy et al did not find an effect on neutrophil chemotaxis even when doses of up to 2.25 g EPA+DHA/d were used. (Schmidt et al., 1991; Healy et al., 2000) The latter study used a fish oil high in DHA and low in EPA, such that the highest dose of EPA provided was actually still lower than the dose of EPA provided in the lowest effective dose used by Schmidt et al, implying that EPA rather than DHA is likely responsible for fish oil's anti chemotactic effects. It is probable that DHA and EPA have some similar or even identical effects, but it is also certain that they have at least some functional differences as well, which have not yet been entirely determined by current research. Future studies should therefo re
22 differentiate between DHA and EPA mechanisms and take into account specific amounts of these two omega 3 fatty acids, to determine ideal dosages of each. 3.3 Application of Fish Oil Supplementation in Surgical Patients: Potential Risks and Benefits S ince lowering the omega 6:omega 3 ratio causes a decrease in not only pro inflammatory prostaglandin activity, but also thromboxane activity, and would therefore theoretically decrease clotting and arterial constriction, it is possible that preoperative fi sh oil supplementation could lead to increased blood loss in surgical patients. Although the potential of fish oil to decrease clotting should be taken into account for potential combinational effects in patients taking prophylactic aspirin, beta blockers or blood thinners, this effect has not been seen to any significant extent in current studies (Bernabe Garcia et al., 2011). Fish oil is considered safe, and is currently recommended internationally in guidelines for enteral and parenteral nutrition (Si nger et al., 2009; Wischmeyer, 2011). Incorporation of fish oil into patient treatment is lagging in many hospitals, however, and discussions on fish oil supplementation often ignore patients who are able to take food by mouth. Although patients in this demographic tend to be in less severe condition than those who require enteral or parenteral nutrition, and therefore attract less attention as subjects for research, these patients could very likely also benefit from fish oil supplementation, or even con sumption of foods high in omega 3 fatty acids. Fatty fish, like salmon or sardines, which have a high EPA/DHA content, but are low in heavy metal content, could be served routinely to patients. Alternatively, in order to cater to
23 patient preference, and thereby reduce food waste and under consumption, foods like milk or yogurt that have been artificially supplemented with EPA and DHA could also be used advantageously in the hospital setting. (Jacobsen, 2010) IV. Virgin Coconut Oil (VCO) Coconut oil i s widely used in traditional medicine throughout Asia and in some parts of Latin America. It has been used in the Ayurvedic system of medicine in India, and in parts of Indonesia and Thailand, for example, to treat wounds, microbial and parasitic infecti ons, various skin conditions, and even heart disease. (Nevin and Rajamohan, 2010; DebMandal et al., 2011) Virgin coconut oil (VCO) has also recently been marketed as a health promoting "functional food" throughout the world, including in the United States Recent research suggests that coconut oil has significant antimicrobial and antioxidant activity and may have anti inflammatory, antinociceptive, antipyretic, antithrombotic, hepatoprotective, antihyperglycemic, and antihyperlipidemic effects. (Intahphu ak et al., 2010; Nevin et al., 2006, 2008; Naskar et al., 2011; Zakaria et al., 2010, 2011) The metabolic effects of coconut oil consumption along with its antioxidant activity could potentially help normalize metabolism and decrease oxidative stress in su rgical patients, and therefore ultimately aid in wound healing and recovery. The little clinical research that has been done on coconut oil, however, has mostly focused on either weight control or lipid profiles (Assuno et al., 2009; Feranil et al., 201 1), and the only studies of coconut oil in hospitalized patients to date have used medium chain triglycerides (MCTs) isolated from coconut oil (Vanek et al., 2012), which
