INSIDER’s Take

• Short-term inflammation is a protective response, but chronic inflammation can have a negative effect on the human body.

• Palmitoylethanolamide (PEA), Terminalia chebula, grape seed extract and magnolia are among the options for formulators.

• The anti-inflammatory market is projected to reach US$130.6 billion by 2026 with a CAGR of 8.5 percent from 2018 to 2026.

Inflammation is one of the body’s natural defense mechanisms, addressing hazardous stimuli such as tissue damage or allergens. On a short-term basis, inflammation can help the body return to a healthy state. However, according to a 2016 review, “Uncontrolled inflammatory response is the main cause of a vast continuum of disorders including allergies, cardiovascular dysfunctions, metabolic syndrome, cancer and autoimmune diseases.”1

While various pharmaceuticals are available to help control and suppress inflammatory crisis, the potential for side effects and the desire for a natural course of action lead many consumers to seek alternative solutions. The review noted several herbs with anti-inflammatory effects that have been evaluated in clinical and experimental studies, including Curcuma longa (curcumin), Zingiber officinale (ginger), Rosmarinus officinalis (rosemary), Borago officinalis (borage), evening primrose and devil’s claw. It also mentioned, “the treatment of inflammation is not a one-dimensional remedy,” and therefore, suggested “a multidimensional therapeutic approach to inflammation with the help of herbal medicine and modification in lifestyle.”

Blake Ebersole, president of NaturPro Scientific, pointed to palmitoylethanolamide (PEA) as an emerging anti-inflammatory ingredient that’s been studied in large trials in Europe. It’s a peroxisome proliferator-activated receptor-alpha (PPAR-α) ligand that exerts anti-inflammatory, analgesic and neuroprotective actions.2 A 2014 review noted PEA was first identified as an anti-inflammatory compound more than half a century ago, but greater exploration didn’t occur until the mid-1990s. PEA was shown to reduce tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS, a pro-inflammatory endotoxin)-induced pulmonary inflammation in mice, as well as mast cell degranulation and edema formation in various inflammatory models.3

The review mentioned more recent investigation of the anti-inflammatory mechanisms. PEA inhibited phosphorylation of kinases involved in activation of pro-inflammatory pathways, and the nuclear translocation of nuclear factor-kappa beta (NF-κβ) and activator protein 1 (AP-1), as well as preventing degradation of the inhibitory IκB-α, which when associated to NF-κβ prevents its nuclear translocation.4,5

PEA also modulated the expression of enzymes involved in pro-inflammatory processes, such as cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), and reduced NO and pro-inflammatory cytokines production in vitro and in vivo, following different pro-inflammatory stimuli, such as carrageenan or LPS.4,6,7,8

Olive oil has been shown to modulate the lipid membrane composition and the production of inflammatory mediators, including prostaglandin E2 (PGE2) and NO.9,10,11 One of the most abundant olive polyphenols is 2-hydroxytyrosol (HT). One study assessed the effects of HT (from DSM) on inflammatory mediators, cytokines and chemokines, and identified anti-inflammatory constituents of aqueous olive extracts (olive vegetation water [OVW], from DSM).12 Results indicated HT inhibited production of NO and PGE2, reflecting strong anti-inflammatory activity. HT and OVW diminished secretion of cytokines (interleukin [IL]-1α, IL-1β, IL-6, IL-12, TNF-α) and chemokines (CXCL10/IP [interferon γ-induced protein]-10, CCL [chemokine ligand]2/MCP [monocyte chemoattractant protein]-1). HT and OVW concentration-dependently reduced the expression of genes of iNOS, IL-1α, CXCL10/IP-10, MIP [macrophage inflammatory protein]-1β, matrix metalloproteinase-9 (MMP9) and PGE2 synthase. The effects of HT were partly mediated via the NF-κβ pathway, as shown by RT-PCR analysis. HT was identified as the main bioactive compound of OVW. Researchers concluded the study provided “new insights into the molecular and biochemical mode of action that HT and its natural ‘counterpart,’ OVW, exert in inflammatory processes.”

