Health Benefits Related To Tree Nut Consumption And Their Bioactive Compounds 1

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Abstract: Long-term studies with regular tree nut consumption have indicated positive outcomes for multiple health benefits. Here, we review the beneficial effects of tree nuts, highlighting the impact on glucose modulation, body weight management, cardiovascular risk, inflammation, oxidative stress, cognitive performance, and gut microbiota. Nuts are important sources of nutrients and phytochemicals, which, together with a healthy lipid profile, could help prevent certain chronic diseases, protect against oxidative stress and inflammation, and improve cognitive performance, thus reducing the impact of aging and neurodegeneration.

Keywords: tree nuts;glucose modulation; oxidative stress; inflammation; body weight management;cardiovascular; functional foods; cognitive function; aging

1. Introduction

Tree nuts are considered high in essential nutrients, and their consumption is known to have a beneficial influence on health outcomes [1-3]. Since ancient times, nuts have been part of the human diet and have been used for their medicinal properties [4]. To date, as a result of the health benefits related to habitual nut intake, the consumption of nuts is promoted in many dietary guidelines all over the world. Nut intake, which in the last 20 years has increased considerably, is common in all human diets, especially in the Mediterranean area [5,6].

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Almond (Prunus dulcis Mill. D.A. Webb) is the most consumed tree nut throughout the world. North America is the largest producer of almonds, pistachios(Pistacia vera L.), and walnuts (Juglans regia), while the Middle East countries produce mostly cashews (Anacardium occidentale) and hazelnuts (Corylus avellana) [7].

It is believed that the nutrients contained in tree nuts are responsible for their potential beneficial influence on human health. Numerous in vitro, in vivo, clinical, and epidemiologic studies have associated nut intake with a wide range of health benefits, including the modulation of glucose level[8-12] and serum lipids[13-19], positive influence on body weight [17,20-22] as well as the intestinal microbiota [23-28], antioxidant and anti-inflammatory activities [12,13,29-40], and, consequently, protective effect against certain chronic conditions, such as diabetes [8], obesity [20,21], and cardiovascular diseases [19,41].

The increased chronic inflammation, oxidative stress, and vascular impairment are considered contributing factors to the development of dementia, which is a progressive condition leading to a drastic decline in various cognitive domains, including planning, working memory, and processing speed, as well as codification and executive functions[42]. A number of strategies are currently being evaluated in order to be able to reduce risk factors that could lead to dementia up to 30 years before the onset of the symptoms.

Research suggests that diet is an important factor affecting cognitive performance in healthy people and could therefore have an impact on dementia onset in communities and countries [43]. A recent systematic review has analyzed the effects of nut consumption on cognitive performance [44].

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In the present review, we will summarize the health benefits associated with nut consumption, highlighting the effect on glucose modulation, body weight management, cardiovascular risk, inflammation, oxidative stress, cognitive performance, and gut microbiota. Furthermore, the bioactive compounds that may be involved in cognitive effects are analyzed.

2. Nuts and Health

This review is aimed to report the health outcomes identified with nut consumption, which are summarized in five main categories: glucose modulation, body weight management, cardiovascular disease prevention, inflammation and oxidative stress, functional food properties, and the cognitive performance of nuts.

2.1.Glucose Modulation

Several studies highlighted the role of nuts consumption in modulating glucose homeostasis in healthy [12], pre-diabetic[8,1D],diabetic[9],and obese [11]subjects(Table 1). The beneficial role in the glucose and insulin metabolism of nuts has been associated with their content of fiber, fat, minerals, and other bioactive molecules. It has been shown that the fiber and fat content of almonds[10,12], the PUFA content of walnuts [1], and the PUFA content and the procyanidins, y-tocopherol, and carotenoids such as lutein and β-carotene of pistachio [9,13] are responsible for these positive outcomes.

