key: cord-0698442-5u5cbgma
authors: Margină, Denisa; Ungurianu, Anca; Purdel, Carmen; Nitulescu, George Mihai; Tsoukalas, Dimitris; Sarandi, Evangelia; Thanasoula, Maria; Burykina, Tatyana I.; Tekos, Fotis; Buha, Aleksandra; Nikitovic, Dragana; Kouretas, Demetrios; Tsatsakis, Aristidis Michael
title: Analysis of the intricate effects of polyunsaturated fatty acids and polyphenols on inflammatory pathways in health and disease
date: 2020-07-05
journal: Food Chem Toxicol
DOI: 10.1016/j.fct.2020.111558
sha: 6379ec9d139abc0c3a2df44f0048a290914600d2
doc_id: 698442
cord_uid: 5u5cbgma

Prevention and treatment of non-communicable diseases (NCDs), including cardiovascular disease, diabetes, obesity, cancer, Alzheimer’s and Parkinson’s disease, arthritis, non-alcoholic fatty liver disease and various infectious diseases; lately most notably COVID-19 have been in the front line of research worldwide. Although targeting different organs, these pathologies have common biochemical impairments – redox disparity and, prominently, dysregulation of the inflammatory pathways. Research data have shown that diet components like polyphenols, poly-unsaturated fatty acids (PUFAs), fibres as well as lifestyle (fasting, physical exercise) are important factors influencing signalling pathways with a significant potential to improve metabolic homeostasis and immune cells’ functions. In the present manuscript we have reviewed scientific data from recent publications regarding the beneficial cellular and molecular effects induced by dietary plant products, mainly polyphenolic compounds and PUFAs, and summarize the clinical outcomes expected from these types of interventions, in a search for effective long-term approaches to improve the immune system response.

short-term defence mechanism leads to a chronic inflammatory state, transitioning from solution to 26 cause, becoming in fact a lesion-inducing factor for the affected tissues. This may be a result of the 27 dysregulation of several cellular pathways involving cyclooxygenase-2 (COX-2), signal transducer 28 and activator of transcription 3 (STAT3), matrix metalloproteinase-9 (MMP-9), nuclear factor 29 kappa-B (NF-κB), cytokines with inflammatory outcome: interleukins (IL-1, IL-6, IL-8), tumour 30 necrosis factor alpha (TNF-α), cell adhesion molecules and chemokines, etc. Of note, the resolution 31 of the inflammatory process cannot be simply switched off by restricting the synthesis of the pro-32 inflammatory molecules, requiring cellular intervention through anti-inflammatory and pro-33 resolving molecules (Minihane et al., 2015; Ortega-Gomez et al., 2013; Serhan et al., 2008) . 34

Mitigating the pathological pathways associated with chronic low-grade inflammation 35 through pharmacological agents but, more importantly, through diet and lifestyle changes might 36 constitute an effective strategy in the prevention of NCD and NCD-related deaths. In the current 37 review, we overview recent facts from molecular and animal studies to human clinical reports 38 regarding the intricate pathways that are affected by some of our dietary habits, also discussing the 39 next steps that ought to be taken in addressing these parameters. 40 Figure 1 Regulation of cellular pathways under the influence of pro-inflammatory stimuli (Keap1 -7 (Guzman-Ruiz et al., 2020) . The main components of adipose tissue ECM are collagens, fibronectin 136 and laminin (Mori et al., 2014) . Minor constituents include osteopontin, hyaluronan (HA), 137 thrombospondins, MMPs, as well as A disintegrin and metalloproteinase domain-containing protein 138 (ADAMs), and contribute significantly to ECM remodelling and the regulation of adipose tissue 139 functions (Lin et al., 2016) . 140

The main characteristic of obesity is an increase in lipid tissue infiltration due to the 141 hypertrophy of existing adipocytes, as well as due to the hyperplasia of adipocytes resulting from de 142 novo adipogenesis from precursor stem cells (Schoettl et al., 2018) . Indeed, it was postulated that 143 the ECM, in a spatial as well as temporal manner, regulates adipogenesis (Soukas et al., 2001) . In 144 addition to adipocyte deposition, a notable migration of macrophages and vascular cells was 145 correlated to changes in the ECM structure. This remodelling leads to the release of active 146 mediators that can affect immune cells' recruitment and activation, facilitating the inflammatory 147 state of lipid tissue. Furthermore, the strong upregulation of obese adipose tissue ECM components, 148 including collagens and osteopontin, was suggested to initiate the necrosis of adipocytes, enhance 149 the infiltration of immune cells, leading to tissue inflammation and metabolic dysfunction (Catalan 150 et al., 2012; Ruiz-Ojeda et al., 2019) . Thus, the overexpression of endotrophin, resulted from the 151 cleavage of the α-3 chain of collagen VI (Col6a3), facilitates the deposition of fibrotic collagen and 152 initiates adipose tissue inflammation and insulin resistance (Sun et al., 2014) . A recent study 153 demonstrated that the expression of MMP14 is strongly upregulated in the adipose tissue of 154 transgenic obese mice. Interestingly, MMP14 proteolytic activity results in the release of 155 endotrophin with concurrent formation of enlarged adipocytes and increase in body weight, altered 156 lipid metabolism and insulin resistance . Furthermore, Springer et al recently 157 demonstrated a link between alterations in the ECM of obese women and breast cancer. Thus, 158 enhanced adipose tissue interstitial fibrosis facilitates the generation of M2/M1 type macrophages 159 pattern similar to that of tumour-associated macrophages, as well as the generation of associated 160 inflammatory cues (Springer et al., 2019) . Under these conditions a paracrine loop consisting of free 8 fatty acids and TNF-α is established among adipocytes and infiltrating macrophages that enhances 162 inflammation-mediated alterations in the adipose tissue (Engin, 2017) . Recently, lumican, a small 163 leucine-rich proteoglycan (Nikitovic et al., 2014b) , was shown to be overexpressed in ECM of 164 subcutaneous fat of insulin resistant obese individuals. Lumican was demonstrated to alter the 165 organization of collagen I, dysregulate adipogenesis and trigger oxidative stress, facilitating the 166 pathology of obesity-associated insulin resistance (Guzman-Ruiz et al., 2020) . A separate study 167

showed that the effect of lumican was diet-dependent and correlated to adipose tissue inflammation. 168 Indeed, the same authors suggest that the ECM protein lumican could pose a convergent point 169 among the ECM, the glucose homeostasis and the metabolic syndrome (Wolff et al., 2019) . 170

