Air pollution is becoming an ever increasing health concern for people all over the world. Evidence increasingly suggests that poor diet, including clinical malnutrition may increase the risk for oxidative stress and chronic diseases.[1-7] Nutrition is known to play a significant role in the prevention and management of these same chronic diseases and has been shown to modulate the toxicity of polychlorinated biphenyls (PCBs, found in sealants, paint plasticizers, wood finishes and flame retardants).[2-6] One study has suggested that there may be increased susceptibility to NO2 when someone is in a fasting state  but it is not known if it is the same for other pollutants.
Oxidative stress, resulting from an imbalance between reactive oxidant species and antioxidants, can lead to tissue damage, airway inflammation with increased asthma severity and abnormal immune responses.[9-11] Serum concentrations of antioxidants have been positively associated with FEV1 in people with and without asthma.[12,13] Vitamin, mineral and botanical compounds have been researched in relation to pollutants over the past 20 years.
Vitamin C and E
Observational studies have reported that low vitamin C and vitamin E intakes are associated with a higher prevalence of asthma. Exposure to O3 results in dose dependent depletion of antioxidants vitamin C and E in the skin. Antioxidant supplementation with vitamin C and E above the minimum dietary requirement led to attenuated nasal inflammation and partially restored antioxidant levels in asthmatic patients exposed to high levels of O3 . A meta-analysis of 24 observational studies in children and adults found lower dietary intake (but not serum level) of vitamin E was also significantly associated with increased asthma severity . A review of 15 observational studies (including 3 birth cohorts), suggested that the evidence linking low vitamin E to asthma development was methodologically weak but sufficiently supportive of a potential effect warranting follow-up in clinical trials.
Four RCTs reported that vitamin E-containing antioxidants reduce O3-induced bronchoconstriction in subjects with [19,20] and without [21,22] asthma, suggesting potential protective effects of vitamin E against the detrimental effects of O3. A study in children looked at total antioxidant intake and asthma rates, and there appeared to be a link between higher antioxidant intake (total antioxidant capacity) and diminished sensitivity to inhaled allergens. Children in areas of low traffic pollution displayed a stronger association between sensitivity to allergens and antioxidant capacity. In people with exercise induced asthma, vitamin C and Vitamin E supplement aided recovery by improving flow rates. A London based bidirectional case cross-over study looked at whether individual plasma antioxidant concentrations (uric acid and vitamins C, A, and E) and 10 antioxidant genes could modify the response to PM with respect to hospital admissions for COPD or asthma. Two hundred and thirty four admissions were recorded and the level of PM10 was noted 14 days before and after each event. Combined admission rates were related to a 10 μg/m increase in PM10. Serum vitamin C modified the effect of PM10 on asthma/COPD exacerbations. A similar (although weaker) influence was observed for low levels of uric acid and vitamin E, whereas vitamin A showed no effect modification.
Vitamin D is key to the metabolism of calcium and phosphorus. In adults with Asthma, normal vitamin D levels correlated with improved asthma control and therefore supplementation may play a role in uncontrolled asthmatics with vitamin D deficiency.
Irrespective of the threshold used, in a US cohort, reduced serum or plasma vitamin D concentrations are commonly detected in children and adults particularly in subgroups at high risk for asthma or asthma morbidity.[27,28]
Three population-based studies (two cross-sectional [27,29] and one longitudinal  showed an association between reduced serum vitamin D concentrations and severe disease exacerbations or core measures (eg, hospitalisations) of severe exacerbations in Costa Rican, North American, and Puerto Rican children with asthma. In the most recent of these studies, vitamin D insufficiency or deficiency (a serum 25[OH] D concentration <30 ng/mL) was associated with increased odds of one or more severe asthma exacerbations in the previous year even in non-atopic children. This suggests that vitamin D affects the risk of severe asthma exacerbations through mechanisms other than regulation of allergic immune responses. Reduced vitamin D concentrations are also associated with increased airway smooth muscle mass, decreased lung function, and worse disease control in children with severe, therapy-resistant asthma. A Cochrane database systematic review was undertaken on vitamin D and asthma. Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use.