Another study evaluated the effect of HT-supplemented refined olive oil at 0.5 and 5 mg/kg in a rodent model of rheumatoid arthritis (RA).13 The results suggested the supplementation of refined olive oil with HT may be advantageous in RA with significant impact not only on chronic inflammation, but also on acute inflammatory processes.

In an in vitro and in vivo murine study, melon extract (Cucumis melo LC) was shown to attenuate inflammatory response, thanks in part to its high enzymatic superoxide dismutase (SOD) activity.14 A double-blind study examined the effect of vegetarian GliSODin® (from Paris-based Isocell S.A. and distributed in the United States by PLT Health Solutions) on selected inflammatory markers in competitive rowers.15

GliSODin provides a melon source of SOD with gliadin, a wheat protein that guards SOD during digestion. After six weeks, SOD activity was significantly higher (P=0.0037) in the supplemented group than the placebo group, and C-reactive protein (CRP) was significantly (P=0.00001) lower in athletes receiving GliSODin than in the placebo group. Researchers concluded “supplementation with an extract rich in SOD activity promoted antioxidant status and protected against increased inflammation in the serum of professional rowers.”

Through cellular, animal and human experiments, green tea and its major polyphenolic component epigallocatechin gallate (EGCG) have shown anti-inflammatory effects, likely by suppressing the gene and/or protein expression of inflammatory cytokines and inflammation-related enzymes.16 A 2016 review concluded, “Most of the results from the human studies indicated the beneficial effects of green tea and tea catechins against inflammatory diseases,” and “can be largely explained by a mechanism wherein green tea/EGCG acts as an antioxidant to scavenge reactive oxygen species (ROS), leading to attenuation of nuclear factor-κB activity.”

A 2017 review17 added, “Studies revealed green tea polyphenols attenuate inflammatory responses in signaling pathways, by downregulating IKK [I kappa B kinase], NF-κβ (0.4 mg/mL [14]), cytokines like TNF-α, inflammatory markers, COX-2 and Bcl [B-cell lymphoma]-2.”

A 2015 review summarized current and prospective treatments for osteoarthritis (OA), with primary focus on the dietary supplement avocado/soybean unsaponifiables (ASU).18 ASU modulated OA pathogenesis by inhibiting a number of molecules and pathways implicated in OA. ASU’s anabolic properties stimulated the synthesis of collagen and aggrecan by inhibiting inflammatory cytokines such as IL-1, IL-6, IL-8, TNF and PGE2 through modulation of NF-κβ. What’s more, the combination of ASU and EGCG affected an array of inflammatory molecules, including expression of COX-2 and production of PGE2 in chondrocytes.

Extracted from turmeric, curcumin (Curcuma longa L.) has been indicated as an anti-inflammatory, blocking NF-κβ activation increased by several different inflammatory stimuli—as well as suppressing inflammation through other mechanisms.19

One study20 pointed out: “Extensive research within the past two decades has shown that curcumin mediates its anti-inflammatory effects through the downregulation of inflammatory transcription factors (such as nuclear factor-kappa β), enzymes (such as cyclooxygenase-2 and 5-lipoxygenase [LOX]) and cytokines (such as TNF, IL-1 and IL-6). Because of the crucial role of inflammation in most chronic diseases, the potential of curcumin has been examined in neoplastic, neurological, cardiovascular, pulmonary and metabolic diseases.”

Despite its success in research, concerns have been raised about curcumin’s bioavailability, which has led to the development of unique solutions and delivery systems. According to a 2017 review21: “Curcumin has received worldwide attention for its multiple health benefits, which appear to act primarily through its antioxidant and anti-inflammatory mechanisms. These benefits are best achieved when curcumin is combined with agents such as piperine [the major active component of black pepper], which increase its bioavailability significantly. Research suggests that curcumin can help in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety and hyperlipidemia. It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and subsequent performance in active people. In addition, a relatively low dose can provide health benefits for people that do not have diagnosed health conditions.”

A study at St. John’s Medical College, Bangalore, India, provided clinical evidence of piperine’s role in increasing the bioavailability of curcumin.22 When 2,000 mg of curcumin (as C3 Complex®, from Sabinsa) was co-administered with 20 mg of piperine (as BioPerine®, from Sabinsa), the bioavailability of curcumin was enhanced 2,000 percent compared to bioavailability of curcumin alone at doses that were devoid of adverse side effects.

