Other Dietary Factors
Resveratrol and Pterostilbene. The exact mechanism by which resveratrol exerts anti-inflammatory activity has not been established, although it inhibits a variety of pro-inflammatory compounds (cyclooxygenase, TNF-α, IL-1β, IL-6, NF-κβ) in animal models and human cell culture (Jha et al. 2010; Khanduja et al. 2004). The related compound pterostilbene has demonstrated similar inhibition of inflammatory markers in cell culture (Pan et al. 2008). Modulation of the inflammatory immune response likely contributes to resveratrol’s protective role in animal models of heart disease, cancer, acute pancreatitis and inflammatory bowel disease (Clarke et al. 2008). Resveratrol may be protective against general, low-level para-inflammation as well: when taken with a single high-fat, high-carbohydrate meal (930 kcal), resveratrol (100 mg) prevented the sharp post-meal increases in markers of oxidation and inflammation in a small crossover study of 10 healthy volunteers. For example, synthesis of IL-1β increased by 91% over 5 hours following the test meal; with resveratrol, this increase was significantly less (29%) (Ghanim et al. 2011).
Curcumin. Extensive in vitro and animal studies have examine the effects of curcumin on experimentally-induced inflammatory diseases (atherosclerosis, arthritis, diabetes, liver disease, gastrointestinal disorders, and cancers) and disease markers (lipoxygenase, cyclooxygenase, TNF-α, IL-1β, NF-κβ, and others) (Chainani-Wu 2003, Bengmark 2006). Fewer human studies have examined curcumin’s effects on patient-oriented outcomes in inflammatory diseases, but most of the small randomized controlled trials of curcumin have consistently shown patient improvements in several inflammatory diseases, including psoriasis, irritable bowel syndrome, rheumatoid arthritis, and inflammatory eye disease (Epstein et al. 2010)(reviewed in White et al. 2011).
Tea polyphenols. The anti-inflammatory effects of green and black tea polyphenols have been substantiated by dozens of in vitro and animal studies (Singh et al. 2010) The polyphenols EGCG and theaflavin exert their anti-inflammatory effects through the inhibition of the NF-κβ signaling pathway, which decreases expression of several inflammatory proteins (lipoxygenase, cyclooxygenase, TNF-α, IL-1β, IL-6, and IL-8) in cell culture experiments (de Mejia et al. 2009). EGCG also inhibits the production and release of histamine, a key mediator of allergic and inflammatory response, in vitro (Melgarejo et al. 2010). In observational studies of tea consumption, >2 cups of tea/day (black or green) was associated with a nearly 20% reduction in CRP compared to non-tea drinkers, and significantly lower levels of two other inflammatory markers (serum amyloid A and haptogen, which are elevated in coronary heart disease) (De Bacquer et al. 2006). In clinical interventions, black tea appears to be more successful in reducing inflammatory markers than green (Galland 2010). A 25% reduction in CRP was also observed in a small trial of healthy, non-smoking men consuming a black tea extract (equivalent to 4 cups of tea/day) for 6 weeks (Steptoe et al. 2007). A similar average reduction was observed in a larger study of healthy, individuals at high risk for coronary heart disease, but revealed a more dramatic 40-50% reduction in CRP amongst individuals with the highest starting CRP values (>3 mg/L) (Bahorun et al. 2010).
Carotenoids. In the Women’s Health and Aging Study, participants with the highest blood levels of α-carotene and total carotenoids were significantly more likely to have the lower IL-6 levels than participants with low carotenoid levels at the onset of the study (Walston et al. 2006). Participants with the lowest blood levels of α- and β-carotene, lutein/zeaxanthin, or total carotenoids were more likely to experience increases in IL-6 over a period of 2 years.
DHEA. Low levels of sex hormones are associated with systemic increases in inflammatory markers (Singh et al. 2011); DHEA (dehydroepiandrosterone) an adrenal steroid hormone, the precursor to the sex steroids testosterone and estrogen. DHEA is abundant in youth, but steady declines with advancing age and may be partially responsible for age-related decreases sex steroids (Heffner 2011). In cell culture and animal models, DHEA can suppress inflammatory cytokine activity, in some cases more effectively than either testosterone or estrogen (Gordon et al. 2001). Chronic inflammation may itself reduce DHEA levels (Ernestam et al. 2007). DHEA supplementation in elderly volunteers (50 mg/day for 2 years) significantly decreased TNF-α and IL-6 levels, as well as lowered visceral fat mass and improved glucose tolerance (both associated with inflammation) in a small study (Weiss et al. 2011).