24 would likely not demonstrate the full therapeutic potential of whole virgin coconut o il that has been suggested by studies in rats (Nevin and Rajamohan, 2004, 2006, 2008, 2010). 4.1 Not All Coconut Oil is Created Equal Various methods can be used to produce coconut oil. The two primary methods are dry processing, involving extraction f rom copra (dried coconut meat), and wet processing, using fresh coconut milk. Oil extracted from copra is subsequently refined, bleached and deodorized to make it edible. (Marina et al., 2009) Virgin coconut oil, on the other hand, is extracted from cocon ut milk without the use of chemical solvents, using mechanical methods, fermentation, or sometimes moderate heating to break the emulsion. Although there is great variety in the specific processing methods used to make virgin coconut oil, in general these gentler methods preserve minor biological components that are largely lost in the refining process for copra oil. (Carandang, 2008) Refined, bleached and deodorized (RBD) coconut oil has virtually the same fatty acid compositions as virgin coconut oil, b ut VCO maintains a significantly higher polyphenol content and therefore higher antioxidant activity. (Marina et al., 2009; Nevin and Rajamohan, 2006) The biologically active substances in VCO include tocopherols, tocotrienols, phytosterols, flavonoids, a nd stanols. Although even in VCO these substances are present in very small quantities, they are thought to be responsible for many of the oil's health benefits. (Carandang, 2008) Coconut oil, as a saturated fatty acid, was until recently believed to be h yperlipidemic and therefore detrimental to cardiovascular health, and some controversy
25 still surrounds this idea. As it turns out, many studies supposedly confirming detrimental hyperlipidemic effects of coconut oil used hydrogenated coconut oil rather th an VCO, and therefore reflected the negative effects now known to be associated with hydrogenated oils rather than the true effect of natural coconut oil. Recent clinical and animal studies using VCO have not found any hyperlipidemic effect, and have even demonstrated improved lipid profiles, with raised HDL ("good") cholesterol levels and lower LDL to HDL cholesterol ratios. (Feranil et al., 2011; Nevin and Rajamohan, 2004) VCO has also been found to have a greater beneficial effect on lipid parameters t han RBD copra oil. (Nevin and Rajamohan, 2004) The high polyphenol content of VCO may help to maintain a healthy lipid profile by inhibiting LDL oxidation, reversing cholesterol transport, and reducing intestinal absorption of cholesterol. (DebMandal et al ., 2011; Nevin and Rajamohan, 2004) 4.2 Minor Active Components of Coconut Oil VCO contains a long list of minor active components, including tocopherols, tocotrienols, phytosterols, squalene, stanols, flavonoids, and other polyphenols. (Carandang, 2008; Zakaria et al., 2011) Many of the various beneficial properties that have been attributed to virgin coconut oil, including increasing antioxidant enzymes and reducing lipid peroxidation (Nevin et al., 2006), and moderate antinociceptive and anti inflammato ry properties (Zakaria et al., 2011), are likely caused by one, or several, of these minor components. Tocopherols and tocotrienols have vitamin E activity, and are therefore effective antioxidants, and may also have anti atherogenic, anticarcinogenic, an d immunomodulatory actions. Phytosterols, which are cholesterol like plant
26 compounds, and squalene, a metabolic precursor of sterols, are thought to help lower cholesterol levels, improve diabetic blood sugar levels, and reduce inflammation in autoimmune disorders. Stanols are also believed to help lower cholesterol levels, primarily through blocking absorption of cholesterol in the gastrointestinal tract. Flavonoids and other polyphenols have antioxidant activity, and flavonoids may also be anti viral, anti allergic, antiplatelet, anti inflammatory, and antitumor. (Carandang, 2008) 4.3 Medium Chain Triglycerides Although polyphenol content distinguishes VCO from copra oil and contributes significantly to its beneficial effects, the fatty acids common t o both forms of coconut oil have benefits of their own. Coconut oil is rich in medium chain triglycerides (MCTs), particularly lauric acid, caprylic acid, and capric acid. (Marina et al., 2009) Medium chain triglycerides (MCTs) undergo oxidation more rapi dly than longer fatty acids, most likely because they are able to enter mitochondria for oxidation independently of the carnitine acyl transferase system used to transport long chain fatty acids. (Ippagunta et al., 2011; Assuno et al., 2009) Additionall y, MCTs are not readily incorporated into the triglycerides of adipose tissue. (St Onge et al., 2002) MCTs are therefore a very efficient source of energy, which may both have anti obesity effects (Assuncao et al, 2009) and provide an efficient source of e nergy for those with high energy demands, including post surgical patients. It is important to note that although some studies have found that coconut oil helped maintain a healthy energy balance and contributed to favorable lipid profiles, raising HDL le vels and lowering LDL levels, studies using quantities of coconut oil greater than the normal recommended fat intake have found opposite effects