Longvida®, the patented optimized curcumin extract from Verdure Sciences®, features SLCP™ (solid lipid curcumin particle) technology. According to the company, SLCP encapsulates the curcumin in a lipid matrix, allowing it to survive digestion and enter the bloodstream, reaching target tissues with a 24-hour circulation of free curcumin. 

One study examined the effects of Longvida on creatine kinase (CK), and inflammatory cytokines (TNF-α, IL-6, IL-8 and IL-10) following exercise-induced muscle damage (EIMD) in college students.23 The results indicated Longvida supplementation reduced biological inflammation, resulting in significantly smaller increases in CK (-48 percent), TNF-α (-25 percent) and IL-8 (-21 percent) compared to placebo. 

Indena S.p.A. uses its Phytosome® delivery format to improve absorption. A human clinical study indicated overall curcuminoid uptake was about 29-fold higher for Meriva®, the company’s patented Phytosome turmeric formulation curcumin, as compared to an unformulated curcuminoid mixture.24

“Meriva is supported by more than 30 clinical trials demonstrating effectiveness in 10 different health conditions, showing the ability to modulate the inflammatory response,” reported Cosimo Palumbo, Indena’s marketing director. He pointed to an eight-month study involving 100 subjects with OA, where the ingredient “induced a statistically significant reduction of numerous markers of inflammation such as CRP levels that decreased by 16-fold.”25

In another study of 50 individuals with OA, the treatment group took Meriva in a dose reflecting 200 mg/d of curcumin.26 After three months, for subjects receiving Meriva, the global Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score decreased by 58 percent (P<0.05); walking distance in the treadmill test was prolonged from 76 m to 332 m (P<0.05); and CRP levels decreased from 168 ± 18 to 11.3 ± 4.1 mg/L in the subpopulation with high CRP. In comparison, the control group experienced only a modest improvement in the parameters. Researchers concluded Meriva was clinically effective as a complementary management tool in OA.

OmniActive Health Technologies also uses a unique method for enhancing the bioactives in its CurcuWIN. The company’s UltraSOL Nutrient Delivery System converts lipophilic compounds and poorly absorbed nutrients to water-dispersible ingredients for enhanced bioavailability. In a human clinical trial, CurcuWIN increased relative absorption of total curcuminoids 46 times over standard curcumin.27 According to the company, the ingredient contains a minimum 20 percent curcuminoids in the same profile as found naturally in turmeric.

AyuFlex® from Natreon Inc. is an aqueous extract derived from the ancient Indian Ayurvedic edible fruits of Terminalia chebula, offering a vegan option for joint health formulations. Backed by seven clinical studies to promote optimal joint health and reduce chronic discomfort, its mechanism of action is to inhibit the enzymes responsible for pain and inflammation. The ingredient was shown to reduce the inflammation biomarker hs [highly sensitive] CRP and support healthy joints in people with activity-dependent knee pain.28

Another study of 100 subjects experiencing knee joint discomfort for at least six months found Ayuflex supported joint health, demonstrated through modified WOMAC scores, visual analogue scale (VAS) and knee-swelling index (KSI).29

Root extracts of the adaptogen Withania somnifera (ashwagandha) have been studied for their potential anti-inflammatory and chondroprotective effects. One review noted ashwagandha “can inhibit cyclooxygenase, the enzyme responsible for the formation of important biological mediators of inflammatory and anaphylactic reactions.30,31 Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain.”

Sensoril® from Natreon Inc. is a patented blend of the roots and leaves of the ashwagandha plant, which the company says results in a high level of bioactives. In a randomized, double-blind, placebo-controlled clinical study, 60 patients with knee joint pain and discomfort were given 250 or 125 mg/d of Sensoril or placebo.32 At the end of 12 weeks, compared to baseline and placebo, significant reductions were observed in mean modified WOMAC and KSI in Sensoril 250 mg (P<0.001) and 125 mg (P<0.05) groups. VAS scores for pain, stiffness and disability were significantly reduced in Sensoril 250 mg (P<0.001) and 125 mg (P<0.01) groups. The 250-mg group showed earliest efficacy, at four weeks.