Fish Oil, is the best source of the omega-3 fatty acids eicosapentaenoic acid -- EPA, and docosahexaenoic acid – DHA that can only be synthesized to a limited extent in humans, which is why fish oil supplementation is so critical. Omega-3 fatty acids have been well studied for their prevention of cardiovascular disease and mortality in tens of thousands of patients; the anti-inflammatory effects of omega-3’s contribute to this activity (Marik et al. 2009). They have also proven successful at improving patient outcomes in scores of studies of other inflammatory diseases, particularly asthma, inflammatory bowel disease, and rheumatoid arthritis (Calder 2006) (Giugliano et al. 2006).
The association between greater fish oil/omega-3 consumption and reduced systemic inflammation is substantiated by data from several large observational trials. In 855 healthy participants from the Health Professionals Follow-Up Study, intake of omega-3 fatty acids was associated with lower plasma levels of markers of TNF-α activity; interestingly, high intake of both omega-3 and omega-6 fatty acids (which are usually assumed to be pro-inflammatory) was associated with the lowest level of inflammation (Pischon et al. 2003). The Nurses’ Health Study I cohort of 727 women revealed lower concentrations of inflammatory markers (including CRP and IL-6) amongst those in the top 20% of omega-3 consumption, when compared to those who consumed least amount (Lopez-Garcia et al. 2004). In the ATTICA study of over 3000 Greek men and women without any evidence of cardiovascular disease, participants who consumed over 300 g of fish per week had, on average, 33% lower CRP, 33% lower IL-6, and 21% lower TNF-α than participants who did not consume fish (Zampelas et al. 2005). In a sample of 5,677 men and women without cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, long-chain omega-3 intake (from fish or supplements) was associated with reduced plasma concentrations of multiple inflammatory markers (including CRP, IL-6, and TNF-α receptor, a measure of TNF-α activity)(He et al. 2009)
N-acetyl cysteine (NAC). Activation of the NF-κB pathway plays a central role in the activation of inflammatory cytokine genes; N-acetyl cysteine inhibits NF-κβ in cell culture, lowering expression of cytokines such as IL-6 and IL-8 (Araki et al. 2007) (Radomska-Leśniewska et al. 2006). Data establishing the effects of NAC on lowering chronic inflammation in humans is limited, but shows promise. NAC supplementation for 8 weeks demonstrated modest, but statistically significant decreases in circulating IL-6 levels in patients with chronic kidney disease (Nascimento et al. 2010). The effects were more pronounced in persons with significant inflammation at the start of the study (as measured by hs-CRP). NAC also reduced markers of systemic inflammation in a small study of patients with burn injuries (Csontos et al. 2011).
Boswellia. Boswellia serrata (frankincense) is a traditional anti-arthritic in Ayurvedic medicine; its anti-inflammatory properties have been attributed to the specific inhibition of 5-LOX and reduction in the production of pro-inflammatory leukotrienes by boswellic acids, a constituent of the Boswellia gum resin (Boswellia serrata. 2008). In cell culture, both crude and highly purified Boswellia extracts inhibited the production of pro-inflammatory TNF-α and IL-1β (Gayathri et al. 2007). One of the boswellic acids, Acetyl-11-keto-beta-boswellic acid (AKBA), was an inhibitor of NF-Kb activity in mice (Cuaz-Pérolin et al. 2008), while a topical mixture of the four most abundant boswellic acids decreased inflammation in a rodent inflammation model (Singh et al. 2008). A recent systematic review of human trials of Boswellia for inflammatory conditions revealed that the small number of randomized controlled trials on the extract have produced encouraging results for its use for asthma and osteoarthritis (Ernst 2008), warranting larger studies to confirm the extract as an effective therapy. Standardized Boswellia extracts (30% AKBA) have been effective in mitigating pain in osteoarthritis patients (Sengupta et al. 2008); when combined with non-volatile Boswellia oil, the standardized extract (called AprèsFlex™, or Aflapin®) demonstrated improved activity at a lower concentration (Sengupta et al. 2010). The use of Boswellia extracts for inflammatory bowel diseases has been investigated in multiple clinical trials, although results have been mixed (Gupta et al. 1997; Gupta et al. 2001; Holtmeier et al. 2011).