Osteopontin, an ECM glycoprotein, excessively secreted by adipose tissue macrophages 171 (Nomiyama et al., 2007) enhances adipose tissue inflammation and facilitates the onset of insulin 172 resistance (Aouadi et al., 2013) . Another important ECM component, the glycosaminoglycan HA, 173 has been strongly correlated to increased inflammatory burden, including cancer-associated 174 (Nikitovic et al., 2015) and sterile inflammation (Kavasi et al., 2017; Kavasi et al., 2019; Nikitovic 175 et al., 2014b) . The biologic role of HA is dependent on its size. Thus, high molecular weight HA 176 (HMWHA), physiologically secreted by cells facilitates normal tissue stability (Kavasi et al., 2017) . 177

In contrast, low molecular weight HA (LMWHA) fragments, produced via enzymatic action or 178 chemical reactions, are pro-inflammatory and have been characterized as a danger-associated 179 molecular patterns (DAMP) (Kavasi et al., 2017; Kavasi et al., 2019; Nikitovic et al., 2014a) . 180

Indeed, the generated LMWHA fragments can trigger a Toll-like receptor 4 (TLR4)/NF-κB 181 signalling pathway to regulate inflammatory genes transcription in immune cells (Kavasi et al., 182 2017; Termeer et al., 2002) . Interestingly, HA levels were increased in various tissues of type-2 183 diabetes mellius (T2DM), but not in type-1 (T1DM) subjects, and independent of glycaemic 184 control. Taking into account that T2DM, in contrast to T1DM, is linked with systemic 185 inflammation, it was suggested that inflammatory factors and not hyperglycaemia upregulate HA 186 levels (Nagy et al., 2019) . Importantly, it was demonstrated that the expression of genes involved in 9 the metabolism of HA was positively correlated to the process of adipocyte differentiation 188 (Allingham et al., 2006) . Recently, it was shown that HA exerts inhibitory effects in vitro regarding 189 adipogenesis of 3T3-L1 cells, whereas downregulating HA prevented insulin resistance and 190 NAFLD correlated to excess deposition of abdominal fat in HFD-feeding C57BL/6J mouse model 191 . Moreover, treatment of HFD-fed obese mice with a stable hyaluronidase complex, 192 where human recombinant hyaluronidase was Pegylated, was shown to decreases adiposity, adipose 193 tissue inflammation and insulin resistance (Kang et al., 2013). 194 A hallmark of metabolic diseases is a high NADH/NAD + ratio, originating from excessive 195 electron supply. This dysregulation results in an altered mitochondrial function and sirtuin-3 3) activity, which result in oxidative stress and distorted fatty acid β-oxidation (Cortes-Rojo et al., 197 2020) . Increased ROS production was shown to induce excessive remodelling of the ECM in a 198 pathological milieu (Nikitovic et al., 2013) . Thus, oxidative stress induced by high-glucose levels, 199 in rat glomerular mesangial cells, resulted in an increased deposition of collagen IV and fibronectin, 200 through the involvement of the TXNIP-NLRP3 inflammasome signalling (Wang et al., 2017) . 201 Importantly, the remodelling of renal ECM is involved in the progression of diabetic nephropathy, 202 one of the most serious complications of diabetes mellitus. Treatment aimed at downregulating 203 ROS generation, such as the utilization of dihydroquercetin (DHQ), an important natural 204 dihydroflavone, attenuated the activation of NLRP3 inflammasome and the subsequent of increased 205 deposition to ECM of renal fibrosis-associated proteins upon exposure of renal cells to high glucose 206 levels (Ding et al., 2018) . 207

These data highlight the complex interactions between the ECM, inflammation, and 208 metabolic diseases. The reorganization of the ECM as well as ECM-originating pro-inflammatory 209 cues needs to be taken account when designing efficient therapy for inflammation associated 210 disease. Dietary measures might constitute important means to mitigating these pathological 211 pathways. 212 and fats consumed is the major influencing factor of systemic inflammatory status. Thus, clinically, 239 even a 4-day low-carbohydrate diet intervention improved the insulin and fasting plasma glucose 240 levels in T2DM patients (Myette-Cote et al., 2018) . When comparing low-carb to low-fat diets in 241 diabetics, some older studies reported a similar effects on cardiovascular risk markers (Davis et al., 242 2011) , while more recent ones asserted the beneficial effects of restricting carbohydrates on the 243 systemic low-grade inflammation, reducing IL-6 (Asle Mohammadi Zadeh et al., 2018; Jonasson et 244 al., 2014) , resistin, leptin (Asle Mohammadi Zadeh et al., 2018) , E-selectin, sICAM (Davis et al., 245 2011) and increasing adiponectin (Asle Mohammadi Zadeh et al., 2018) . Furthermore, the 246 improvement of systemic inflammatory status was also reported in obese adults, with no T2DM or 247 CVD . 248