Another botanical, Zingiber officinale—commonly known as ginger—has been linked to joint health benefits, particularly in the autoimmune condition RA. Brian Appell, activation marketing manager, OmniActive Health Technologies, specified, “The potent anti-inflammatory properties in the gingerols in ginger are believed to help provide protection against harmful free radicals.”33

He added, “As an anti-inflammatory, ginger has been shown to reduce the production of cytokines IL-1 and IL-6, and inhibit COX-2 and 5-LOX enzymes, which play a role in the inflammatory process.”34

Another root extract commonly used in Ayurveda, Bacopa monnieri (also known as Brahmi), acts by selectively inhibiting the COX-2 enzyme, and consequently reducing prostaglandins synthesis.35

Deanne Dolnick, science director, TR Nutritionals, pointed to research that touted, “In modern biomedical studies, Bacopa monnieri has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNF-α and IL-6 to aid in the treatment of arthritis.”36

The omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are long-chain polyunsaturated fatty acids (PUFAs) found in fish, algae and other marine oils. Nate Matusheski, Ph.D., scientific leader, nutrition science and advocacy, at DSM Nutritional Products, stated EPA and DHA serve as biological precursors to resolvins and protectins (bioactive metabolites) that help regulate inflammatory processes.37

Omega-3 supplementation has been found to lower concentrations of pro-inflammatory eicosanoids in the bloodstream,38 a biological mechanism that may have implications for joint health. Gretchen Vannice, MS, RDN, head of global nutrition education at AlaskOmega, mentioned if people consume enough EPA to have it readily available in their cells, the body uses it to make eicosanoids.37

Vannice identified “the newest and most exciting research about EPA and DHA regarding inflammation” as the discovery in this century that both EPA and DHA are precursors to special pro-resolving mediators (SPMs)—omega-3 derived molecules made in the human body that resolve inflammation.39 “There are several families of SPMs, the most common of which are resolvins, protectins and maresins,” she explained. “These SPMs have been shown to promote resolution of inflammation, reduce pain, reduce swelling and redness, promote clearance of bacteria, yeast and fungi, and promote tissue regeneration which leads to tissue healing. Among scientists, SPMs help explain part of the answer on how the body returns to homeostasis.”

A meta-analysis of randomized controlled trials (RCTs) found a decrease in nonsteroidal anti-inflammatory drug (NSAID) use when individuals with RA were supplemented with more than 2.7 g/d of EPA and DHA for three months or longer.40 These results were consistent with the findings of a systematic review by a different research group that identified similar drug-sparing effects, and also modest beneficial effects on joint swelling and pain, and duration of morning stiffness.41

Oils such as chia and flaxseed are plant sources of omega-3 alpha-linolenic acid (ALA). In a study of healthy volunteers, flaxseed oil use in domestic food preparation for four weeks inhibited TNF‐α and IL‐1β production by approximately 30 percent.42

Carolina Chica, who works in nutrition research and regulatory issues at Benexia, pointed to another study evaluating the effects of a diet high in ALA on serum pro-inflammatory cytokine concentrations and cytokine production in subjects with high cholesterol levels.43 Compared to participants eating the average American diet, those consuming an ALA-rich diet saw serum levels of TNF‐α decrease by 43 percent, and the production by immune cells of TNF‐α and IL‐1β decreased between 18 and 22 percent. Scientists concluded, “The cardioprotective effects of ALA are mediated in part by a reduction in the production of inflammatory cytokines.”

One review emphasized the role of omega-6 gamma linolenic acid (GLA) in modulating inflammatory response, and hence its potential application as an anti-inflammatory nutrient or adjuvant.44 GLA works to limit pro-inflammatory molecules while promoting anti-inflammatory molecules directly on cells.1 Plant-based sources rich in GLA include borage oil, black currant seed oil and evening primrose oil. 

