Dilip Ghosh, PhD, FACN, Director, nutriConnect 01.05.15
A large body of epidemiological and experimental data has demonstrated a direct link between chronic inflammation and complex diseases such as obesity, asthma and allergies, cardiovascular disease, type 2 diabetes, rheumatoid arthritis, bowel disease and several types of cancer.
While chronic diseases are caused by dysregulation of multiple genes, many modern medicines are used based on the modulation of only a single target, and therefore are less likely to be effective. Additionally, these medicines often produce numerous side effects and cannot be consumed over long periods of time. Therefore, the new paradigm proposed for the prevention and treatment of inflammatory chronic diseases either combines multiple single-targeted agents or involves a molecule that can target multiple pathways.
According to one estimate, more than 63% of the anti-cancer drugs introduced over the past 25 years have been natural products or can be traced back to natural sources (Newman & Cragg. Journal of Natural Products, 2007). In addition, some dietary agents have shown potential to inactivate inflammatory molecules by direct binding. For example, curcumin, one of the most widely studied dietary agents, has been found to bind to a number of inflammatory molecules.
Lessons from Ancestors
The Neolithic and Industrial Periods have fundamentally altered seven crucial nutritional characteristics of ancestral hominid diets by introducing food staples and food processing procedures: 1) glycemic load, 2) fatty acid composition, 3) macronutrient composition, 4) micronutrient density, 5) acid-base balance, 6) sodium-potassium ratio and 7) fiber content. These foods, in turn, adversely influence proximate nutritional factors, which universally underlie or exacerbate virtually all chronic diseases of civilization.
What is Inflammation?
Inflammation is an adaptive response triggered by noxious stimuli and conditions such as chemical or physical injury. Inflammation activates cellular and systemic components of the immune system. The initial response involves the recruitment of immune cells including macrophages, mast cells and dendritic and natural killer cells at the site of injury and subsequent release of chemical mediators such as cytokines, chemokines and reactive oxygen species to control pathogens and/or tissue repair. Chronic inflammation, by contrast, is a prolonged, dysregulatory and maladaptive response that involves persistent active inflammation, tissue destruction and failed attempts at repair. Inflammation may occur in various parts or organs of the body, including the brain, heart, lungs, eyes, nasal passages, gastrointestinal tract, throat, reproductive organs, urinary tract, joints, bones, blood vessels, etc., and is generally associated with cardiovascular disease, obesity, cancer and other disorders.
Inflammation & Chronic Diseases
Atherosclerosis. Atherosclerosis is a chronic, inflammatory disease and one of the most common causes of cardiovascular disease (CVD). Atherosclerosis begins in fetal life, slowly progresses during childhood and adolescence, and then accelerates in fits and spurts in adult life. The atherosclerotic process is initiated when cholesterol-containing low-density lipoproteins accumulate in the intima and activate the endothelium.
Cancer. An association between cancer and inflammation was made more than a century ago from the identification of leukocytes in tumor tissue. More recently, inflammation has also been implicated as affecting the patient’s ability to tolerate cytotoxic drugs.
Metabolic Syndrome. Obesity is associated with a chronic, systemic low-grade state of inflammation. Obesity-induced inflammation also plays an important role in the development of insulin resistance and type 2 diabetes.
Inflammatory Biomarkers
Although numerous biomarkers have been proposed and used in basic research to assess inflammation and risk factors associated with inflammatory diseases and to monitor the effects of prevention and/or therapy, very few of them are considered to be applicable in clinical and public health practice (see Table 1).
What’s Next?
Anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAID) and disease-modifying anti-rheumatic drugs (DMARDS), are widely used in treating various disorders. However, many of them have dose-dependent side effects, and none of them are suitable for primary prevention, which significantly limits their use.
On the other hand, it has been recognized that lifestyle and environment play an important role in inflammatory responses. In this respect, diet and dietary supplements can be key elements in managing the inflammatory process. In the past decade, understanding of the role of diet in promoting health by regulating inflammation, especially via certain nutrients or dietary components, has grown substantially (see Table 2).