Sesame Lignans. The observation that sesame oil could decrease the production of arachidonic acid in fungi and rat liver cells led to the identification of the sesame lignans (sesamin, sesamolin, sesaminol) as specific inhibitors of Δ5 desaturase (delta-5-desaturase), one of the enzymes used in the synthesis of arachidonic acid (Shimizu et al. 1991). By inhibiting Δ5 desaturase, sesame lignans may reduce the synthesis of pro-inflammatory prostaglandin, leukotrienes, and thromboxanes, each of which require arachidonic acid as a starting material (Harikumar et al. 2010). In animal models, diets high in sesame seed oil reduced production of the pro-inflammatory prostaglandins PGE-1 and -2, as well as thromboxane B2 (Chavali et al. 1997). In humans, 5 weeks of sesamin supplementation (39 mg/day) reduced the production of the pro-inflammatory vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE; a product of the enzyme 5-LOX) by 30% (Wu et al. 2009). This potential anti-inflammatory property of sesame lignans may partially explain its observed hypotensive (blood pressure-lowering) activity (Miyawaki et al. 2009).
Bromelain. The anti-inflammatory activity of the proteolytic enzyme preparation bromelain has been attributed to its ability to reduce COX-2 activity, decrease prostaglandin and thromboxane synthesis, lower circulating fibrinogen levels, and reduce cellular adhesion of pro-inflammatory white blood cells to the sites of inflammation (Yuan et al. 2006). Human trials of bromelain for inflammatory conditions have yielded promising results (Bromelain Monograph 2010). In a blinded study from Germany, researchers divided 90 patients with painful osteoarthritis of the hip into two groups: one half receiving an oral enzyme preparation containing bromelain for six weeks, while the other half received the anti-inflammatory drug diclofenac (sold under the brand name Voltaren® and generic names). They found that the bromelain preparation was as effective as diclofenac in standard scales of pain, stiffness and physical function, and better tolerated than the drug comparator. The researchers concluded, “[the bromelain preparation] may well be recommended for the treatment of patients with osteoarthritis of the hip with signs of inflammation as indicated by a high pain level” (Klein 2006).
Another study comparing a standardized commercial enzyme preparation containing bromelain with diclofenac reached the same conclusion. The study reported that the supplement containing bromelain (90 mg, three times daily) to be as effective as diclofenac (50 mg, twice daily) in improving the symptoms of osteoarthritis of the knee. Patients reported comparable reductions in joint tenderness, pain and swelling, and improvement in range of motion at the end of the study. The investigators found bromelain to be as good as diclofenac on a standard pain assessment scale and to be better than the drug in reducing pain at rest (by 41% for bromelain versus 23% for the drug), improving restricted function (by 10% for bromelain versus 0% for the drug), being rated by more patients in improving symptoms (24% for bromelain versus 19% for the drug), and being evaluated by more physicians as having good efficacy (51% for bromelain versus 37% for the drug). In summary, the investigators determined bromelain to be an effective and safe alternative to NSAIDs such as diclofenac for painful osteoarthritis (Akhtar 2004).
In further research from the United Kingdom, a three-month study looked at the dose-dependent effects of bromelain, either 200 mg or 400 mg a day in volunteers with mild acute knee pain. Pain evaluation was based on patient symptom scores, which were reduced by 41% in the 200 mg bromelain group and by 59% in those receiving 400 mg of bromelain, indicating a dose-response relationship. This was also observed for scores of stiffness and physical function, which decreased significantly in the higher-dose bromelain group compared with those receiving 200 mg. The researchers also noted that overall psychological well-being was significantly improved in both bromelain groups, leading to their conclusion that this natural therapy may be effective in improving general well-being as well as symptoms in otherwise healthy adults suffering from mild knee pain (Walker 2002).