27 (Assuno et al., 2009). Although these latter studies have been used to "demonize" coconut oil, they should n ot be used to rule out promising benefits of more reasonable dosages, which can be used in combination with a small amount of other oils to prevent essential fatty acid deficiency. In a clinical trial in obese women by Assuno et al., coconut oil increase d high density lipoprotein (HDL) levels and decreased LDL:HDL ratios, thereby theoretically reducing risk for heart disease (Assuno et al., 2009) As some biochemical studies using isolated lauric acid have shown effects consistent with hypercholesterole mia, however, it is likely VCO's combination of antioxidants with its saturated fatty acids that prevents any hyperlipidemic effects (Wong et al., 2009). MCTs are generally considered inflammatorily neutral. A combination of caprylic and capric acid extr acted from coconut oil has been added to some lipid emulsions for total parenteral nutrition (TPN), including SMOFlipid (30% MCT), and Lipofundin MCT (50% MCT), which are currently available in Europe but not in the United States (Bernabe Garcia et al., 20 11; Vanek et al., 2012). These emulsions are considered safe and preferable to soybean only lipid e mulsions, but do not produce the same anti inflammatory and immune modulating effect as fish oil containing emulsions Lauric acid and capric acid have bee n shown to enhance insulin secretion (Garfinkel et al., 1992), however, which might help counteract the effects of post surgical insulin resistance. Additionally, MCTs have been known to have antimicrobial effects since at least the 1970s, when a study by Kabara et al. found that many fatty acids, particularly lauric acid were inhibitory against gram positive organisms (Kabara et al., 1972) The antiviral and antibacterial effects of fatty acids likely originate from their ability to disrupt these
28 microor ganisms' lipid membranes, while antifungal effects come from inhibition of spore germination or radial growth. Monolaurin, derived from lauric acid, and capric acid are particularly potent antifungal agents. (DebMandal et al., 2011) Ingestion and/or topica l application of coconut oil can therefore help fight or prevent infection in susceptible patients. (Nevin and Rajamohan, 2010) 4.4 Proposed Therapeutic Mechanism of Virgin Coconut Oil in Surgical Patients Research on coconut oil is relatively sparse, b ut promising. Inadequate study designs and the general paucity of research particularly in the form of human clinical trials, has prevented complete acceptance of coconut oil as a health food in western medicine. Although virgin coconut oil has not been extensively considered for use in surgical patients, its metabolic, antioxidant, and antimicrobial effects suggest that it could potentially be beneficial if incorporated into the diets of these patients. Several of the conditions that occur in surgical patients as described in Chapter 2 could be combated by the components of VCO. Enhancement of insulin secretion by lauric acid and capric acid (Garfinkel et al., 1992) could help counteract insulin resistance and hyperglycemia; the antioxidant activity of VCO's polyphenol fraction ( Nevin and Rajamohan, 2006) would help reduce tissue damage from oxidative stress, perhaps particularly in the gastrointestinal tract, which is thought to play an important role in the development of sepsis and multiple organ fai lure; the antimicrobial properties of lauric acid and other MCTs in coconut oil (DebMandal et al., 2011) could help fight infection; and energy from readily oxidizable MCTs (Ippagunta et al., 2011 ) could help meet patients' increased energy demand and ther eby perhaps help to reduce excessive catabolic
29 metabolism and fatigue. (Figure 5) Clinical trials in surgical patients should be carried out to determine whether the proposed effects of coconut oil are effective in the postoperative setting, and whether th ese effects can indeed improve clinical outcomes as might be expected.