Botanical Ingredients
Botanical compounds have a long history of medicinal use. The World Health Organization described traditional medicines as a principal source of healthcare for 80% of the world’s population, and there is an increased interest in the Western world for dietary supplements, functional foods and nutraceuticals. The ingredients of botanical origin are classified upon their biochemical properties based on mechanism such as antioxidants, anti-carcinogens, inflammation-inhibitors, blood pressure-reducing agents or anti-diabetics. Table 3 shows major botanicals used as anti-inflammatory compounds.
Clinically Researched Ingredients
Cyactiv, the “Blue Antioxidant.” Cyactiv (cyactiv.com) from Cerule, Klamath Falls, OR, is a proprietary, GRAS-approved extract from microalgae belonging to the photosynthetic Cyanophyta group. The primary bioactive component of Cyactiv is phycocyanin, which is known to act as an antioxidant and a selective COX-2 inhibitor with documented regulating properties.
In addition to phycocyanin, Cyactiv also contains bioactive compounds (“Non-PC Fraction”) that inhibit inflammatory actions by a different pathway, namely by inhibition of the enzyme lipoxygenase. In vitro and in vivo data have shown that Cyactiv enhances the production of regulatory and regenerative cytokines and also supports healthy cellular migration as part of immune surveillance. Three clinical studies have been completed on Cyactiv and demonstrated overall benefits including promoting healthy joints, healthy aging through antioxidant activity and increased joint and muscle comfort during daily activity.
Perluxan. Perluxan (perluxan.com) from Proprietary Nutritional Inc. (PNI), Kearny, NJ, is a proprietary, standardized supercritical extract of hops cones (Humulus lupulus L.), found to inhibit specific pro-inflammatory chemicals and derivatives based on alpha acids.
Perluxan works promptly in concert with numerous biochemical pathways responsible for inflammation with both enzymatic and non-enzymatic targets such as prostaglandin E2, cyclooxygenase 1+2, interlukein-1 and isoprostanes. This extract is virtually devoid of the undesirable phytoestrogenic and sleep inducing compounds contained in normal hops extracts and powders. Perluxan is a stable, free-flowing aromatic powder standardized to contain a minimum of 30% alpha acids (humulone, co-humulone, etc.) with high bioavailability in both tablet and capsule forms. Extensive in vitro and human clinical research has been conducted over the last decade to establish the phytomedical credibility of Perluxan.
Celadrin. Celadrin (celadrininfo.com) from PNI is a clinically effective compound in both oral and topical application in pain management developed through a proprietary process of esterifying oils. The Celadrin compound represents a matrix of fatty acid carbons, which have been scientifically arranged to achieve maximum efficacy for joint mobility and health. Results have shown fast acting (within 30 minutes) properties with rapid and deep absorption/penetration to the affected area. It works similar to the essential fatty acids EPA and DHA from fish oils. Extensive toxicity studies have demonstrated this to be a safe mix of fatty acids with no known or reported negative reactions or side effects.
Cannabidiol (CBD). One of many cannabinoids extracted from industrial hemp oil (not marijuana), CBD is considered a major non-psychoactive component. CBD is inherently safe with no known or reported toxicity. An extract from Mastix Medica, Hunt Valley, MD, (mastixmedica.com) has a very high level of CBD (15% or more) and can be used in different formats such as chewing gum and lozenges. Industrial hemp (e.g., Cannabidiol) contains only about 0.3-1.5% tetrahydrocannabinoids (THC), while marijuana that can be smoked contains about 5-10% or more THC. It is reported that CB2 receptors are primarily found in the immune system and are keyed to CBD with significant anti-inflammatory and anti-spasmodic properties.
AppleActiv. An open-label, clinical pilot study was recently conducted by NIS Labs, and involved healthy individuals experiencing moderate loss of joint range of motion (ROM), and associated recurring pain. The goal of the study was to evaluate the effects of consumption of dried apple peel powder (DAPP) on joint function and ROM. Additional in vitro and clinical testing was performed to investigate specific mechanisms of action. A full manuscript of the study has been published in The Journal of Medicinal Food, and a study abstract may be found on the PubMed site.
“We are pleased with the results of this clinical pilot study, which suggest multifaceted anti-inflammatory properties of dried apple peel powder,” said Gitte Jensen, research director at NIS Labs. “The study indicated that daily consumption of AppleActiv DAPP was associated with a statistically significant improvement in serum antioxidant protective status, as well as improved ROM.”