Switching to a very strict low-carb diet was associated with an increase of systemic 249 inflammation in apparently healthy subjects (Rosenbaum et al., 2019) , while in subjects with 250 metabolic syndrome or obesity, a short-term ketogenic diet yielded beneficial cardiometabolic 251 effects (Gyorkos et al., 2019; Ruth et al., 2013) . In T2DM patients, a one-year nutritional ketosis 252 intervention resulted in a lower cardiovascular risk (Bhanpuri et al., 2018) . Importantly, these 253 beneficial effects are amplified by physical exercises (Alves et al., 2016; Asle Mohammadi Zadeh 254 et al., 2018; Myette-Cote et al., 2018) , and by the diet supplementation with nuts (Hou et al., 2018) , 255 soy (Kani et al., 2017) , or even carefully choosing the types of ingested carbohydrates. In obese and 256 overweight adolescents and adults, a diet based on low glycaemic index food improved 257 inflammation, metabolic as well as cardiovascular risk factors (Rouhani et al., 2016) , while the 258 addition of functional foods resulted in further benefits (Izadi et al., 2018) . Also, the consumption 259 of complex carbohydrates led to a decline of pro-inflammatory molecules' level in pregnant women 260 (Hernandez et al., 2016) . The results of most recent clinical studies concerning the link between 261 low-carb diet and systemic inflammation are summarized in Table 3 . 262 inflammatory profile of T2DM and obese patients while low-carb and low-fat diets induce the same 264 type of effects on cardiovascular risk markers of diabetes patients. 265

The Mediterranean diet (MD) is based on the dietary pattern found in the Mediterranean 267 basin (Greece, southern regions of Italy and Spain), and includes high amounts of fresh vegetables 268 and fruits, seeds, nuts, along with olive oil and whole grain cereals. Milk, cheese, yogurt, eggs, fish 269 and poultry are consumed in moderate amounts, as is wine (especially red), with low amounts of red 270 meat and sugary deserts Tosti et al., 2018) . This diet is abundant in 271 minerals and vitamins, antioxidants and phytochemicals (Tosti et al., 2018) . Although several of its 272 components exerted beneficial actions, most likely their combined synergistic effects contribute to 273 reducing the systemic inflammatory burden (Tosti et al., 2018) . Some authors posit that MD exerts 274 a hormetic effect, similar to caloric restriction, highlighting the Nrf2 pathway, regulating the pro-/ 275 anti-inflammatory processes equilibrium (Martucci et al., 2017) . Epigenetic regulation was also 276 hypothesized, especially due to components found in nuts and extra virgin olive oil, which were 277 reported to alter the methylation of some genes related to inflammation, metabolism and signal 278 transduction (Arpon et al., 2017; Arpon et al., 2016) . 279

In healthy subjects, even one MD-style meal was shown to reduce the expression of pro-280 inflammatory molecules (De Lorenzo et al., 2017) , with no differences between sexes regarding 281 effects on systemic inflammatory status (Bedard et al., 2015) . In elderly individuals, a MD 282 intervention lead to lower glycoxidative impairment (Lopez-Moreno et al., 2018) and inflammatory 283 response (Camargo et al., 2012; Yubero-Serrano et al., 2012) , paralleled to a diet based on saturated 284 fatty acids (fig 2) . 285

Diets rich in proteins, lipids and carbohydrates induce the production of pro-inflammatory 287 molecules that lead to the activation of several inflammatory pathways including JAK/STAT 288 pathway, NF-Kβ pathway and MAPK kinase cascade. These pathways lead to oxidative stress, as 289 wells as, COX-2, TNF-α, and interleukins production via transcriptional regulation ultimately 290 leading to chronic inflammation. Oxidative stress either directly or via metabolic dysfunctions 291 causing e.g insulin resistance, as well as the rest of the inflammatory molecules as a result of 292 unhealthy diet promote the onset of several chronic diseases including CVD, neurodegenerative 293 diseases, autoimmunity, pulmonary diseases and are-related frailty; (NF-kβ -nuclear factor kappa-294 light-chain-enhancer of activated B cells heterodimer, consisting of p50, p65 and IkBα proteins; 295 STAT3 -Signal transducer and activator of transcription 3; ERK/MAPK -mitogen-activated 296 protein kinases; JNK -c-Jun N-terminal kinases; COX-2 -cyclooxygenase 2; TNF-α -Tumour 297 necrosis factor alpha; IL-1/6/8 -interleukin 1/6/8) 298

A marked reduction of inflammatory molecules (C reactive protein -CRP, E-selectin, P-299 selectin, TNF-α, IL-1β, IL-6) and of mRNAs of pro-inflammatory genes was reported in overweight 300 diabetics and patients with high cardiovascular risk, MD determined a significant reduction of 303 serum levels of CRP, interleukins and adhesion molecules (Casas et al., 2014; Ceriello et al., 2014; 304 Maiorino et al., 2016; Mayr et al., 2018) . In a group of asthmatic children, MD supplemented with 305 150g cooked fish twice a week resulted in significantly improved pulmonary function and markedly 306 increased docosahexaenoic acid (DHA) levels and improved omega-6 to omega-3 ratio 307 (Papamichael et al., 2019) . The recent clinical trials addressing the relationship between MD and 308 inflammation are summarized in Table 4 . 309

In recent years, the effects of a diet similar to MD started to be investigated: the Nordic diet 310 (ND). Similarly, ND is based on fruits, especially berries, and vegetables, fish, whole grains, and 311 includes low amounts of processed red meat and is almost lacking saturated fats. As olive oil is 312 specific for the Mediterranean basin, the ND includes canola oil (Lankinen et al., 2019; 313 Magnusdottir et al., 2017) . Literature reports are reviewed elsewhere (Lankinen et al., 2019) and 314 although scarce, they indicated that ND exerted anti-inflammatory effects, as it was able to reduce 315 the serum levels of CRP (de Mello et al., 2011; Lankinen et al., 2019) . 316

Dietary interventions based on Mediterranean/Nordic style induce positive effects on both 317 inflammation and redox stress, both in healthy patients and in those with metabolic impairments 318 (diabetes mellitus, obesity, metabolic syndrome). The hormetic effects induced at the level of the 319 immune system is pointed out by the positive results induced by MD on people with inflammatory 320 phenomena impacting the respiratory system, including children with asthma. 321

Literature data mentions two main groups of polyunsaturated fatty acids (PUFAs), of plant 323 or animal origin: omega-3 (n-3) and omega-6 (n-6). The most discussed molecules of each group 324 are α-linolenic acid (ALA) and linoleic acid (LA), respectively. Functionally, notable among the 325 (Calder, 2015) , although docosapentaenoic acid (DPA) is materializing as an important member of 327 the n-3 family (Kaur et al., 2011) . In human diets, the two essential PUFAs, LA, and ALA are 328 usually derived from plant sources (such as seeds, nuts, seed oils and derived products), as only 329 plants synthesize them (Calder, 2011) . Linseeds and their oil habitually contain 45-55% of n-3 330