30 Figure 5: Possible therapeutic mechanisms of VCO in surgical patients. Insulin Resistance and Hyperglycemia Tissue Damage from Oxidative Stress Infection Increased Energy Demand The Surgical Patient Virgin Coconut Oil Lauric and capric acid enhance insulin secretion (Garfinkel et al., 1992) Polyphenols with high antioxidant activity ( Nevin and Rajamohan, 2006) Potent a ntimicrobial fatty acids (Kabara et al., 1972) MCTs provide a readily available energy source (Assuncao et al., 2009)
31 V. Turmeric (Curcumin) Turmeric is yet another functional food that h as been used for centuries, but has only recently found its way into peer reviewed journals. The southeast Asian spice, best known in the West for its use in curries, contains curcuminoids, which give turmeric both its yellow color and its pharmacological properties. Curcumin is the most abundant of these curcuminoids, and is often used to refer to the entire group of active compounds. (Figure 6) Figure 6: (From Epstein et al., 2010)The curcuminoids: curcumin and it natural analogues and metabolite s. Curcuminoids have confounded the traditional single active ingredient mindset of pharmacology, as they have been shown to be more effective in their natural combination in turmeric than any single compound alone. (Epstein et al., 2010) Curcumin has be en shown to enhance anti inflammatory, antioxidant, anticarcinogenic, antimutagenic, OCH 3 OCH 3
32 anticoagulant, antidiabetic, antibacterial, antifungal, antiviral, antifibrotic, antivenom, antiulcer, hypotensive, antihypercholesterolemia, and cardioprotective biologic al activities. (Ammon and Whal, 1991; Chattopadhyay et al., 2004) The bright yellow compound functions in multiple ways to create a complex array of effects, primarily stemming from its antioxidant and anti inflammatory properties. 5.1 Curcumin Target s Multiple Aspects of Inflammatory Pathways Curcumin exerts its therapeutic effects though targeting multiple aspects of potentially pathological inflammatory pathways. Curcumin has been found to inhibit the catalytic activities of phospholipase A 2 and t herefore modulate AA cascades through affecting cyclooxygenase II (COX 2) and lipoxygenase (LOX). (Ahmed et al., 2005) It can also inhibit matrix metalloproteinase gene expression by inhibiting the c Jun N terminal kinase (JNK), activation protein 1 (AP 1) and nuclear factor kappa B (NF kB) pathways in human chondrocytes, and hence also inhibits inflammation through affecting production of IL 8, monocyte inflammatory protein 1 (MIP 1), monocyte chemotactic protein 1 (MCP 1), IL 1, IL 6, TNF alpha, and lipo polysaccharide (LPS) stimulated monocytes and macrophages. Curcumin also suppresses nitric oxide synthase (NOS), and protects hemoglobin, lipids, and DNA against degradation from oxidative stress. (Naik et al., 2011; Epstein et al., 2010) The action of cu rcumin on inflammation is dynamic, complex and multi faceted.