Nena Dockery, technical services manager at Stratum Nutrition, suggested Ahiflower® (Buglossoides arvensis seed) as a sustainable plant source for a unique balance of omega-3 fatty acids, omega-6 GLA and omega-9. She pointed to 2018 research indicating EPA and DHA in providing support against inflammaging, “a term coined to describe age-related chronic systemic inflammation involved in the etiology of many age-related disorders.”45 

High levels of circulating pro-inflammatory cytokines are characteristic of inflammaging. The results showed EPA and DHA therapy had a significant lowering effect on levels of IL-6, IL-1β and TNF-α after four weeks of therapy and an even greater lowering effect after eight weeks of therapy. Further, after adjusting for baseline difference, the treatment group had significantly lower levels of IL-6 compared to control. 

Tomato phytonutrients have been linked to potential benefits on inflammation related to bone and joint health. One study examined whether carotenoid derivatives inhibit NF-kβ, as well as determining the molecular mechanism underpinning the inhibitory action.46 Researchers found that lycopene preparations purified from tomato extract (from Lycored) inhibited NF-kβ reporter gene activity.

When considering bone and joint formulations, Karin Hermoni, Ph.D., head of science and nutrition at Lycored, suggested, “The mechanism of action of such an effect may involve the control of inflammatory processes as well as the antioxidant properties of tomato phytonutrients. Of note, carotenoids such as lycopene act not only by quenching reactive oxygen species, but also by boosting the cell’s own antioxidant defense mechanism.”

Methylsulfonylmethane (MSM) is a popular joint health ingredient boasting anti-inflammatory activity. In a study examining the effect of MSM on murine macrophages, MSM demonstrated the ability to inhibit the expression of inflammatory markers through the suppression of iNOS and COX-2 genes.47 MSM also strongly inhibited the inflammatory cytokines IL-6 and TNF-α, both key in producing an inflammatory response to acute injury. MSM’s inhibition of NF-kβ was identified as a possible mechanism. MSM blocked the degradation of a key protein, essentially disabling the expression of various inflammatory response mediators.

In an in vitro study examining the effect of MSM on human chondrocyte cells, MSM demonstrated powerful IL-6 and IL-8 suppression by deactivating the protein kinase that would allow for the production of these inflammatory cytokines.48

And another in vitro study demonstrated MSM to be a selective inhibitor of NLRP3 inflammasome activation, a multiprotein complex operating as a platform for the inflammatory response mediator IL-1β.49

Boswellia serrata (frankincense) has been used anecdotally for millennia, but only in recent decades has its clinical potential been analyzed in Western trials. A systematic review noted collective “data seem to indicate that B. serrata extracts are effective in treating a range of conditions caused or maintained by inflammatory processes,” and that it’s traditionally been used against inflammatory diseases.50 Additionally, “Its main pharmacologically active ingredients are α and β boswellic acid, as well as other pentacyclic triterpenic acids. These compounds have been shown to inhibit pro-inflammatory processes by their effects on 5-lipooxygenase and cyclooxygenase and on the complement system [part of immune health].”The inhibitory effects of Boswellia serrata extract (as WokVel®, from Verdure Sciences) on OA were investigated in an in vitro and in vivo rat study.51 Of the botanical, the authors wrote, “Extract treatment significantly reduced and normalized the productions of pro-inflammatory factors, nuclear transcription factor κB, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6 at a concentration of 20 μg/mL. Treatment of chondrocytes with [WokVel] extract significantly reduced 5-lipoxygenase activity and production of prostaglandin E2, especially at a concentration of 10 to 20 μg/mL.”

The lignans magnolol and honokiol are phenolic compounds found in magnolia (Magnolia officinalis) bark extract. A study investigating the anti-inflammatory effect of magnolol on pleurisy in mice found it reduced PGE2 and leukotriene B4 (LTB4) levels in the pleural fluid.52 The researchers concluded magnolol may be a dual COX and LOX inhibitor, whose effects are at least partly dependent on the reduction of the formation of eicosanoids mediators in the inflammatory site.

Magnolol also suppressed NF-κB-mediated inflammatory mediator synthesis in a rat model involving periodontitis—of which oral pathogen-driven inflammation is a hallmark.53

Another study looked at the potential role of honokiol in a collagen-induced arthritis model in mice.54 Researchers summarized honokiol played a “prominent anti-inflammatory role … potentially in both the cognitive phase of the immune response, as well as the effector phase, by inhibiting cytokines that lead to chronic inflammation and additional pathology.”