PUFAs, mainly ALA, whereas soybean or rapeseed oil, and walnuts only about 10% ALA (Kris-331 Etherton et al., 2002) . 332

Another important food source of n-3 PUFAs are fatty fish and also other seafood or derived 333 products, known as "fish oils". All these products contain significant quantities of DPA, EPA and 334 DHA, as a result of plankton and algae consumption and not as a result of endogenous synthesis 335 (Poudyal et al., 2011) . Noteworthy, the dominant PUFAs in fish, as well as fish oils, vary between 336 species. For instance, cod liver oil contains more EPA than DHA, whereas tuna oil has a higher 337 content of DHA (Calder, 2012) . One portion of fish could bring into diet between 200 to 300 mg n-338 3 PUFAs, while 1 g of fish oil contains almost 30% EPA and DHA, highlighting the importance of 339 diets including seafood. In the absence of fish or derived products, the daily intake of n-3 PUFAs in 340 most adults is below 200 mg/day (Meyer et al., 2003) . As plants produce much more LA than ALA, 341 the former is the most customary PUFA in Western diets (Blasbalg et al., 2011) . The daily dietary 342 intake of ALA is 0.5-2 g, while of LA greatly increased in the last 50-60 years, along with a 343 significant change of n-6 / n-3 ratio (Calder, 2017) , reaching as high as 20 in some Western-type 344 diets (Calder, 2011) . 345 LA and ALA share a common metabolic pathway in animals and humans (Poudyal et al., 346 2011) . LA is metabolised by Δ6-desaturase to γ-linolenic acid (GLA), and later by elongase and Δ5-347 desaturase to arachidonic acid (ARA), while ALA is converted by the same enzymes into EPA, 348 subsequently to DPA then, finally, to DHA. The rate of transformation from ALA to EPA and later 349 to DHA is affected by several factors such as age, sex, or genetics (Baker et al., 2016) . In addition, 350 levels of ALA, LA and DHA are affected by chronic diseases as shown in a study comparing lipid 351 levels between patients with autoimmune diseases and healthy controls (Tsoukalas et al., 2019b) . 352

The conversion of dihomo-gamma-linolenic acid (DGLA) to ARA is regulated by insulin 353 and ARA/EPA ratio is a sensitive marker for insulin resistance, a common denominator of most 354 chronic inflammatory diseases. In a study of healthy adult volunteers AA to EPA ratio and the ARA 355 precursor -DGLA, significantly changed with age (Tsoukalas et al., 2019a) . The metabolism of n-6 356

PUFAs is more prevalent compared with n-3 PUFA, due to the fact that LA is much more common 357 in actual diets (Blasbalg et al., 2011) , although ALA, and not LA, is the preferred substrate for Δ6-358 desaturase (Calder, 2015) . 359

Noteworthy, LA, ARA, EPA and DHA are important constituents of membrane 360 phospholipids and have important roles in membrane function, which greatly influences cell activity 361 (Burdge and Calder, 2015) . The proportion of PUFAs found in the membrane is dependent on cell 362 type, dietary intake and metabolism (Calder, 2017) . For example, in healthy subjects receiving a 363 typical Western diet, the percentages of DHA, EPA, and ARA, in mononuclear cells were 2.5, 0.5 364 and, respectively, 20% of total fatty acids (Calder, 2011) . 365

The effects exerted by n-3 PUFAs are arbitrated either by the fatty acid molecules or by 366 their bioactive metabolites from one of the three categories: protectins, resolvins, and maresins. The 367 E-resolvins (such as E1, E2, and E3), are produced from EPA, while the D-series resolvins 368 including D1, D2, D3, D4 and D5, neuroprotectins/protectins (NPD1/PD1), and the maresins 369 (MaR1), are biosynthesized from DHA (Dalli et al., 2013; Serhan and Petasis, 2011) . The 370 biotransformation of n-3 PUFAs involves the COX and LOX pathways. S-resolvins, S-protectins, 371 and S-maresins are produced from DHA and EPA via LOX pathway, while R-resolvins and R-372 protectins are derived from aspirin-activated COX-2 or cytochrome P450 metabolic transformation 373 of DHA and EPA (Calder, 2015) . In most cell types, ARA is highly predominant and exhibits direct 374 links to inflammatory pathways, since it constitutes the substrate for enzymes such as cytochrome 375 synthesis of pro-resolving mediators is increased when the diet is rich in n-3 PUFAs. Thus, in 377 healthy subjects, a daily supplement for 3 weeks of 1 g DHA and 1.5 g EPA, quantified measurable 378 levels of resolvins D1, D2, and 17-R resolvin D1 (> 25 pg/ml plasma) (Mas et al., 2012) . In obese 379 women treated for 3 months with a daily supplement of 1.8 g EPA and DHA, DHA-derived pro-380 resolvins mediators were measured and found to be increased (RvD1 and RvD2 > 60 pg/ml plasma) 381 (Polus et al., 2016) . 382

Nowadays, the mechanisms of action by which n-3 PUFAs regulate the inflammatory 384 processes are widely investigated. The suppression of inflammation by n-3 PUFAs is associated 385 with one of the following mechanisms (1) competitive inhibition of n-6 PUFA pathway; (2) 386 modification of cell membrane composition; (3) affecting the formation of rafts or (4) direct anti-387 inflammatory effect of their bioactive metabolites (resolvins, protectins, and maresins) (Poudyal et 388 al., 2011) . 389

It has been demonstrated that the dietary supplementation with DHA and EPA from fish 390 increases in a dose-response manner the content of DHA and EPA in the cell inflammation-391 responsible phospholipids (Calder, 2017) ; increased content of DHA or EPA in different tissues, 392 such as adipose tissue or heart was also observed in correlation with their intake (Calder, 2015) PPARs, or by inhibiting TLR2/4 which normally activates NF-κB. Moreover, omega-3 fatty acids 399 regulate inflammation by activating MAPK and GPR120 which in turn inhibits inflammation. 400