33 5.2 Epigenetic Regulation Curcumin has epigenetic effects on inflammation related genes. Bora Tatar et al. found that curcumin is a more potent histone deactetylase (HDAC) inhibitor than even the known HDAC inhibitors valproic acid and sodium butyrate. (Bora Tatar et al., 2009) Studies have shown that curcumin treatment significantly reduces levels of HDAC 1, 3, and 8, all of which are involved in pro inflammatory transcriptional regulation. (Chen et al., 2007) At the same time, curcumin actually restores the histone deacetylase 2 (HDAC2) enzyme, which is a critical component of corticosteroid anti inflammatory action. (Reuter et al., 2011) Additionally, curcumin has been found to be a potent histone acetyltransferase (HAT) inhibitor. (Balasubramanyam et al., 2004) Perhaps due to its epigenetic activity, curcumin can exert therapeutic effects even at relatively low concentrations. (Reuter et al., 2011) 5.3 Antioxidant Properties of Curcumin C urcumin also has antioxidant properties, which help regulate the damage to keratinocytes and fibroblasts from oxidative stress during the wound healing process. (Phan et al., 2001; Naik et al., 2011) Multiple possible antioxidant mechanisms have been prop osed for curcumin, and a plethora of mechanistic studies show seemingly contradictory results. However, considering that curcumin most likely acts via a variety of mechanisms, depending on the nature of the free radical and the polarity of the environment can reconcile apparent discrepancies between studies. (Galano et al., 2009) The reaction of curcumin with DPPH most likely takes place mainly through sequential proton loss electron transfer (abbreviated as the SPLET mechanism). The reaction of
34 curcumi n with OCH 3 and similar alkoxyl radicals appears to occur through hydrogen atom transfer from neutral curcumin (HAT mechanism). In highly polar environments, free radicals with high electron withdrawing character may interact with curcumin through single elect ron transfer (SET) reactions. The phenolic groups of curcumin have been experimentally confirmed to be the primary sites for all of these antioxidant reactions. (Galano et al., 2009) (Figure 7) (b) Single Electron Transfer (SET): H 3 CU + R H 3 CU + + R (c) Sequential Proton Loss Electron Transfer (SPLET): H 3 CU H 2 CU + H + H 2 CU + R H 2 CU + R H 2 CU HCU + H + (d) Hydrogen Atom Transfer from neutral curcumin (HAT): H 3 CU + R H 3 CU + R H Figure 7: Curcumin as an antioxidant (adapted from Galan o et al., 2009). H 3 CU represents protonated curcumin in the equations. (a) Shows the enol form of curcumin, which represents the majority of curcumin in most solvents (99% or more). The phenolic groups have been experimentally demonstrated to be directly i nvolved in antioxidant acivity. (b) Single Electron Transfer (SET) reaction (c) Sequential Proton Loss Electron Transfer (SPLET) reaction (d) Hydrogen Atom Transfer from neutral curcumin (HAT) reaction. (a) (
35 5.4 Wound Healing In vivo studies in mice have sho wn that curcumin greatly enhances the kinetics and extent of muscle regeneration after trauma. (Thaloor et al., 1999) These results were likely due to curcumin's inhibition of the transcription activator nuclear factor B (NF B) through inhibition of the activator phosphorylase kinase (PhK). PhK activates I B kinase, which must be phosphorylated to remove the inhibitory protein I B from NF B. By blocking NF B, curcumin blocks signaling pathways for fibroblast proliferation that could lead to scarring as well as macrophage and T cell activation, TGF #1 secretion, and conversion of fibroblasts into myofibroblasts (Heng et al., 2011) In murine wound biopsies, curcumin treated wounds showed increased collagen deposition and neovascularization. (Sidhu et al., 1998) Wounds treated with curcumin also have been found to contain increased levels of TGF #1, which stimulates the expression of fibronectin (FN) and collagen by fibroblasts and increases the rate of granulation tissue formation in vivo. (Yadav et al., 2011) 5.5 Angiogenesis Curcumin also facilitates healing through its effects on angiogenesis. (Yadav, 2011) A study by Karin et al. demonstrated curcumin's differential effects on angiogenesis in the presence and absence of serum. Curcumin inhibits angiogenesis in a serum containing environment, and is therefore useful as an anti tumor agent, but stimulates angiogenesis in a serum free environment, contributing to its positive effects on wound healing. Fibroblast growth factor (FGF) and vascular en dothelial growth factor (VEGF) are the most important pro angiogenic mediators. In both the absence and