Jenkins et al. reported on the influence of almond intake on glycemic control. Fifteen 12h fasting healthy subjects (aged 19-51, BMI>17.4 and <29.5 kg/m2) were assigned to five different dietary sessions, with a one-week wash-out period in between. Each session included four different test meals, each containing 50 g of available carbohydrates: two bread control meals and three test meals: almonds (60 g) and bread, parboiled rice, and instant mashed potatoes, which were balanced in carbohydrates, fat, and protein. cistanche cholesterol The almond-containing meal promoted satiety(the incremental response area was higher than the control after 2 h and 4h,p =0.047 and 0.011, respectively), and it positively affected postprandial glycemia(glycemic indices of the almond (55±7)and rice meals(38±6)were lower than that of the instant mashed potato meal (94±1) and the postprandial glucose peak heights for the almond (5.9±0.2 mmol/L) and rice meals (5.8±0.1mmol/L)were less than the peak height for the potato meal (6.6±0.2mmol/L) and the control white bread meal (6.9±0.2mmol/L)(p<0.001).

The insulin indices of the almond (91 ±19) and rice meals(73±9)were lower than the potato meal (171±19) (p< 0.001), and the insulin peak height for the almond (224±24 pmol/L) and rice(239±28 pmol/L)meals were both lower than the potato meal (388±30 pmol/L)(p<0.001) and the control white bread meal(321±36 pmol/L)(p <0.042). Furthermore, the changes in the protein thiol concentration (15±14mmol/L following the almond meal and -10±8 mmol/L after the control bread, rice, and potato meals) demonstrated that the almond-containing meal positively influenced oxidative stress [12].

A similar study was conducted on 137 individuals with type 2 diabetes mellitus （T2DM） risk （aged 18-60， BMI≤27 and <18.5 kg/m²） over a 4-week period. The intake of 43 g/d of almonds promoted a lower serum glucose concentration after 60 min ingestion compared with the control (no almond supplementation). According to the authors, the moderating effects of almond consumption on postprandial glycemia may be attributable to the fiber and fat content of almonds. Fiber reduces glycemia by increasing the viscosity of intestinal contents and thus hindering glucose diffusion, by reducing carbohydrate availability in the gastrointestinal tract, and by starch encapsulation. Fat may have also caused lower postprandial glycemia by slowing gastric emptying times and dilution. In addition, serum glucose concentrations decreased when almonds were consumed alone as snacks, suggesting an enhancement of clearance. Furthermore, almond consumption positively affected satiety during the acute-feeding session increased dietary of monounsaturated fat and α-tocopherol, and, over a 4-week period, did not affect body weight or postprandial lipid profiles [10]. Gulati et al. also demonstrated that the inclusion of almonds in a healthy balanced diet had multiple beneficial effects on glycemic and CVDs risk factors amongst Asian Indian patients suffering from type 2 diabetes[45].

Pistachio intake has also been shown to confer positive metabolic effects on prediabetic [8] and diabetic [9] individuals. In a crossover study, 54 prediabetic individuals （aged 25-65， BMI< 35 kg/m²）consumed two diets， a pistachio-supplemented diet（PD）and a control diet (CD), each for 4 months. cistanche deserticola side effects A 2-week washout period separated study periods. Diets were isocaloric and matched for protein, fiber, and saturated fatty acids. A total of 55% of the CD calories were derived from carbohydrates and 30% were derived from fat, whereas 50 and 35% of carbohydrates and fat, respectively, were included in the PD diet (with 57g/day of pistachios).Pistachio intake promoted a significant decrease in fasting glucose(FBG)(mean-5.17 and 6.72 respectively for PD and CD;p<0.001),insulin (mean-2.04 and 2.51 respectively for PD and CD;p<0.001),and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (mean-0.69 and 0.97 respectively for PD and CD;p<0.001). cistanche dosage reddit Furthermore, pistachios showed beneficial effects on the inflammatory and oxidative state. According to the authors, the benefits for glucose metabolism and cardiovascular health promoted by pistachios are due to their higher amount of polyunsaturated fatty acids (PUFA) and other bioactive compounds, including procyanidins, y-tocopherol, and carotenoids such as lutein and β-carotene [8].