Polyphenols inhibit the inflammatory response by directly inhibiting NF-κB, or via the PPARs. 401

They also promote fatty acid b-oxidation and inhibit VCAM-1, ICAM-1, MAPK pathway, PGE2 402 and COX-2 that all promote chronic inflammation (PGE2 -prostaglandin 2; NF-κB -nuclear factor 403 kappa-light-chain-enhancer of activated B cells; PPARs -peroxisome proliferator-activated 404 receptors; TLR2/4-toll-like receptor; MAPK -mitogen-activated protein kinase; GPR120 -G-405 protein coupled receptor 120; VCAM-1 -vascular cell adhesion molecule 1; ICAM-1 -406 intracellular cell adhesion molecule 1; COX-2 -cyclooxygenase 2; TNF-α -tumour necrosis factor 407 alpha; MCP-1 -monocyte chemoattractant protein 1; AMPK -AMP kinase;) 408 409 These n-3 PUFAs frequently substitute n-6 PUFAs like ARA, resulting in decreased 410 availability of ARA for eicosanoid synthesis. EPA also inhibits ARA metabolism as a competitive 411 substrate for COX-2, decreasing prostaglandin E2 (PGE2) production. In rats, dietary supplementation with ALA inhibits PG biosynthesis from ARA, while equivalent quantities of ALA 413 and LA decreased up to 40% n-6 PUFAs incorporation in phospholipids (Calder, 2017) . 414 Furthermore, Rees et al. observed that a daily EPA intake of 2.7 g or 4.05 g for 3 months decreases 415 the PGE2 production by lipopolysaccharide-stimulated mononuclear cells, while a lower dose of 416 1.35 g did not. EPA was integrated in a linear dose-dependent manner into mononuclear cell 417 phospholipids and plasma. This study suggested a daily threshold in the range of 1.35 to 2.7 g EPA 418 for the anti-inflammatory action (Rees et al., 2006) . 419

Besides decreasing production of PGE2, DHA and EPA are also substrates for the 420 biosynthesis of lipid derivatives, but the EPA-derived mediators as series-3 prostaglandins (PGD3) 421 or series-5 leukotrienes are typically less biologically potent, having a lower ability to interact with 422 relevant eicosanoid receptors (Calder, 2015) . For example, EPA-derived leukotriene B5 (LTB5) is 423 almost 100 times less active as a leucocyte chemoattractant than ARA-derived LTB4 (Calder, 424 2017) . However, in some cases, EPA-derived mediators have similar potency with ARA-derived 425

mediators. It appears that EPA-derived PGD3 inhibits the effect of the ARA-derived PGD2, due to 426 a stronger interaction with the DP1 receptor compared to PGD2 (Wada et al., 2007) . In other cases, 427 EPA-derived mediators exhibited a similar magnitude of effect (e.g. inhibition of TNF-α production 428 by blood monocytes) (Dooper et al., 2002) . 429

There are several pharmacological studies suggesting molecular targets for the anti-431 inflammatory effects of n-3 PUFAs and their metabolites: PPAR-γ, GPR120, CMKLR1 (known as 432 ChemR23), BLT1(leukotriene B4 receptor 1), GPR32 and ALX/FPR2 (Im, 2012) . Thus, resolvins 433 E1 and D1 exhibited a higher affinity for these receptors compared to EPA or DHA. Chem R23 and 434 BLT1 are receptors of resolvin E1, while GPR32 and ALX/FPR2, bind to lipoxin A4 and resolvin 435 D1 with high affinity. GPR120 was reported to be a receptor of EPA and DHA (EC50 ~ 1-10 µM), 436 while ALX/FPR2 to annexin I and lipoxin A4 (Serhan and Petasis, 2011) . Furthermore, some 437 studies on GPR120 KO mice suggest that n-3 PUFAs that activate GPR120, interact with β-arrestin 438 2, and suppress NF-κB activation and macrophage-mediated inflammatory responses (Oh et al., 439 2010) . However, it is important to highlight that the in vivo anti-inflammatory effects of n-3 PUFAs 440 in humans are minor and might only occur at high n-3 PUFA levels, it was demonstrated in vitro 441 that BSA-conjugated n-3 PUFA are incapable of activating GPR120 (Im, 2012) . 442 DHA and EPA are weaker agonists of PPAR-γ (EC50 ~ 10-100 µM), while their oxidized 443 metabolites (such as protectin D1) are much more potent (Yamamoto et al., 2005) . Also, ALA or 444 ARA has a similar potency to DHA or EPA for on PPAR-γ, and higher for PPAR-α (Calder, 2015) . 445

As PPAR-γ activation reduces inflammatory responses, via the NF-κB pathway, this mechanism 446 could partially explain the anti-inflammatory effects of n-3 PUFAs. Furthermore, n-3 PUFAs were 447 reported to suppress NF-κB activation in a PPAR-γ-independent manner by binding to TLR-4 under 448 certain conditions (Im, 2012) . Taking into account all these reports, it looks like three mechanisms 449 are employed by n-3 PUFAs to suppress inflammatory signalling via NF-κB: (1) preventing NF-κB 450 nuclear translocation via PPAR-γ activation, (2) interfering with membrane activation of NF-κB via 451 TLR4 and (3) interaction with GPR120 initiating an anti-inflammatory signalling cascade (Calder, 452 2015) . 453