AppleActiv DAPP is certified organic, and contains a rich polyphenol blend with high levels of antioxidants. In the study, DAPP was shown to increase antioxidant activity, including cell protection from oxidative damage in vitro. The consumption of AppleActiv DAPP daily for 12 weeks showed both inhibited COX-2 and lipoxygenase enzyme activity. The study also observed pain reduction, which may be associated with the improved antioxidant status, and is likely linked to the anti-inflammatory effects of the polyphenols.
CurcuWIN. CurcuWIN from OmniActive Health Technologies, Morristown, NJ, (omniactives.com) is a new formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants that significantly increases curcuminoid appearance (46 times) in the blood in comparison to unformulated standard curcumin.
Curcumin is known for its antioxidant and anti-inflammatory properties and has been studied extensively for various risk factors and disease conditions. There is potential industry confusion between turmeric and curcumin. Curcumin in CurcuWIN refers to three curcuminoids naturally found in turmeric. CurcuWIN utilizes patented UltraSOL Dry Nutrient System Technology for enhancing solubility and bioavailability of lipophilic compounds with support from a well-controlled randomized human trial. Crystalline curcumin is converted into a molecular dispersion with food grade excipients and antioxidants to make this compound more water-soluble.
Mi LABS Joint Support. Multiple fruits and herbal ingredients in Mi LABS’ (milabs.in) Joint Support formula work along synergistic pathways to decrease inflammation and promote the body’s natural synthesis and maintenance of joints, ligaments, muscles and tendons. This proprietary formulation is scientifically formulated and biologically tested to support the indication. It protects, prevents and helps in the repair of musculoskeletal injuries and inflammation, regardless of the cause, according to the company. A cell-based study has shown anti-inflammatory properties and a decrease in TNF-a in a study conducted on RAW 264.7 (Mouse leukaemic monocyte macrophage cell line).
Epigenetic Foods in Chronic Inflammation
Today, nutritional research has shifted from alleviating nutrient deficiencies to chronic disease prevention. Lifestyle, environmental conditions and nutritional compounds influence gene expression. It was believed that gene mutation was restricted within cells as heritable chromatin states. However, only recently, it has been observed that the environmental conditions and daily diet can affect transgenerational gene expression via ‘‘reversible’’ heritable epigenetic mechanisms.
It has been recently demonstrated that the differences between identical twins and their variable susceptibility to most diseases are mainly due to epigenetic changes, which accumulate during life following exposure to different environmental conditions.
Epigenetic changes recently emerged as major governing factors in cancer, chronic inflammatory and metabolic disorders, and have driven re-exploration of anti-inflammatory, bioactive food components for characterization of their effects on epigenome-modifying enzymatic activities. This understanding may allow for improvement of healthy aging by reversing disease-prone epimutations involved in chronic inflammatory and metabolic disorders.
Conclusion
A large and growing volume of scientific investigation supports a comprehensive food and supplement-based strategy for controlling inflammation and thus reducing the incidence and severity of many chronic illnesses. The cost-benefit of societal promotion of such strategies is enormous.
It is now evident that genes and cells are responding to certain foods containing nutrients and phytochemicals that induce cell communication and affect gene expression. Because epigenetic changes are reversible, developing drugs that control epigenetic regulation now attract substantial research investment, including the development of functional foods or supplements as nutrition-based epigenetic modulators.
The next challenge to scientists is to determine which adverse epigenomic markers are reversible by specific diets, supplements or lifestyle changes. This is an area of increasing interest. In contrast, there is a growing appreciation for the scope of this reversibility in some cases. For example, CNS changes driven by suboptimal diet exposure are more difficult to reverse if the diet exposure occurs during vulnerable developmental periods such as early life and adolescence. The future understanding and outcome will support the new hypothesis of “fetal programming” and “developmental origin of health and disease” (DOHaD).
It is important to keep in mind that FDA and other major regulatory bodies do not approve of the word “inflammation” in marketing and advertising. This word is linked to serious disease conditions. Therefore, it is wise to seek legal counsel before making any high-level health claims.