The phytochemical curcumin, from turmeric, has been found to be a potent anti-inflammatory agent, and has been studied in regards to its anti-tumour, antifungal and antioxidant properties. Animal models have demonstrated that curcumin is a potent anti-inflammatory agent in the lungs  and that it may also protect against pulmonary fibrosis. A number of studies have suggested that curcumin may have some protective role against the DNA damage caused by arsenic.[36,37] In a pre-clinical renal cancer study, addition of curcumin to cancer cells exhibited a strong potential for protection against diesel exhaust and cisplatin-induced cytotoxicity . Preclinical trials have also shown that curcumin inhibited POP associated cellular and DNA damage.[39,40] It has also reversed nicotine induced liver toxicity in an animal study.
Pre-clinical studies have shown that curcumin can prevent cadmium-induced IL-6 and IL-8 inflammatory secretion by human airway epithelial cells. Cadmium (Cd) is a toxic metal present in the environment and its inhalation can lead to pulmonary disease including lung cancer and COPD. Curcumin could therefore potentially be used to prevent airway inflammation due to cadmium inhalation.
Specifically in COPD, curcumin has been shown in animal models to have a beneficial effect in smooth muscle cells and improve the mean pulmonary artery pressure and right ventricular myocardial infarction (RVMI) through stimulating the suppressor of cytokine signalling (SOCS) -3/JAK2/STAT signalling pathways. In another model, curcumin was shown to suppress chemokines and affect corticosteroid sensitivity in COPD through modulating Histone deacetylase 2 (HDAC2) expression and its effect on histone modification. Another animal model showed that curcumin attenuates alveolar epithelial injury in COPD, which may be partially due to the down-regulation of Protein 66 homologous- collagen homologue (p66Shc). In a randomised, double blinded, parallel group study in patients with mild COPD and raised LDL cholesterol, 90mg curcumin was found to reduce the α1-antitrypsin–low-density lipoprotein (AT-LDL) complex, thus reducing risk of future cardiovascular events.
In other patients, a population based study of 2478 people found that people taking dietary curcumin through eating curry had better pulmonary function. The mean adjusted FEV1 associated with curry intake was 9.2% higher among current smokers, 10.3% higher among past smokers, and 1.5% higher among non-smokers. In 89 patients who had poor pulmonary function due to sulphur mustard, curcumin (1500 mg/day) + piperine (15 mg/day) or a placebo were given for 4 weeks. The active supplement reduced systemic oxidative stress and clinical symptoms, and also improved health related quality of life.
Omega-3 oils (or n-3 polyunsaturated fats-PUFAs) have received much attention due to their ability to reduce inflammation, and for its anti-coagulant properties, thus reducing risk of cardiovascular diseases. Two randomised controlled studies have investigated early life fish oil dietary supplementation in relation to asthma outcomes in children at high risk of atopic disease (at least one parent or sibling had atopy with or without asthma). In a study, powered only to detect differences in cord blood, maternal dietary fish oil supplementation during pregnancy was associated with reduced cytokine release from allergen stimulated cord blood mononuclear cells. However, effects on clinical outcomes at one year, in relation to atopic eczema, wheeze and cough, were marginal. In a second study, fish oil supplementation started in early infancy with or without additional house dust mite avoidance, was associated with a significant reduction in wheeze at 18 months of age. By five years of age fish oil supplementation was not associated with effects on asthma or other atopic diseases. In the absence of any evidence of benefit from the use of fish oil supplementation in pregnancy, the British Thoracic Society SIGN 2016 guidelines do not recommend it as a strategy for primary prevention of childhood asthma.
There are recent studies which use omega-3 oils to combat the effects of pollution. Animal models of fine particle matter pollution, demonstrated that omega-3 oils prevented and improve inflammation caused by these fine particles  with a further pre-clinical study showing that omega-3 oils reduced the oxidative damage in the intestines after heavy metals ingestion .
For the early and milder forms of allergic asthma, dietary supplementation with long-chain polyunsaturated fatty acids (LCPUFA), predominantly fish oil-associated eicosapentaenoic (C20:5 ω-3) and docosahexaenoic acid (C22:6 ω-3), and distinct crop oil-derived fatty acids have been proposed to provide a sustainable treatment strategy.[54,55] C20:5 and C22:6 ω-3 fatty acids inhibit cyclooxygenase (COX) activity and decrease eicosanoid synthesis from amino acids. They also suppress immunoglobulin (Ig) E production and thereby reduce airway inflammation and bronchoconstriction in asthma. In 2002 a Cochrane database review concluded that there was insufficient evidence to recommend fish oil supplementation for the treatment of asthma.