In addition, diabetic patients have been shown to benefit from the consumption of pistachios. Forty-eight patients with type 2 diabetes were equally assigned to two groups (aged 53±10 and 50±11,BMI32.16±6.58 and 3024±4.03kg/m2, respectively). One group received a snack of 25 g of pistachio nuts twice a day for 12 weeks and the second received a control meal without nuts. After 12 weeks intervention, patients had an 8-week washout and the groups were exchanged. A decrease in glycosylated hemoglobin Al (HbAlc)(-0.4%) and FBG concentrations(-16 mg/dl) in the pistachio group compared with the control group (p ≤0.001 for both) were observed. Analysis of the two phases separately shown that pistachio consumption reduced systolic blood pressure (p =0.007), BMI (p=0.011),and CRP (p=0.002) in patients from the treatment groups. However, no overall significant differences between the two groups in terms of BMI, blood pressure,

HOMA-IR and C-reactive protein (CRP)concentrations have been reported. According to the authors, these results are attributed to the washout period, which may have been too short [9]. Kendall et al. assessed the effect of pistachios on postprandial glucose and insulin levels, gut hormones, and endothelial function: results demonstrated that pistachios consumption reduced postprandial glycemia, increased glucagon-like-peptide levels, and could have insulin-sparing properties [46].

A study was carried out on 50 overweight adults with type2 diabetes mellitus (mean age 54±8.7 years， and BMI>25 and <32 kg/m²） over a 1-year period who were randomized into two groups: control and diet. The control diet comprised 30% fat (10%saturated fatty acids (SFA),15% monounsaturated fatty acids (MUFA),5% PUFA, and a P/S ratio of 0.5),20% protein, and 50% carbohydrates, whereas the walnut diet included 30 g of walnuts per day (which provided 10% MUFA,10%PUFA, and a P/S ratio of 1.0). Within the first three months, the walnut diet promoted an increased dietary PUFA and a greater reduction in fasting insulin levels (p =0.046) and body weight (which was significantly different from baseline,p=0.028). The authors asserted that walnuts induced significant effects in the early stages of nutritional change in a delivered PUFA healthy diet, although long-term effects were subjected to fluctuations, which may be due to dietary intake and the disease process[11].

2.2.Body Weight Management

A large number of studies reported no adverse effects of nut consumption on energy balance or body weight [11,17,20-22] (Table 2). In addition, nut consumption, thanks to both the content in unsaturated fatty acids, dietary fiber, plant protein, antioxidants, vitamin E, arginine, phytosterols, and minerals such as potassium, calcium, and magnesium content and the non-bioaccessible nutrients, present prebiotic properties, has been shown to be inversely associated to metabolic syndrome (MetS) and excess weight [10,20]. An A24-week randomized controlled trial in 95 overweight individuals consuming mixed tree nuts resulted in both weight loss and increased satiety, together with decreased heart rate, and increased serum oleic acid after 24 weeks [47].

Through a meta-analysis, despite the heterogeneity of the observations, Liet al. cistanche extract benefits highlighted the beneficial influence of nuts on the metabolic profile, analyzing the association of nut consumption with MetS and overweight/obesity. This meta-analysis of prospective cohort studies included six prospective cohort studies with 420,890 subjects and 62 randomized feeding trials with 7184 participants. The study showed that for every 1-serving/week increase in nut consumption, the risk was reduced by 4% for Mets, by 3% for overweight/obesity, and by 5% for obesity only. Furthermore, pooled data of randomized feeding trials suggested that nut supplementation was related to a reduction in body weight (weighted mean difference (WMD):-0.22 Kg,95% CI:-0.40 to -0.04), body mass index(WMD:-0.16 Kg/m2,95% CI:-0.31 to-0.01),and waist circumference (WMD:-0.51 cm,95%CI:-0.95 to-0.07). According to the authors, the observed benefits of nuts are due to the abundant bioactive compounds including unsaturated fatty acids, dietary fiber, plant protein, antioxidants, vitamin E, arginine, phytosterols, and minerals such as potassium, calcium, and magnesium. These healthy nutrients, alone or in combination, may improve inflammatory response, oxidative stress, and endothelial function, thus contributing to the improvement in individual MetS components. In addition, the non-bioaccessible nutrients from nuts (polymerized polyphenols, polysaccharides, and fiber), which have prebiotic properties, play an important role. The weight-loss effect of nuts was likely to be related to enhanced satiety, increased resting energy expenditure, diet-induced thermogenesis, and incomplete mastication and fat malabsorption [20].

Recently, a randomized crossover study reported that the energy content of almonds may less bioaccessible in individuals with hyperlipidemia than what was predicted by Atwater factors[48]. These findings support previous investigations on the role played by food processing and structure on the metabolizable energy of almonds[49,50].