Resolvin D1 is a potent agonist to GPR32 and ALX/FPR2 (EC50=8.8 pM and 1.2 pM), 454

while Resolvin E1 strongly binds to Chem R23 (Kd= 4.5 nM), reducing IL-12 production 455 (Krishnamoorthy et al., 2010) and is a partial agonist to BLT1, so it induces NF-κB activation via 456 BLT1, inhibiting neutrophil migration (Arita et al., 2007) . For the other resolvins, protectins or 457 maresins, the molecular targets are not yet identified. 458 Isolated n-3 PUFAs and their bioactive mediators were extensively examined in animal 459 models of colitis or arthritis or using specific transgenic models. n-3 PUFAs and RvD1, RvD5, PD1 460 and MaR1 administration proved effective in animal models of colitis, decreasing inflammation and 461 chemically induced colonic damage. The beneficial effects are, in all cases, correlated with the 462 reduction of ARA-derived mediators in the colonic mucosa (Bosco et al., 2013; Charpentier et al., 463 RvD1) displayed a stronger anti-inflammatory effect than RvD2 in experimental colitis, through 465 lipoxin A4 receptor (ALX) activation (Bento et al., 2011) . Furthermore, n-3 PUFAs as fish oil has 466

shown not just anti-inflammatory effects in peripheral tissues, but several beneficial effects in 467 obesity-induced animal models, such as improved lipid profile, decreased hepatic steatosis and 468 insulin resistance (Bargut et al., 2015; Pimentel et al., 2013) . Indeed, beneficial effects of DHA and 469 EPA in adipose tissue were reported in mice fed a high-fructose diet, including modulating pro-and 470 anti-inflammatory markers and ameliorating adipocyte abnormalities. The effects were significantly 471 higher for DHA compared to EPA (Bargut et al., 2017) . 472

Additionally to anti-inflammatory effects, correlated with down-regulation of IL-6 and 473 TNF-α expression in liver, n-3 PUFAs also exhibited triglyceridemia lowering effects in diabetic 474 rats via modulation of PPAR-α (Devarshi et al., 2013; Ghadge et al., 2016) . Additionally, Lee et al. 475 demonstrated that a diet with a high n-6/n-3 PUFAs ratio (~9) induced dysbacteriosis of the gut 476 microbiota in obesity-induced T2DM or high-fat-diet treated rats, while a low ratio (~3) enhanced 477 blood glucose homeostasis (Lee et al., 2019) . The outcomes of the most recent animal studies are 478 summarized in table 5. 479

In healthy subjects, different daily doses of EPA and DHA up 1800 mg, administered up to 481 5 months, showed no significant effects on the CPR, IL-6, and TNF-α (Asztalos et al., 2016; Flock 482 et al., 2014; Muldoon et al., 2016) . A comparable conclusion was drawn by other authors. 483

According to Rangel-Huerta's meta-analysis, consumption of 900 mg to 2000 mg n-3 PUFAs does 484 not change inflammatory biomarkers in healthy subjects (Rangel-Huerta et al., 2012) . On the other 485 hand, doses between 1250 and 2400 mg n-3 PUFA for 4 months lowered inflammation in sedentary 486 and overweight middle-aged and older adults (Kiecolt-Glaser et al., 2012) . Lp-PLA2, another anti-487 inflammatory marker was significantly reduced by a high dose of EPA (1800 mg) but not by DHA 488 (Asztalos et al., 2016) . Interestingly, only DHA modified the lipid profile by decreasing 489 postprandial triglyceride concentrations and significantly increasing low-density lipoprotein 490 cholesterol, with no significant changes in inflammatory biomarkers (Asztalos et al., 2016) . In 491 elderly subjects, daily supplementation with 2500 mg EPA and DHA, for 8 weeks, significantly 492 reduced the plasma levels of fatty acids, IL-1β, IL-6, and TNF-α (Tan et al., 2018) . Similarly, in 493 obese patients who received different doses of combined n-3 PUFAs (380 -1290 mg DHA and 360-494 460 mg EPA) for 2 to 3 months, the intervention reduced the expression of proinflammatory genes 495 in adipocytes and systemic inflammatory markers sVCAM-1, CRP, IL-6, and TNF-α (Itariu et al., 496 2012; Polus et al., 2016) . Furthermore, other relevant metabolic findings connected with n-3 PUFA 497 treatment were reported, such as decreasing fasting triglycerides and insulin (Allaire et al., 2016; 498 Polus et al., 2016) or decreasing fasting blood glucose in obese diabetics (Ellulu et al., 2016) . 499

Partially, these results are in line with the modest reduction in waist circumference and body-weight 500 found in a meta-analysis (Bender et al., 2014) . The authors indicated that the effect regarding waist 501 circumference produced by fish intake or fish oil supplementation and might be greater in men than 502 in women. The beneficial effect in overweight and obese adults concerning waist circumference and 503 triglyceridemia was confirmed by two other meta-analyses (Du et al., 2015; Zhang et al., 2017) . 504

As most of the cited trials utilize a mixture of DHA and EPA which may mask the effects of 505 each compound, the individual effects of DHA or EPA in obese patients were also investigated, but 506 the results were inconclusive. A significant reduction in serum IL-18 and adiponectin with DHA 507 than with EPA was observed in one study (Allaire et al., 2016) , while no differences between DHA 508 and EPA in the expression of pro-inflammatory genes were observed in another study (Vors et al., 509 2017) . 510

In patients with impaired glucose metabolism and T2DM in almost all studies, none of the 511 combined EPA and DHA doses had any effect on IL-6, IL-1β, CRP, VCAM, and sICAM (Clark et 512 al., 2016; Mocking et al., 2012; Sawada et al., 2016) . Further, no effects on glycated haemoglobin 513 (HbA1c) (Sawada et al., 2016; Wong et al., 2010) , insulin (Clark et al., 2016) or lipid profile 514 decreased significantly, and fasting blood glucose increased after n-3 PUFAs treatment for 24 516 weeks, but no other key findings. An overview of the most recent human studies where the 517 inflammatory biomarkers as a result of PUFAs treatments, were assessed as the main outcome, is 518 summarized in Table 6 . 519

Currently, the recommended daily intake of n-3 PUFAs varies as regarding expert 521 committees, ranging from 250 to 500 mg for healthy adults (Flock et al., 2013) . The European Food 522 Safety Authority's (EFSA) recommendation is 250 mg/day n-3 PUFAs (EPA and DHA) for adult 523 males and non-pregnant females, and supplementation of 100-200 mg/day of DHA in pregnancy 524 (EFSA Panel on Dietetic Products, 2010). For children less than 2 years old, the daily 525 recommendation corresponds to 100 mg DHA, while for children more than 2 years and in 526 adolescents, the daily recommendation is similar to that for adults (EFSA Panel on Dietetic 527