36 presence of serum, curcumin decreases FGF2 levels, but in serum free conditions curcumin also raises levels of VEGF. (Karin et al., 2008) 5.6 Curcumi n Targets Gastrointestinal Inflammation Pathway for Initiation of Inflammatory Syndromes Based on mechanistic evidence, as well as animal and human studies, curcumin would likely be particularly advantageous in preventing the GI initiated pathway for ini tiation of inflammatory syndromes as described in 2.3. Avci et al. found that curcumin had significant protective effects against skeletal muscle ischemia reperfusion injury in rats most likely d ue to its potent antioxidant activity (Avci et al., 2012). Curcumin has also been directly found to ameliorate small intestinal inflammation and inhibit pathological bacterial translocation in mice (Bereswill et al., 2010), and has been found to suppress expression of pro inflammatory cytokines in an acute lung i njury (ALI) model, partly through inhibition of TLR4 and NF kB. (Lui et al., 2012) Through both preventing ischemia reperfusion injury and inhibiting excessive cytokine release, the potent antioxidant and anti inflammatory mechanisms of curcumin could prov e to be a powerful combination for prevention and treatment of common post surgery inflammatory syndromes, including ALI, systemic inflammatory response syndrome (SIRS), and multiple organ failure (MOF). Results from animal studies and mechanistic studies have together provided an overwhelming amount of evidence for the therapeutic potential of curcumin, sparking great interest in pursuing curcumin as a therapeutic compound. As of 2009, there were
37 31 human clinical trials in progress investigating the use of curcumin for treatment of various conditions. (Epstein et al., 2010) VI. Conclusion Although nutritional therapy is not a new idea, it has been only inconsistently incorporated into hospital care. Throughout the past several decades, numerous studi es have shown both the importance of nutrition in clinical outcomes and, at the same time, the prevalence of protein and energy malnutrition in hospitals. The perioperative period is a critical period in patient care, and is an ideal time for implementati on of diet based therapy. Implementation of specialized healing diets for hospital patients, close monitoring of nutritional status, and even meeting food preferences to increase food consumption are all reasonable goals in the hospital setting, which cou ld greatly improve clinical outcome. Doctors should also make use of pre surgery diets since many dietary treatments are more effective when begun preoperatively. In each case, individual patient diets should be tailored their individual clinical situati on. Considering the known importance of many pharmaconutrients in healing, it is not far fetched to imagine that more similarly influential substrates could exist that have not yet been elaborated on by modern science or made use of in western medicine. Many more foods besides those discussed in this thesis including chia seeds, beets, cranberry juice, and kale, have already accumulated some evidence for therapeutic potential. Differential use of a variety of functional foods has great potential for tre ating disease without the development of drug resistance. The relatively recent discoveries
38 illuminating the roles of omega 3 fatty acids, turmeric, coconut oil, and other compounds in healing and disease prevention and therapy suggest that there are like ly more potential pharmaconutrients that have not yet been "discovered" or put into use in conventional western medicine. Although the popular idea that consuming any "natural" product is always safer or better is extremely fallible there are plenty of natural poisons and carcinogens in contrast to synthetic pharmaceuticals, most items now considered food have been tested for safety in humans over the course of hundreds or even thousands of years Famous drug recalls like that of thalidomide, a mornin g sickness medication that caused birth defects, and the frequent additions to the FDA drug recall webpage highlight the risks involved in introducing new pharmaceuticals for human use, even with rigorous testing protocols. It is, however, also important t o establish safe and effective dosages for pharmaconutrients, and secure non adulterated sources, so that they can be used to their best advantage. In order to be effectively incorporated into modern medicine, doctors must learn how to use natural product s in the same way that they use drugs keeping in mind possible contraindications and interactions between products, and ensuring that correct dosages are used. Successful incorporation into standard medical practice relies on research to establish drug interactions, dosages, and contraindications.
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