Dhillon and co-authors showed the positive influence of almond intake on overweight and obese individuals[21]. Eighty-six overweight or obese adults (aged 18-60, BMI>25 and <40 kg/m2) were randomly assigned, for a 12-week period, to 2500-kcal deficit diets:an almond-enriched diet (AED),in which 15% of energy come from almonds, or a nut-free diet (NFD).The almond intake promoted a reduction in truncal fat(AED:-1.21% ±0.26%;NFD:-0.48%±0.24%;p=0.025),totalfat(AED:-1.79%±0.36%;NFD:-0.74%±0.33%;p=0.035),diastolic blood pressure BP(AED:-2.71±1.2mm Hg;NFD:0.815±1.1mm Hg；p=0.029）and in visceral adipose tissue （VAT）loss（AED∶-8.19±1.8cm²；NFD∶-3.99±1.7 cm²；p =0.09）. The authors suggested that moderate almond consumption may contribute to reduce metabolic disease risk in obesity [21].

In a long-term diet intervention trial, carried out over 18 months, conducted by Foster et al. on 123 overweight and obese subjects(46.8±12.4 BMI:34.0±3.6kg/m2), randomized into AED (28 g almonds daily) or NFD diet intervention groups, no statistically significant differences were shown between the two groups in terms of weight loss, body composition, or blood pressure, although the AED group experienced greater improvements in lipid profiles [17].

In addition, the effects of chronic peanut consumption on energy balance and body weight have been evaluated. Fifteen healthy, normal-weight participants (aged 33±9, BMl =23.3±1.8 kg/m2)during a 30-week period were sequentially assigned to three different arms: the free-feeding (FF) arm was an 8-week trial where 50% of dietary fat energy was supplied by peanuts and the background diet was not controlled; the addition (ADD) arm was a 3-week trial including an isocaloric diet, in which 50% of dietary fat energy was supplied by peanuts; the substitution (SUB) arm was an 8-week trial where participants decreased fat intake by 50%, and this was replaced with an equivalent amount of fat from peanuts. Washout periods between each arm of the study were 4 weeks. During FF, total daily energy intake was significantly lower than predicted. The mean energy compensation score was 66%. Body weight gain (1.0 kg) was significantly lower than predicted (3.6 kg;p <0.01). When customary dietary fat was replaced with the energy from peanuts, energy intake, as well as body weight, were maintained precisely [22].

In a randomized controlled study with non-diabetic overweight/obese adults, regular consumption of pistachios was associated with weight loss and reductions in BMI and waist circumference [51]. Furthermore, daily intake of pistachios (44 g) improved nutrient intake without affecting body weight in healthy women [52].

2.3. Cardiovascular Disease Prevention and Serum Lipid

Table 3 reports the cardiovascular disease prevention and serum lipid effects related to nut consumption. Epidemiological studies have consistently proven an association between nut intake and reduced risk of CVD [19], ischemic heart disease (IHD),and CVD incidence and mortality [41]. Nut consumption may not only offer protection against heart disease but also increased longevity [55,56].

As reported, nuts, due to their dietary fiber content, magnesium, PUFA fats, vitamin E, folic acid, flavonoids, polyphenols, and L-arginine, may play an important role in reducing the cardiovascular risk through multiple mechanisms: by having a positive influence on the glucose [8-12] and/or lipid homeostasis [13-19], obesity [11,17,20-22], hyperc-holesterolemia [14,19],MetS or T2DM[9-11,19,20,38],blood pressure[9,21,33],oxidation biomarkers and antioxidant defenses [8,9,18,29,37,38,40],flow-mediated dilatation [53,54], lipid [15,16,40],or DNA modification [34] and inflammatory status[30-36,39].