In addition to immune-controlling prostaglandins, leukotrienes, and thromboxanes, specialised mediators, such as lipoxins, resolvins, protectins, and maresins are metabolised from different LCPUFA, which actively resolve inflammation. Where people with asthma are allergic to pollutants and other allergens, omega-3 and some omega 6 oils also act to reduce inflammation, rebuilding fatty acid homeostasis in cellular membranes, modifying eicosanoid metabolic pathways, thus reducing clinical symptoms.[59,60] Most recently, an animal study compared the effects of olive oil, coconut oil and fish oil. Although fish oil protected against O3 induced vascular damage, it increased pulmonary injury/inflammation and impaired lipid transport mechanisms.
In a COPD randomised placebo controlled trial of 86 patients, an omega-3, vitamin D and leucine supplement drink was given to half the group for 4 months alongside high intensity training, whilst the other half undertook the exercise alone. The population had moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. There were significant differences after 4 months favouring the supplement group for body mass, plasma vitamin D, eicosapentaenoic acid, docosahexaenoic acid and number of steps.
Choline is a lipotropic agent involved in several biological functions (eg, neurotransmitter production, signalling lipids, and components of structural membranes), and as a methyl group donor . Dietary sources of choline include meat, liver, eggs, poultry, fish and shellfish, peanuts, and cauliflower. Choline deficiency is associated with neurological disorders, cardiovascular diseases, and inflammation.
Intranasal or oral administration of choline has been shown to reduce the number of eosinophils and reactive oxidant species in bronchoalveolar lavage fluid in a murine model of allergic airway disease. In human studies, 76 asthma patients were recruited and treated with a choline supplement (1500 mg twice) or standard pharmacotherapy for 6 months in two groups. The patients were evaluated by clinical, immunologic and biochemical parameters. The treatment with choline showed significant reduction in symptom/drug score and improvement in FEV1 compared to baseline or standard pharmacotherapy. Choline therapy significantly reduced IL-4, IL-5 and TNF-alpha level as compared to baseline or standard pharmacotherapy after 6 months (p<0.01). Blood eosinophil count and total IgE levels were reduced in both of the treatment groups. In a cross-sectional survey that enrolled 1514 men and 1528 women with no history of cardiovascular disease (the ATTICA Study), fasting blood samples were collected and inflammatory markers were measured. Compared with the lowest tertile of choline intake (<250 mg/d), participants who consumed >310 mg/d had, on average, 22% lower concentrations of C-reactive protein (P < 0.05), 26% lower concentrations of IL-6 (P < 0.05), and 6% lower concentrations of tumour necrosis factor-alpha (P < 0.01). These findings were independent of various sociodemographic, lifestyle, and clinical characteristics of the participants. This suggests that choline might attenuate allergic inflammation in general and airway inflammation in particular.
Read the full paper as a pdf: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930792/pdf/12931_2018_Article_785.pdf
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Diet and food supplements are of increasing interest in view of their potential in obesity management. Xanthohumol (XN) is a prenylated flavonoid found in hops, which have been used since ancient times as a medicinal plant. Traditional medicinal indications included the treatment of anxiety and insomnia, mild pain reduction or combating dyspepsia. Today, hops are used in the manufacturing of beer and female infertile plants, e.g. Humulus lupulus L, are cultivated especially for brewing. Biologically active substances, which are important for brewing, are concentrated inside hop cones in lupulin glands which contain hop resins, bitter acids, essential oils and prenylated flavonoids. For humans, beer is the major dietary source of XN. The beer content of XN varies significantly depending on the type of beer (in the range of 0.052–0.628 mg/l).