In animal models and cell culture experiments, bromelain has consistently demonstrated a variety of anti-inflammatory properties (Fitzhugh 2008; Secor 2008; Onken 2008; Secor 2005).
Mung bean extract. Mung bean (Vigna radiata) has been used for centuries in Asia as a traditional food and herbal medicine for inflammatory conditions, and modern research is supporting its anti-inflammatory effects (Zhu 2012). Two flavonoids in particular, vitexin and isovitexin, appear to be major contributors to mung bean’s beneficial properties. In one study, mung bean seed coat was found to contain 96% of the vitexin and isovitexin in mung bean, and accounted for 87% of the free radical-neutralizing potential of the bean (Cao, Li 2011). In preclinical studies, vitexin inhibited the production of inflammatory cytokines and maintained levels of defenses against oxidative stress (Borghi 2013; Dong 2013). In an animal model of lung injury, isovitexin demonstrated anti-inflammatory effects related to inhibition of cytokines and reduction in oxidative tissue damage (Lv 2016). Laboratory research has found additional compounds called mung bean seed coat saponins also inhibit cytokine expression (Lee 2013). One laboratory trial found mung bean coat extract powerfully inhibited both a herpes and respiratory virus to a similar degree as the antiviral drug acyclovir, while in this case inducing antiviral cytokines including TNF-α and IL-6 (Hafidh 2015).
In a trial in obese mice, mung bean seed coat extract significantly reduced inflammatory cytokine levels (Kang 2015). Mung bean sprout extract demonstrated anti-arthritic activity in arthritic rats (Venkateshwarlu 2016), and both mung bean seed coat and sprout extracts markedly improved glucose tolerance and metabolic health in diabetic mice (Yao 2008).
In one trial, mice that received mung bean seed coat extract were protected from lethal bacterial infection; the survival rate was 70% in treated mice versus 29.4% in untreated mice. In a laboratory component of the study, mung bean seed coat extract was found to inhibit a protein that mediates lethal systemic inflammation, and the inflammatory cytokine IL-6, while also demonstrating possible direct antibacterial activity (Zhu 2012). In a mouse study, treatment with a fermented mung bean preparation protected mice from cancer while inhibiting inflammation and stimulating immunity (Yeap 2013).
Reactive oxygen species generated during mitochondrial respiration contribute to inflammation, as outlined above. Aging individuals are especially susceptible to mitochondria-related oxidative stress since mitochondria become increasingly dysfunctional with age. Taking steps to support mitochondrial integrity and efficiency can help alleviate some of the systemic oxidative and inflammatory burden caused by poorly functioning mitochondria. Two nutrients, coenzyme Q10 (CoQ10) and pyrrloquinoline quinone (PQQ) are powerful mitochondrial protectants (Sourris 2012; Tao 2007), and studies support an anti-inflammatory role for these compounds.
Pyrroloquinoline quinone is a cofactor for enzymes critically important for cellular energy homeostasis and redox balance (Rucker 2009). Several studies have shown that PQQ exerts a protective effective during circumstantial mitochondrial stress and increased oxidative load (Tao 2007; Xiong 2011). In one study, rats given a diet supplemented with PQQ displayed greater energy expenditure and, remarkably, increased mitochondrial density in liver tissue. PQQ supplemented rats also had lower triglycerides and their hearts were more protected against lack of oxygen than rats that had not been given PQQ (Bauerly 2011). During periods of limited oxygen supply to cardiac tissue, a dramatic spike in oxidative stress and subsequent inflammation damages cells; the findings from this animal model indicate that PQQ can stave off this inflammatory cell destruction by preserving mitochondrial efficiency in adverse conditions.