In addition, nut consumption was shown to significantly improve endothelial func-tion, which is an important risk factor for CVD. A recent systematic review and meta-analysis reported the improved flow-mediated dilatation (FMD) upon nut consumption and highlighted that amongst other nuts considered (almonds, pecans, peanuts, hazelnuts, pistachios, cashews, macadamia nuts, and soy nuts), walnuts significantly increased the FMD in comparison with control (weighted mean difference: 0.40%). According to the authors, the different nutrient profiles of walnuts, consisting of higher amounts of w-3 fatty acid, o-linolenic, and a-tocopherol may, at least partially, explain why walnuts markedly improved FMD.In addition, the authors highlighted the important role of L-arginine in improving endothelial function in subjects with impaired nitric oxide (NO) production—for example, patients with hypercholesterolemia or congestive heart disease[53].

The positive effects of nuts consumption on various cardiovascular disease risk fac-tors included improvements in triglycerides[13,17], total cholesterol (TC)[13,14,17], and lipoprotein cholesterol[13-15,17]. In vivo experimental mouse models, in which animals were assigned to three groups (n=10) based on initial body weight, were fed either an isocaloric control diet (no nuts), 8.1% pistachio diet (single nut), or7.5% mixed nut diet (almonds, brazil nuts, cashews, macadamia nuts, peanuts, pecans, pistachios, and walnuts) for 8 weeks. Pistachios and mixed nuts significantly decreased triglycerides, TC,and LDL-C (p<0.05) compared with controls and exhibited reductions in C-reactive protein (p =0.045) and oxidative stress (p =0.004). Furthermore,in the mixed nut group, the activities of the antioxidant enzymes, such as superoxide dismutase (p =0.004) and catalase (p =0.044), were significantly higher in the mixed nut group compared to the control group, and the aspartate aminotransferase (p =0.048) concentration was lower than the control group. The authors concluded that mixed nuts and individual nut varieties have comparable effects on CVD risk factors in rats[13].

Forty-eight individuals (aged 30-65,BMI>20and ≤35kg/m2) with elevated LDL-C(149±3mg/dL) were enrolled and randomized in two 6-week feding settings: a cholesterol-lowering diet (51% carbohydrates,16% proteins,32% total fat) supplemented with almonds (about 42.5 g of almonds/day) and a control diet(58% carbohydrates 15% proteins,26% total fat)supplemented with an isocaloric muffin substitution (no almonds/day). The differences in the nutrient profiles of the two diets were due to nutrients inherent to each snack; diets did rot differ in saturated fat or cholesterol. The almond diet significantly decreased non-HDL-C(-18±3versus 11±3mg/dL;p=0.01);-LDL-C(-19±2versus-14±2mg/dL;p=0.01),TC/HDL-C(-0.17±0.08 versus 0.06±0.08;p<0.01),LDL-C/HDL-C(-0.23±0.07 versus-0.03±0.07;p<0.01),and apoB/apoA1(-0.04±0.01 versus -0.00±0.01;p<0.01)ratios. The abdominal mass (-0.28±0.09 versus-0.09±0.09 kg; p=0.02)and abdominal fat mass(-0.13±0.03 versus-0.06±0.03 kg;p=0.02)as well as the leg fat mass(-0.26±0.06 versus-0.14±0.06 kg;p =0.02)were significantly reduced with the almond diet. These findings were validated by waist circumference, which also decreased with the almond diet(-1.7±0.4 versus-0.9±0.4 cm;p=0.02)compared with the control diet.

The authors attributed the cardioprotective effect of almonds, in part, to their unique fatty acid profile, which is high in unsaturated fat, predominantly oleic acid, and low in saturated fat, and suggested that other nutrients and bioactive compounds in almonds, such as dietary fiber and phytosterols, may contribute to their LDL-C-lowering and HDL C-conserving effects [15]. Berryman et al. (2017) have later reported that the incorporation of almonds in a cholesterol-lowering diet improved plasma HDL and cholesterol efflux to serum in normal-weight participants with high LDL cholesterol [57].

These results are in line with a previous study, where significantly greater reductions in TC and an improvement in the ratio of TC to HDL cholesterol were observed after a 6-month intervention [17].