Acacia gum (AG) is a prebiotic fiber from the acacia tree. With impairment of gut wall functionality common in many inflammatory diseases such as irritable bowel syndrome (IBS), one study examined the potential of AG (as Fibregum™, from Nexira) in aiding inflammation and gut barrier issues.55

Under LPS stimulation, experiments on pro-inflammatory cytokines involving IBS patient donors indicated Fibregum completely inhibited NF-kβ/AP1 activity by the end of the treatment. For TNF-α the trend fluctuated, and IL-8 secretion was mildly reduced. In a complementary way, the anti-inflammatory cytokine IL-10 was increased by Fibregum. Regarding the pro-inflammatory cytokines involving IBS patient donors, Fibregum produced the strongest decrease in NF-kβ/ AP-1 activity in the proximal and distal colon, where secretion of IL-8 and IL-6 was also reduced. IL-10 was increased in the distal colon.

According to Julie Impérato, marketing manager at Nexira, the results demonstrated the anti-inflammatory effect of Fibregum is based on two combined actions: inhibition of pro-inflammatory cytokines and stimulation of anti-inflammatory ones.

Grape seed extract (GSE) has also been studied for its anti-inflammatory effects. One study looked at the potential of GSE (as Meganatural Gold Extract, from Polyphenolics) in improving vascular risk markers (such as inflammation) in high-risk cardiovascular subjects with type 2 diabetes.56 Meganatural Gold Extract “significantly improved markers of inflammation” such as hsCRP over a four-week period. Scientists concluded GSE “may have a therapeutic role in decreasing cardiovascular risk.”

Vitamin E (as EVNol® and EVNol SupraBio™ full-spectrum tocotrienol/tocopherol complex extracted from virgin red palm oil [Elaeis guineensis], from ExcelVite Inc.) offers anti-inflammatory properties. An in vitro study examined the effects of EVNol on artificially induced inflammation in cell culture by measuring various inflammatory mediators including NO, PGE2, COX-1, COX-2 and cytokines.57

Cells were exposed to an inflammatory agent (1µg/ml LPS) alone or with various concentrations of EVNol (0.5, 1.0 & 5.0µg/ml) to study palm tocotrienol complex’s ability to inhibit inflammatory reactions. EVNol prevented inflammation-induced cell death, exhibiting potent anti-inflammatory properties as evidenced by a dose-dependent reduction of NO and PGE2 production. It also significantly inhibited the production of pro-inflammatory cytokines and displayed selective inhibition of COX-2 while sparing COX-1, which protects against gastric ulcer.

In other studies, EVNol demonstrated immunoregulatory effects on LPS-induced inflammatory responses of microglia by inhibiting NO production and reducing CD40 (a microglial co-stimulator molecule) expression of BV2 microglia.58,59 Increased expression of CD40 on microglia is implicated in various types of neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease.

The prebiotic dietary fiber partially hydrolyzed guar gum (PHGG, as Sunfiber®, from Taiyo) decreased hsCRP significantly in glucose-intolerant subjects after 12 months, revealing its potential to slow inflammation during prolonged supplementation.60

And a preclinical study showed improved outcomes of IBS and attenuation of pro-inflammatory cytokine TNF-α when mice were fed Sunfiber.61

The anti-inflammatory therapeutics market is projected to reach US$130.6 billion by 2026 with a compound annual growth rate (CAGR) of 8.5 percent from 2018 to 2026.62

“At some point, virtually everyone will have inflammation somewhere in the body, and will seek out a way to resolve it,” Dockery said. With increasing numbers of individuals seeking out natural anti-inflammatories—especially for long-term use—she concluded, “The potential is great for this area of the dietary supplement industry to grow.”

For a list of references, email [email protected].

Inflammation can be a common response to exercise outside one’s norm. Looking for more on the science of dietary supplements for muscle recovery, anti-inflammatory ingredients for post-exercise joint soreness, or optimizing metabolic recovery? Join us for the "Nutritional Strategies for Exercise Recovery" workshop on Thursday, Nov. 8, at SupplySide West 2018. This workshop is underwritten by Verdure Sciences.