Dilip Ghosh, PhD, FACN, is director of nutriConnect, based in Sydney, Australia. He can be reached at dilipghosh@nutriconnect.com.au; www.nutriconnect.com.au.
While chronic diseases are caused by dysregulation of multiple genes, many modern medicines are used based on the modulation of only a single target, and therefore are less likely to be effective. Additionally, these medicines often produce numerous side effects and cannot be consumed over long periods of time. Therefore, the new paradigm proposed for the prevention and treatment of inflammatory chronic diseases either combines multiple single-targeted agents or involves a molecule that can target multiple pathways.
According to one estimate, more than 63% of the anti-cancer drugs introduced over the past 25 years have been natural products or can be traced back to natural sources (Newman & Cragg. Journal of Natural Products, 2007). In addition, some dietary agents have shown potential to inactivate inflammatory molecules by direct binding. For example, curcumin, one of the most widely studied dietary agents, has been found to bind to a number of inflammatory molecules.
Lessons from Ancestors
The Neolithic and Industrial Periods have fundamentally altered seven crucial nutritional characteristics of ancestral hominid diets by introducing food staples and food processing procedures: 1) glycemic load, 2) fatty acid composition, 3) macronutrient composition, 4) micronutrient density, 5) acid-base balance, 6) sodium-potassium ratio and 7) fiber content. These foods, in turn, adversely influence proximate nutritional factors, which universally underlie or exacerbate virtually all chronic diseases of civilization.
What is Inflammation?
Inflammation is an adaptive response triggered by noxious stimuli and conditions such as chemical or physical injury. Inflammation activates cellular and systemic components of the immune system. The initial response involves the recruitment of immune cells including macrophages, mast cells and dendritic and natural killer cells at the site of injury and subsequent release of chemical mediators such as cytokines, chemokines and reactive oxygen species to control pathogens and/or tissue repair. Chronic inflammation, by contrast, is a prolonged, dysregulatory and maladaptive response that involves persistent active inflammation, tissue destruction and failed attempts at repair. Inflammation may occur in various parts or organs of the body, including the brain, heart, lungs, eyes, nasal passages, gastrointestinal tract, throat, reproductive organs, urinary tract, joints, bones, blood vessels, etc., and is generally associated with cardiovascular disease, obesity, cancer and other disorders.
Inflammation & Chronic Diseases
Atherosclerosis. Atherosclerosis is a chronic, inflammatory disease and one of the most common causes of cardiovascular disease (CVD). Atherosclerosis begins in fetal life, slowly progresses during childhood and adolescence, and then accelerates in fits and spurts in adult life. The atherosclerotic process is initiated when cholesterol-containing low-density lipoproteins accumulate in the intima and activate the endothelium.
Cancer. An association between cancer and inflammation was made more than a century ago from the identification of leukocytes in tumor tissue. More recently, inflammation has also been implicated as affecting the patient’s ability to tolerate cytotoxic drugs.
Metabolic Syndrome. Obesity is associated with a chronic, systemic low-grade state of inflammation. Obesity-induced inflammation also plays an important role in the development of insulin resistance and type 2 diabetes.
Inflammatory Biomarkers
Although numerous biomarkers have been proposed and used in basic research to assess inflammation and risk factors associated with inflammatory diseases and to monitor the effects of prevention and/or therapy, very few of them are considered to be applicable in clinical and public health practice (see Table 1).
What’s Next?
Anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAID) and disease-modifying anti-rheumatic drugs (DMARDS), are widely used in treating various disorders. However, many of them have dose-dependent side effects, and none of them are suitable for primary prevention, which significantly limits their use.
On the other hand, it has been recognized that lifestyle and environment play an important role in inflammatory responses. In this respect, diet and dietary supplements can be key elements in managing the inflammatory process. In the past decade, understanding of the role of diet in promoting health by regulating inflammation, especially via certain nutrients or dietary components, has grown substantially (see Table 2).
Botanical Ingredients
Botanical compounds have a long history of medicinal use. The World Health Organization described traditional medicines as a principal source of healthcare for 80% of the world’s population, and there is an increased interest in the Western world for dietary supplements, functional foods and nutraceuticals. The ingredients of botanical origin are classified upon their biochemical properties based on mechanism such as antioxidants, anti-carcinogens, inflammation-inhibitors, blood pressure-reducing agents or anti-diabetics. Table 3 shows major botanicals used as anti-inflammatory compounds.