Coenzyme Q10 is an indispensable intermediary in mitochondrial ATP production. Studies have shown that CoQ10 levels are low during inflammatory conditions. In one investigation, patients with septic shock were found to have CoQ10 levels substantially lower than healthy individuals, and, among patients, lower CoQ10 levels correlated with higher levels of an inflammatory mediator called VCAM (Donnino 2011). In an animal model in which rats were given drinking water with added fructose, an experiment that leads to obesity, diabetes, and other inflammatory complications, CoQ10 supplementation attenuated the inflammatory response by decreasing hepatic expression of CRP and other inflammatory mediators (Sohet 2009). Laboratory experiments indicate that CoQ10 modulates the expression of several hundred genes, many involved in inflammatory signaling (Schmelzer 2008). Of particular significance, one experiment showed that CoQ10, at physiologically relevant concentrations, was able to blunt induced TNF-α by more than 25% via modulation of the NF-kB signaling pathway (Schmelzer 2008).
Guarding Against Inflammatory Glycation Reactions
The role of elevated blood sugar and glycation end products in initiating an inflammatory storm has been discussed above. Fortunately, in addition to reducing caloric intake to suppress both fasting and post-meal glucose concentrations, some natural compounds ameliorate the glycation process and may help rein in the sugar-induced inflammatory cascade. Chief among these anti-glycation nutrients are benfotiamine, a member of the B-vitamin family, and carnosine, an amino acid.
Benfotiamine has been used to target diabetic complications since the mid 1990’s (Stracke 1996). More recent evidence continues to support its use as a powerful protector against blood sugar-induced tissue damage. In a clinical trial, 165 subjects with diabetes were randomized to receive benfotiamine at either 300 or 600 mg per day, or a placebo for 6 weeks. After the intervention period, those taking benfotiamine exhibited improvements in neuropathic pain in a dose-dependent fashion (Stracke 2008). An animal model found that benfotiamine relieved neuropathic pain by powerfully suppressing inflammation (Sanchez-Ramirez 2006). Moreover, laboratory experiments have shown that, in addition to blocking glycation reactions, benfotiamine may regulate inflammation more directly by modulating COX and LOX enzyme activity (Shoeb 2012).
Carnosine exerts a range of favorable biochemical effects within the body; it powerfully blunts glycation reactions and eases oxidative stress (Vistoli 2012). In addition, several experiments have revealed a marked ability of carnosine to suppress inflammation in various cell types (Fleisher-Berkovich 2009; Tsai 2010; Boldyrev 2007). Unfortunately, carnosine levels decline as much as 63% between ages 10 and 70 (Hipkiss 2009). Furthermore, in patients with type II diabetes, skeletal muscle carnosine content is markedly lower than in healthy control subjects (Gualano 2011). When carnosine is administered as a supplement to animals with chemically–induced diabetes, it is able to protect delicate retinal cells from inflammatory complications related to high blood sugar (Pfister 2011).
Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to treat several health conditions, including dyslipidemia, type 2 diabetes, and inflammation (Gauhar 2012). Its effects are due, at least in part, to its ability to activate a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK). This enzyme, which affects glucose metabolism and fat storage, has been called a “metabolic master switch” because it controls numerous pathways related to extracting energy from food and storing and distributing that energy throughout the body (Winder 1999).
Being overweight has a significant effect on AMPK activation and chronic inflammation; it suppresses AMPK activation, leading to abdominal fat deposits which, in turn, activate systemic inflammation. At the same time, inflammation itself suppresses AMPK activation, creating a viscous circle (Ruderman 2013).
Yet greater AMPK activation contributes to weight loss and can suppress inflammation (Park 2014; Towler 2007; Salminen 2011). In addition, increased AMPK activation is associated with reduced liver fat accumulation, another source of inflammatory chemicals (Bijland 2013).
Evidence demonstrate the anti-inflammatory effects of G. pentaphyllum. In one laboratory study, researchers found extracts of the herb significantly inhibited several inflammatory chemicals, including tumor necrosis factor-alpha, interleukin-6, and COX-2 mRNA (Xie 2012). Another study in 24 patients with type 2 diabetes found drinking a tea made with the herb for 12 weeks significantly reduced insulin resistance, which is a key contributor to systemic inflammation (Huyen 2010; Bastard 2006).
Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels (Umeno 2016; Devi 2015). Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity (Li 2017; Roohbakhsh 2014). Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway (Jia 2015; Rizza 2011; Zhang 2012). Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging (Li 2017).
Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury (Homayouni 2017). Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level (Sun 2015).
In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo (Rizza 2011). In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation (Salden 2016). Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism (Haidari 2015).
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