A recent randomized controlled trial demonstrated that almond snacking may reduce the CVD risk by increasing heart rate variability during mental stress in healthy adults, and whole almond consumption was associated with better diet quality and lower cardio-vascular disease risk factors in the UK adult population [58,59]. The same authors have also reported a significant improvement on endothelial function associated to consuming whole almonds as snacks, in addition to LDL cholesterol lowering amongst adults with above-average risk of CVD[54]. cistanche genghis khan In addition, pistachio consumption has been investigated on plasma lipid profiles in the parallel-design study by Kocyigit et al. Forty-four healthy individuals, equally randomized into two groups (mean age 32.8±6.7, BMI 24.6 ±5.6 and 33.4±7.2，BMI24.2±6.1kg/m²，respectively） were assigned to 3-week diet interventions∶regular diet and whole-pistachio diet (20%of daily caloric intake). After the intervention, the mean plasma TC,malondialdehyde (MDA)levels,and TC/HDL and LDL/HDL ra-tios were found to be significantly decreased (p<0.05,p<0.05,p<0.001 and p<0.01 respectively) in the pistachio group. On the other hand, HDL levels,antioxidant potential (AOP),and AOP/MDA ratios were significantly increased (p<001,p<0.05,and p<01,respectively). These results indicated that pistachio consumption not only improved TC and HDL levels but also decreased oxidative stress [18].

A recent study involving54subjects（aged 25-65， BMI35kg/m²）with prediabetes who followed two crossover sequences, a pistachio-supplemented diet (PD, 50% carbohydrates, 33% fat,including57g/d of pistachios daily) and a control diet (CD,55% carbohydrates 30% fat) for 4 months each, separated by a 2-week washout, confirmed the positive ef-fects associated with nut consumption and showed the ability of nut intake to shift the lipoprotein size and particle profile to a less atherogenic pattern. Diets were isocaloric and matched for protein, fiber, and saturated fatty acids. Chronic intake of 57g of pistachio decreased small low-density lipoprotein particles (sLDL-P), non high-density lipoprotein particles (non HDL-P), and the mean size of high-density lipoprotein particles (HDL-P), despite the absence of change in TC,LDL-C, or HDL concentrations. According to the authors, independently of changes in the total plasma lipid profile, pistachios may play a beneficial role in cardiovascular disease. It is known that small, dense LDL particles are responsible for greater atherogenic riskthan large LDL particles. This is due to their interaction with the arterial wall. Furthermore, high levels of small, dense LDL have been positively correlated with microalbuminuria, with more non-calcified plaque and an atheroprotective role, whereas they were negatively correlated with glomerular filtration rate as predictors of diabetic nephropathy [16].

In addition, walnut supplementation increased the HDL after a 6-month treatment, which was possibly due to the higher PUFA intakes, although no long-term effects have been shown [11]. Cashew supplementation(from 28 to 64g/day) in mildly hypercholes-terolemic adults （aged 21-79，BMI>18，and <32 kg/m²）following a typical American diet (50% carbohydrates,18% protein,32% fats) decreased TC(-3.9% versus 0.8%,p=0.005)LDL-C(-4.8% versus1.2%,p=0.008),non-HDL cholesterol(-5.3% versus1.7%,p=0.007)and total cholesterol/HDL cholesterol ratio(-0.0% versus 3.4%,p=0.035),in comparison with a control diet, consisting of potato supplementation (54% carbohydrates,18% protein, and 29% fat)[14].

Results of a systematic review by Mukuddem-Petersen et al. showed that the con-sumption of moderate-fat diets (35% of energy) containing ca. 50-100 g/d of nuts, es-pecially almonds, peanuts, pecan nuts, or walnuts, significantly lowered TC and LDL-C concentrations compared with subjects consuming control diets. In particular, a diet sup-plemented with almonds (50-100 g/d),peanuts(35-68 g/d),pecan nuts(72g/d),and walnuts(40-84 g/d) resulted in a decrease in total cholesterol between 2% and 16% and LDL cholesterol between 2% and 19% compared to an unsupplemented control diet. The consumption of macadamia nuts(50-100 g/d) produced less significant results. The au-thors concluded that the consumption of about 50-100 g of nuts approximately 5 times per week as part of a healthy diet with a total fat content (high in MUFA and/or PUFA)of about 35% energy may significantly decrease total cholesterol and LDL cholesterol in normo- and hyperlipidemia individuals [19].

2.4. Effect on Inflammation and Oxidative Stress

Nuts are sources of tocopherols and phenolic compounds with potent antioxidant and anti-inflammatory properties. A large number of in vitro [34], in vivo [30-36,39], and epidemiological [8,12,29,37,38,40] studies have highlighted the beneficial efects of nut intake on inflammatory and oxidative processes(Table 4).