Products, 2010). The upper daily value of acceptable for EPA and DHA consumption has been set 528 at 2000 mg, but higher doses used in clinical trials did not induce adverse effects (Rangel-Huerta et 529 al., 2012) . 530

There are also some additional recommendations in patients with high and extremely high 531 fasting-triglyceride levels. The American Heart Association (AHA) recommends a daily intake of 532 500 mg-1000 mg DHA and EPA in patients with borderline levels (150 -199 mg/dl), 1000 -2000 533 mg in patients with high levels, and 2000 -4000 mg in patients with very high triglyceride levels ( 534 > 500 mg/dl) (Kris-Etherton et al., 2002) . Importantly, further research should be conducted before 535 any definitive daily recommendation or on the routine use of n-3 PUFAs in other chronic 536 inflammatory diseases. 537

Studies show that n-3 PUFAs do not impact in a positive manner the metabolic profile of 538 healthy subjects and induce variable effect on diabetes mellitus cases (no important effects on 539 inflammation but a constant ability to increase the HDL level); on the other hand, a reduction of 540 inflammation is obese and ageing patients as well as in those with metabolic syndrome. 541

Literature data demonstrates that there are approximately 8000 different polyphenolic 543 structures, classified into more than ten classes depending on structural characteristics. Regardless 544 of their differences in chemical behaviour, they are all characterized by having an aromatic ring 545 carrying one or more hydroxyl groups (Bravo, 1998; Del Rio et al., 2013) . The polyphenolic 546 molecules originating from diet are involved as key components in counteracting inflammation, 547 mitigating oxidative stress and protecting endogenous compounds from oxidative lesions, 548 regulating the metabolism and promoting a protective phenotype, in improving the endothelial 549 function as well as the platelet function, among several other beneficial actions (Kaliora et al., 2006; 550 Morita et al., 2017; Nitulescu et al., 2019; Nitulescu et al., 2017) . and metalloproteinases (MMPs) are synthesized (Gradinaru et al., 2018; Gradinaru et al., 2017; 562 they alter the enzymatic processes involved in the proliferation and activation of B-and T-cells, as 566 key components of the inflammatory pathway (by inhibiting tyrosine and serine-threonine protein 567 kinases). Likewise, polyphenols blunt the synthesis of pro-inflammatory mediators such as 568 cytokines, chemokines (IL-8, IL-6, TNF-α, VCAM-1 and ICAM-1), and angiogenic factors, NF-кB 569 or iNOS. Further, an inhibitory effect on several pro-inflammatory enzymes was reported, such as 570 COX-2, MAPK or protein kinase-C (PKC) Gasparrini et al., 2017; 571 Hussain et al., 2016) . Thus, studies performed on macrophages proved that resveratrol inhibited the 572 IFN-γ-induced NO production and down-regulated the IFN-γ inducible genes. In this respect, 573 resveratrol decreased STAT1 activation (an important transcription factor for IFN-γ-induced genes) 574 and hindered JAK-2 activation (Chung et al., 2011) . along calcium release as well as increased phagocytic capacity, thus proving anti-inflammatory and 595 immunomodulatory actions (Marinovic et al., 2015) . In a separate study, EGCG reduced ICAM-1, 596 NF-ĸB and IĸB expressions and reduced ROS levels upon TNF-α-induced inflammation in human 597 retinal pigment epithelial cells. The results suggest the possible therapeutic involvement of EGCG 598 in blocking TNF-α-mediated eye inflammation (Thichanpiang and Wongprasert, 2015) . Moreover, 599 in a study evaluating the effect of epicatechin and catechin on arachidonic acid-activated platelets 600 and, respectively, on platelet-HUVEC interaction, the tested compounds induced a reduction of 601 sICAM1, sVCAM1, and sE-selectin levels, as well as an increase of NO bioavailability, proving an 602 anti-inflammatory effect and the ability to counteract endothelial dysfunction, but only when 603 platelets were harvested from peripheral artery disease patients and not from healthy subjects 604 (Carnevale et al., 2014) . 605

Ellagic acid (EA) was tested for its ability to inhibit MIF-induced chemotactic migration of 606 PBMCs, showing a failure to inhibit this response when PBMCs were stimulated with MIP-1α, but 607 high specificity for MIF-induced effect (Sarkar et al., 2015) . Chlorogenic acid exerted a dose 608 depended anti-inflammatory effect showed by the reduction of IL-1β, TNF-α and IL-6 levels as well 609 as the inhibition of NO synthesis and expression of COX-1 and iNOS in LPS-stimulated murine 610 macrophages and microglial cells (Hwang et al., 2014) . 611

An in vitro experiment evaluated the results induced by various flavonoids on the 612 arachidonic acid release from rat neutrophils; kaempferol, luteolin, quercetin and amentoflavone 613 reduced the inflammatory response and inhibited the activity of β-glucuronidase and lysozyme 614 (Tordera et al., 1994) . The anti-inflammatory effects induced by polyphenols in human studies with dietary 632 interventions and weight related outcomes are heterogeneous, as summarized from recent literature 633 (Table7). Thus, in a clinical study with double-blind, randomized, cross-over design, the effect of a 634 commercially available polyphenols rich extract was tested, the study including patients having 635 more than two metabolic risk factors. Results showed a reduction of MCP-1 and MIF, but not of 636 other markers of CVD risk (CRP, IL-6, HDL, adiponectin and oxidized LDL) (Broekhuizen et al., 637 2011) . In a separate clinical study with cross-over design, overweight patients consumed a high-638 carbohydrate, moderate-fat meal supplemented with strawberry/placebo juice. The anthocyanin 639 supplementation blunted the postprandial inflammatory response (reduced CRP level) induced by 640 the high fat diet and reduced the postprandial insulin response (Edirisinghe et al., 2011) . anthocyanin mixture, resulted in a reduction of their CRP, sVCAM-1 and IL-1β levels. Similar 643 results were obtained for HepG2 and porcine iliac artery endothelial cells exposed to the same 644 purified anthocyanin mixture (reduction of LPS-induced VCAM-1 secretion) (Zhu et al., 2013) . 645