Clinically Researched Ingredients
Cyactiv, the “Blue Antioxidant.” Cyactiv (cyactiv.com) from Cerule, Klamath Falls, OR, is a proprietary, GRAS-approved extract from microalgae belonging to the photosynthetic Cyanophyta group. The primary bioactive component of Cyactiv is phycocyanin, which is known to act as an antioxidant and a selective COX-2 inhibitor with documented regulating properties.
In addition to phycocyanin, Cyactiv also contains bioactive compounds (“Non-PC Fraction”) that inhibit inflammatory actions by a different pathway, namely by inhibition of the enzyme lipoxygenase. In vitro and in vivo data have shown that Cyactiv enhances the production of regulatory and regenerative cytokines and also supports healthy cellular migration as part of immune surveillance. Three clinical studies have been completed on Cyactiv and demonstrated overall benefits including promoting healthy joints, healthy aging through antioxidant activity and increased joint and muscle comfort during daily activity.
Perluxan. Perluxan (perluxan.com) from Proprietary Nutritional Inc. (PNI), Kearny, NJ, is a proprietary, standardized supercritical extract of hops cones (Humulus lupulus L.), found to inhibit specific pro-inflammatory chemicals and derivatives based on alpha acids.
Perluxan works promptly in concert with numerous biochemical pathways responsible for inflammation with both enzymatic and non-enzymatic targets such as prostaglandin E2, cyclooxygenase 1+2, interlukein-1 and isoprostanes. This extract is virtually devoid of the undesirable phytoestrogenic and sleep inducing compounds contained in normal hops extracts and powders. Perluxan is a stable, free-flowing aromatic powder standardized to contain a minimum of 30% alpha acids (humulone, co-humulone, etc.) with high bioavailability in both tablet and capsule forms. Extensive in vitro and human clinical research has been conducted over the last decade to establish the phytomedical credibility of Perluxan.
Celadrin. Celadrin (celadrininfo.com) from PNI is a clinically effective compound in both oral and topical application in pain management developed through a proprietary process of esterifying oils. The Celadrin compound represents a matrix of fatty acid carbons, which have been scientifically arranged to achieve maximum efficacy for joint mobility and health. Results have shown fast acting (within 30 minutes) properties with rapid and deep absorption/penetration to the affected area. It works similar to the essential fatty acids EPA and DHA from fish oils. Extensive toxicity studies have demonstrated this to be a safe mix of fatty acids with no known or reported negative reactions or side effects.
Cannabidiol (CBD). One of many cannabinoids extracted from industrial hemp oil (not marijuana), CBD is considered a major non-psychoactive component. CBD is inherently safe with no known or reported toxicity. An extract from Mastix Medica, Hunt Valley, MD, (mastixmedica.com) has a very high level of CBD (15% or more) and can be used in different formats such as chewing gum and lozenges. Industrial hemp (e.g., Cannabidiol) contains only about 0.3-1.5% tetrahydrocannabinoids (THC), while marijuana that can be smoked contains about 5-10% or more THC. It is reported that CB2 receptors are primarily found in the immune system and are keyed to CBD with significant anti-inflammatory and anti-spasmodic properties.
AppleActiv. An open-label, clinical pilot study was recently conducted by NIS Labs, and involved healthy individuals experiencing moderate loss of joint range of motion (ROM), and associated recurring pain. The goal of the study was to evaluate the effects of consumption of dried apple peel powder (DAPP) on joint function and ROM. Additional in vitro and clinical testing was performed to investigate specific mechanisms of action. A full manuscript of the study has been published in The Journal of Medicinal Food, and a study abstract may be found on the PubMed site.
“We are pleased with the results of this clinical pilot study, which suggest multifaceted anti-inflammatory properties of dried apple peel powder,” said Gitte Jensen, research director at NIS Labs. “The study indicated that daily consumption of AppleActiv DAPP was associated with a statistically significant improvement in serum antioxidant protective status, as well as improved ROM.”