Recently, the potential beneficial effects of cashew nuts on chronic and acute in-flammatory and oxidative processes have been investigated in different in vivo exper-imental mouse models, such as dinitrobenzene sulfonic acid (DNBS)-induced colitis and monosodium iodoacetate (MIA)-induced osteoarthritis, carrageenan-induced paw edema, cerulean-induced pancreatic and lung injury, and ischemia/reperfusion (I/R) in-jury [30-33,35]. It has been shown that cashew nuts intake at a dose of 100 mg/kg (1)alleviated pain perception and histological damage, (2) reduced various pro-inflammatory pathways and molecular mediators, including myeloperoxidase (MPO) and MDA lev-els, mast cell degranulation, neutrophil infiltration, and the release of pro-inflammatory cytokines, (3)modulated NF-kB signaling and ROS generation,(4) enhanced Nrf2 path--way activation, and (5)suppressed the NLRP3 pathway [30-33,35]. Cordaro et al. (2020)highlighted the anti-inflammatory, anti-oxidative, and analgesic properties of cashews and hypothesized a correlation between these beneficial effects and the high content of phenols, which mediate the activation of 5-LOX COX pathways [30]. Fusco et al. (2020b)also demonstrated how cashew nut intake decreased the intestinal barrier dysfunction and mucosal damage and the translocation of toxins and bacteria, which are usually correlated to systemic inflammation and organ injuries, particularly of liver and kidney [33].

In vivo studies have also demonstrated the effectiveness of pistachio, Brazil nut, and mixed nuts against oxidative stress [34,36] and inflammation [36].

Paterniti et al, using the CAR-induced histological paw damage mouse model, showed that treatment with polyphenols-rich extract obtained from natural pistachio (NP)significantly reduced the paw edema, with a decrease in MPO activity, as opposed to roasted pistachio (RP), which did not demonstrate a significant effect. According to the authors, the bioactivity may be due to the synergistic interaction amongst the polyphe-nols identified in NP, to the effect of catechin, which is present in higher concentration in NP compared to RP, as well as the effect of epicatechin and isoquercetin, which are also significantly higher in NP compared to RP [36]. Moreover, Lorenzon dos Santos et al. highlighted the effect of the consumption ofdifferent nuts on oxidative stress biomarkers, which are typically involved in the primary and secondary prevention of cardiovascular disease. The potential of nuts in exerting antioxidant effects by DNA repair mechanisms, lipid peroxidation prevention, modulation of the signaling pathways, inhibition of the MAPK pathways, suppression of NF-kB,and activation of the Nrf2 pathways was proven using in vitro tests. The ability of dietary nuts in improving biomarkers of oxidative stress, such as oxLDL and GPx was shown using animal models[34]

Overall, these results suggest that nut intake may contribute to protection against oxidative stress and the related consequences of inflammatory processes, which are mostly due to the abundance of secondary metabolites such as phenol compounds, flavonoids, and carotenoids, which are present in the skin and in the kernel, as shown in previous studies[39,60].

The antioxidant potential of almond consumption has also been investigated through a randomized crossover study involving 14(12 h fasting)healthy subjects (aged 19-65 BMI>25kg/m²） randomized into three 3-week crossover designs with a 1-week washout period between treatments: walnut (75% of energy intake), almond (75% of energy intake)and control (macronutrient composition similar to the nut containing meal). In both treat-ment groups, plasma polyphenol concentration significantly increased within 30 min after ingestion of walnuts and almonds, reaching peak levels at 90 min (224.3±2.57mgL-gallic acid equivalent (GAE) for walnut diet and 238.48±2.71mgL-1GAE for almond meal). The antioxidant capacity reached a peak value at 150 min and started to decline at 210 min. At 150 min after the consumption of either the walnut and almond meal, both lipophilic and hydrophilic oxygen radical absorbance capacity (ORAC) components showed an increase in plasma antioxidant capacity over baseline(p<0.05)(455.3±3.8 and 130.5±3.4 umol L-l ORAC lipophilic and hydrophilic for walnut diet and 472.5±3.8 and 266.2±8.7 umol L-1 ORAC lipophilic and hydrophilic for almond meal).Agradual significant (p<0.05)reduction in the susceptibility of plasma to lipid peroxidation was observed 90 min after ingestion of the nut meals （6.4±0.9 μmol L-4 MDA for walnut diet and 5.2±0.9 μmol L-1 MDA for almond meal）.The results for the control meal showed no significance [40].