XN has also been proven to exert antioxidative, chemopreventive, and anti-inflammatory effects. It inhibits metabolic activation of food-borne carcinogens, induces phase 2 enzymes related to detoxification of xenobiotics, inhibits the PGE2 or NO production (linked to prevention of carcinogenesis),[6-8] exerts anti-tumour activity in hypoxic tumour cells. Recent studies investigating XN have also focused on the prevention and treatment of cancer.[10,11] XN has been shown to block T-cell lymphoblastic lymphomagenesis through reduction of STAT5 phosphorylation and gene up-regulated in the non-obese-diabetic STAT5bTg mice. Xanthohumol also inhibits the proliferation of lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells. XN exhibits anti-proliferative activity against breast, colon and ovarian cancer cell lines and is a potent inducer of chemoprevention enzymes regulated by the antioxidant response element.[14,15] So called ‘carcinoid’ cancer cell lines have also been treated with XN and this showed antiproliferative effects.
Furthermore, the female benefits of hop extracts are under investigation for their oestrogenic and are being used by women as dietary supplements and alternatives to conventional hormone replacement therapy for the management of menopausal hot flushes. One group investigated the pharmacokinetics of XN together with other three prenylated phenols following oral administration to menopausal women and reported that short-term consumption of a chemically and biologically standardized preparation of spent hops is safe for women and that once daily dosing might be appropriate. Xanthohumol and the other prenylated phenols showed long half-lives but no acute toxicity.
There is some evidence, including in vitro and animal studies that XN might exert beneficial effect in hyperlipidaemia. XN inhibits diacylglycerol acyltransferase (DGAT) and the expression of DGAT or microsomal triglyceride transfer protein (MTP) related to the lowering effects of triglyceride and apolipoprotein B.[19, 20]
XN has been suggested to have anti-atherogenic bioactivity as it is reported to decrease apolipoprotein B (apoB) secretion, inhibit triglyceride (TG) synthesis and prevent LDL oxidation in vitro. Furthermore, previous studies showed that XN reduced plaque formation in aortic lesions via reduced lipogenesis and increased faecal cholesterol excretion in apolipoprotein (apoE)-deficient mice. Moroever, XN has been reported to increase HDL cholesterol via cholesteryl ester transfer protein (CETP) inhibition in a CETP-transgenic mouse model.
Previous studies [20, 24] have shown that XN inhibits diacylglycerol acyltransferase (DGAT) activity or the expression of DGAT or microsomal triglyceride transfer protein in HepG2 cells. Those activities suggest that XN exerts TG lowering effect and amelioration of metabolic disorders in viscera. In 3T3-L1 adipocytes, Yang et al. reported reduced lipid content and decreased adipocyte marker proteins after incubation with XN. However, there have not been sufficient experiments to allow us to ascertain the molecular mechanism through which XN ameliorates metabolic disorders in vivo. Nozawa,  found that XN activated farnesoid X receptor (FXR) in vitro and modulated genes involved in lipid or glucose metabolism in mice.
Hirata et al recently investigated the effects of XN on reverse cholesterol transport in vivo and HDL cholesterol levels using a hamster model. They showed that XN improves the cholesterol efflux capacity of HDL and further enhanced in vivo reverse cholesterol transport from macrophages to faeces in hamsters. They also suggested that it may be possible to extend these findings to humans, since hamsters, like humans, express CETP, suggesting that they have a similar RCT system to humans.
Another group demonstrated that addition of XN to western-type diet ameliorates atherosclerotic plaque formation in ApoE−/− mice by positively affecting plasma cholesterol and MCP-1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase (AMPK). Therefore, the atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase.
Increasing cases of obesity has become a serious social problem in developed countries especially as obesity is closely related to the development of various lifestyle diseases.[28,29] Obesity develops when energy intake, in the form of food, exceeds energy expenditure  and is primarily characterized by excessive adiposity. There are two functionally and morphologically distinct types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT), both of which are mediators of energy homeostasis. In response to specific stimuli, WAT can acquire brown-like characteristics, which is called “beiging” and has been demonstrated in vivo  and in vitro  to improve the metabolic profile and increase thermogenesis.
There is some evidence derived from in vitro and animal studies that XN exerts anti-obesity effects, even if some controversy still exits.