AppleActiv DAPP is certified organic, and contains a rich polyphenol blend with high levels of antioxidants. In the study, DAPP was shown to increase antioxidant activity, including cell protection from oxidative damage in vitro. The consumption of AppleActiv DAPP daily for 12 weeks showed both inhibited COX-2 and lipoxygenase enzyme activity. The study also observed pain reduction, which may be associated with the improved antioxidant status, and is likely linked to the anti-inflammatory effects of the polyphenols.
CurcuWIN. CurcuWIN from OmniActive Health Technologies, Morristown, NJ, (omniactives.com) is a new formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants that significantly increases curcuminoid appearance (46 times) in the blood in comparison to unformulated standard curcumin.
Curcumin is known for its antioxidant and anti-inflammatory properties and has been studied extensively for various risk factors and disease conditions. There is potential industry confusion between turmeric and curcumin. Curcumin in CurcuWIN refers to three curcuminoids naturally found in turmeric. CurcuWIN utilizes patented UltraSOL Dry Nutrient System Technology for enhancing solubility and bioavailability of lipophilic compounds with support from a well-controlled randomized human trial. Crystalline curcumin is converted into a molecular dispersion with food grade excipients and antioxidants to make this compound more water-soluble.
Mi LABS Joint Support. Multiple fruits and herbal ingredients in Mi LABS’ (milabs.in) Joint Support formula work along synergistic pathways to decrease inflammation and promote the body’s natural synthesis and maintenance of joints, ligaments, muscles and tendons. This proprietary formulation is scientifically formulated and biologically tested to support the indication. It protects, prevents and helps in the repair of musculoskeletal injuries and inflammation, regardless of the cause, according to the company. A cell-based study has shown anti-inflammatory properties and a decrease in TNF-a in a study conducted on RAW 264.7 (Mouse leukaemic monocyte macrophage cell line).
Epigenetic Foods in Chronic Inflammation
Today, nutritional research has shifted from alleviating nutrient deficiencies to chronic disease prevention. Lifestyle, environmental conditions and nutritional compounds influence gene expression. It was believed that gene mutation was restricted within cells as heritable chromatin states. However, only recently, it has been observed that the environmental conditions and daily diet can affect transgenerational gene expression via ‘‘reversible’’ heritable epigenetic mechanisms.
It has been recently demonstrated that the differences between identical twins and their variable susceptibility to most diseases are mainly due to epigenetic changes, which accumulate during life following exposure to different environmental conditions.
Epigenetic changes recently emerged as major governing factors in cancer, chronic inflammatory and metabolic disorders, and have driven re-exploration of anti-inflammatory, bioactive food components for characterization of their effects on epigenome-modifying enzymatic activities. This understanding may allow for improvement of healthy aging by reversing disease-prone epimutations involved in chronic inflammatory and metabolic disorders.
Conclusion
A large and growing volume of scientific investigation supports a comprehensive food and supplement-based strategy for controlling inflammation and thus reducing the incidence and severity of many chronic illnesses. The cost-benefit of societal promotion of such strategies is enormous.
It is now evident that genes and cells are responding to certain foods containing nutrients and phytochemicals that induce cell communication and affect gene expression. Because epigenetic changes are reversible, developing drugs that control epigenetic regulation now attract substantial research investment, including the development of functional foods or supplements as nutrition-based epigenetic modulators.
The next challenge to scientists is to determine which adverse epigenomic markers are reversible by specific diets, supplements or lifestyle changes. This is an area of increasing interest. In contrast, there is a growing appreciation for the scope of this reversibility in some cases. For example, CNS changes driven by suboptimal diet exposure are more difficult to reverse if the diet exposure occurs during vulnerable developmental periods such as early life and adolescence. The future understanding and outcome will support the new hypothesis of “fetal programming” and “developmental origin of health and disease” (DOHaD).
It is important to keep in mind that FDA and other major regulatory bodies do not approve of the word “inflammation” in marketing and advertising. This word is linked to serious disease conditions. Therefore, it is wise to seek legal counsel before making any high-level health claims.
Dilip Ghosh, PhD, FACN, is director of nutriConnect, based in Sydney, Australia. He can be reached at dilipghosh@nutriconnect.com.au; www.nutriconnect.com.au.