Epidemiological and clinical studies suggested that some dietary factors, such as w-3 PUFA, antioxidant vitamins, dietary fiber, L-arginine, and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and inflammatory markers has been investigated in controlled feeding intervention and has reported mixed results [8,29,37,38]

Recently, the potential of nuts, when used in controlled amounts in a weight man-agement program, to promote weight reduction and improve the plasma concentration of inflammatory factors was shown in a randomized controlled parallel trial. Sixty-seven overweight and obese stable coronary artery disease individuals (age 58.8±7.4 years, BMI 30.9±3.9 kg/m²） were randomly allocated to an 8-week nut-enriched low-calorie diet (NELCD) or to a nut-free low-calorie diet (NFLCD).The LCD promoted a decrease in ICAM-1(p=0.04)and,IL-6(p=0.02)concentrations compared to NFLCD.No significant difference in concentrations of monocyte chemo-attractant protein (MCP-1) or plasma CRP was observed between diet groups [29].

Liu et al. showed that almond consumption improved inflammation and oxidative stress in 20 Chinese patients (age 58 ± 2 years, BMI 26 kg/m2)with T2DM and mild hyperlipidemia. Within a 12-week randomized, crossover, controlled feeding trial, after a 2-week run-in period, individuals were assigned to receive either a control (56% car-bohydrates,17% protein, and 27% fat) or an almond diet (56 g/day were added to the control diet to replace 20% of total daily calorie intake) for 4 weeks each, with a 2-week washout between alternative diets. The almond diet decreased IL-6 (by a median 10.3%compared to the control diet—95% confidence intervals 5.2,12.6%), CRP(by a median 10.3% compared to the control diet—24.1,40.5),TNF-α(by a median 15.7% compared to the control diet—0.3,29.9) and also the plasma protein carbonyl (PC) (by a median 28.2%compared to the control diet—4.7,38.2), though it did not alter antioxidant capacity and total phenolic content in plasma and plasma MDA. The almond diet also enhanced LDL resistance against Cu2+-induced oxidation (by a median 16.3%—7.4,44.3)as compared to the control diet. Serum intercellular adhesion molecule-1 and vascular adhesion molecule-1 were not changed by either diet [38].

In another study, Tey et al. have reported that the inclusion of hazelnuts into the usual diet did not significantly influence biomarkers of inflammation and endothelial function and blood lipid profiles. In this study,107 weight-stable, overweight and obese participants （aged 18-65， BMI>25kg/m²）followed a randomized， controlled， parallel 12-week intervention including three treatment arms: no nuts (control group),30 g/d of hazelnuts, or 60 g/d of hazelnuts. With the exception of a tendency toward improvement in VCAM-1 concentration in the 60-g/d nut group (p=0.07),no significant differences in follow-up clinical outcomes between groups were observed for the measured parameters, which included blood pressure, body composition, plasma high-sensitivity C-reactive protein (hs-CRP), IL-6, ICAM-1 [37]. The authors suggested that a dietary intervention with either energy restriction or weight loss rnay be necessary in order to improve obesity-related inflammatory markers,as shown by several studies, which reported improvements in these biomarkers[37].

In addition, pistachio intervention has been shown to determine a decrease of IL-6 mRNA and resistin gene expression by 9 and 6%, respectively (p<0.05, for PD vs. CD)in lymphocytes. Furthermore, other cardiometabolic risk markers such as fibrinogen, oxidized LDL, and platelet factor significantly decreased under the PD compared with the CD (p<0.05), whereas glucagon-like peptide-1 increased. According to the authors, the beneficial effects on the inflammatory and oxidative state may be due to the high content in lutein, β-carotene, and tocopherol in pistachios [8].

This article is extracted from Int. J. Mol. Sci. 2021, 22, 5960. https://doi.org/10.3390/ijms22115960 https://www.mdpi.com/journal/ijms