Xanthohumol (XN) has been reported to exert anti-obesity effects in Zucker rats [34,35] and in various mouse strains.[3,36,37] Miranda et al. demonstrated that XN has bioactivities potentially useful for countering the metabolic aberrations of Metformin. In details, they showed that treating high fat diet (HFD)-fed C57BL/6 J mice orally with XN (60 mg/kg/day) reduced their plasma low-density lipoprotein-cholesterol (LDL-c, −80%), interleukin-6 (IL-6, −78%), HOMA-IR (−52%), leptin (−41%), and plasma levels of the LDL receptor-degrading enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) (−44%) levels compared to those of vehicle/HFD control. The same group found that XN and its hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN) improve glucose tolerance and cognitive function in HFD-fed mice. Unlike XN, DXN and TXN are unable to form the estrogenic metabolite, 8-PN, and they themselves have negligible affinity for estrogen receptors. Therefore, the XN derivatives DXN and TXN have potential to prevent or treat the neuro-metabolic impairments associated with HFD-induced obesity and metformin without risk of liver injury and adverse oestrogenic effects.
Takahashi and collegues, in their recent study in animals, observed that dietary purified XN exerted anti-obesity effects by regulating lipid metabolism and inhibiting intestinal fat absorption in KK-Ay mice, thus, they suggested that XN may exert anti-obesity effects. Another team showed that XN suppressed the increase in body weight, mesenteric WAT, liver weight, and triacylglycerol levels in the plasma and liver through regulation of hepatic fatty acid metabolism and inhibition of intestinal fat absorption in Wistar rats fed a high-fat diet. The anti-obesity effects of XN are partly mediated by AMPK signalling pathway suggesting that XN may have potential therapeutic implications for obesity. Yang and collegues confirmed the anti-adipogenic effects of XN under in vitro conditions. Conversely, Mendes and colleagues claimed that XN does not improve the metabolic profile linked to obesity as XN may reduce adipocyte number, contributing to adipocyte hypertrophy.
The prevalence of T2DM, which is often associated to obesity, has increased dramatically in the last decades. T2DM is a chronic, multifactorial and progressive disease, which affects more than 300 million people worldwide. Diabetes is characterized by hyperglycemia due to a deficiency in insulin production and/or its resistance, which contributes to endothelial dysfunction, resulting in macro and microvascular complications.[42,43] Imbalance in kidney and heart neovascularization is seen in T2DM patients. Costa and colleagues reported that XN consumption reduced angiogenesis, vascular endothelial growth-factor receptor (VEGFR)-2 expression/activity, levels of VEGF-B and its receptors (i.e. VEGFR1 and neuropilin-1), VEGF-A and phosphofructokinase-2/fructose-2,6-bisphosphatase-3 enzyme expression, a metabolic marker present in endothelial tip cells in T2DM mice kidney. Altogether, these findings suggest that XN prevent angiogenic impairment and metabolic pathways that are implicated in the pathogenesis of T2DM, being promising compounds to mitigate the increasing number of diabetic patients and inherent health care costs. Another study by Costa and colleagues in the same year found that XN protects mice against the development of T2DM metabolic-related complications. XN was reported to reduce body weight gain, prevent insulin resistance and modulate lipid and glucose metabolic pathways, being these effected mediated by a metabolic switch from fatty acid synthesis to oxidation and by promoting muscle glucose uptake. Furthermore, Nozawa, in their in vitro and in vivo study, reported potential beneficial effects of XN on amelioration of metabolic disorders via farnesoid X receptor (FXR) action and showed the possibility for developing such FXR modulators as functional nutrients in the therapy or prevention of metabolic syndromes.
Legette et al. recently conducted a study in healthy men and women to determine basic pharmacokinetics (PK) parameters for XN with the aim to establish dose-concentration relationships and to predict dose-effect relationships in humans diagnosed with metabolic syndrome. To our knowledge, this is the first study that reports human PK parameters for XN. Xanthohumol PK shows a distinct biphasic absorption pattern with XN and isoxanthohumol (IX) conjugates being the major circulating metabolites following oral consumption of XN in humans. XN metabolism appears to be similar between animals and humans, thus allowing for translation of animal study findings to future clinical work. Based on these and previous findings [34,46] the selection of effective doses to be utilized in future clinical studies aimed at improving lipid and glucose metabolism in humans diagnosed with metabolic syndrome should be possible.
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