Patients with early atherosclerosis, received simple or EGCG-enriched olive oil. Independent of 646 EGCG addition, olive oil reduced inflammatory markers and endothelial dysfunction (sICAM, 647 white blood cells, monocytes, lymphocytes and platelets) (Widmer et al., 2013) . 648

The effects of grape seed extract on pre-hypertension patients were tested. Results of the 649 study in question, showed a reduction of blood pressure (both systolic and diastolic), with 650 improved fasting insulin and insulin sensitivity after 6 weeks of supplementation, but no significant 651 change in sICAM-1 plasma concentration . Furthermore, in a single blinded 652 crossover trial including patients with untreated mild hypertension, cold-pressed chokeberry juice 653 and dried chokeberry powder induced a reduction of IL-10 and TNF-α levels (Loo et al., 2016) . Results regarding the effect of polyphenols on inflammation were obtained not only in 664 metabolically impaired patients, but also in healthy subjects. Thus, in a placebo-controlled study, 665 the effect induced by Montmorency tart cherry concentrate on the inflammatory and redox status 666 concentrate or placebo for 7 days, after which their oxidative stress and inflammatory markers (IL-6 668 and CRP) were reduced, highlighting the ability of the tested extract to improve the stress response 669 in physical exercise conditions (Bell et al., 2014) . 670

Furthermore, in a study with crossover, double-blind design, 49 healthy males with APOE 671 genotype received 150 mg/day quercetin or placebo for 8 weeks, in three phases, separated by 672 three-week washout periods. Quercetin administration led to a decrease of waist circumference and 673 postprandial systolic blood pressure, as well as a moderately increased levels of TNFα (Pfeuffer et 674 al., 2013) . In a separate study with cross-over, double-blind, randomized, placebo-controlled design 675 including 18 healthy subjects, the effect of oleuropeine (51mg) on a single occasion was tested. 676

Blood of the subjects was collected and cells were stimulated with LPS, showing a significant 677 decrease of IL-8 production (Lockyer et al., 2015) . 678

Flavonoid-rich products have also been discussed for their beneficial effect on insulin 679 resistance-related metabolic complications possibly via the upregulation of genes involved in 680 insulin sensitivity (Engin et al., 2018) . In a recent review, the beneficial effect of flavonoid-rich 681 products in a cross-sectional study including 1997 females aged 18-76 years, the correlation 682 between the total flavonoid intake as well as their subclasses (assessed from food questionnaires) 683 and insulin resistance/inflammation was evaluated. Results showed higher anthocyanin and flavone 684 intake were associated with significantly lower peripheral insulin resistance and CRP 685 concentrations (Jennings et al., 2014) . In a randomized controlled dietary study, results showed that 686 consuming a high anthocyanins diet is associated with the reduction of CRP, IL-6, IL-12, and LPS 687 concentrations indicating a positive effect on the long term cardiometabolic risk (Kolehmainen et 688 al., 2012) . 689

According to literature data, polyphenols blunt the inflammatory response in clinical setting, 690 thus reducing the cardio-vascular risk factors for hypertensive, obese or diabetes mellitus patients. and, moreover in trained athletes, who seem to benefit from the metabolic point of view from 693 receiving polyphenols supplements. 694

Just a small number of published studies investigated if n-3 PUFAs may interact with the 695 polyphenols and if a combined diet may have an enhanced beneficial impact. Until now only the 696 beneficial effects on HDL-levels (as a "surrogate" for the anti-inflammatory effect) were identified 697 (Ahn et al., 2020; Annuzzi et al., 2014; Bub et al., 2019) . 698

In an 8-week randomized controlled dietary study on overweight patients, a combined diet 699 of high polyphenols and marine PUFAs-diet showed beneficial, although non-additive effects on 700 plasma triglycerides. Also, the reduction in oxidative stress (measured by urinary 8-isoprostane) 701 was observed, probably as an effect of polyphenols. A negative interaction between PUFAs and 702 polyphenols was observed for some variables (chylomicron cholesterol and apo B-48 in large 703 VLDLs), which suggest a possible kinetic interaction between PUFAs and polyphenols (Annuzzi et 704 al., 2014) . This kinetic finding is also in line with some preclinical data that suggested that dietary 705 polyphenols interact with the metabolism of n-3 PUFAs and increase blood EPA and DHA level 706 (Toufektsian et al., 2011) . 707

Recently, in a three monocentric, parallel-arm, double-blind, randomised, dietary 708 intervention trial, 250 mg DHA and 320 mg grape anthocyanins administered as bioactive-enriched 709 foods, for 4 weeks, had positive effects on serum triglyceride or HDL levels (Bub et al., 2019) . 710

These results are partially in line with a later cross-sectional analysis in the Korean population that 711 suggested beneficial effects exhibited only in men by high amounts of proanthocyanidins or n-3 712

PUFAs on HDL levels. In addition, n-3 PUFAs intake increased polyphenols uptake (Ahn et al., 713 2020) . 714

In conclusion, large-scale cohort studies with a combined diet PUFAs +polyphenols are 715 needed to confirm the limited available data and to investigate possible additive effects. 716

diseases. COVID-19, severe respiratory disease, is an adverse clinical outcome of the ongoing 719 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic 720 Goumenou et al., 2020; Shi et al., 2020) , and has recently been correlated to obesity-dependent 721 inflammation . Indeed, in its most severe form, it entails a bilateral interstitial 722 pneumonia requiring intensive care unit (ICU) ventilation support and has concomitant high 723 mortality rate due to and multi-organ failure. Clinical reports have demonstrated that the most 724 common comorbidities are CVD, hypertension and T2DM, age also being an important risk factor 725 (Grasselli et al., 2020; Zhou et al., 2020) . Lifestyle-associated factors, such as smoking, have also 726 been associated with rapid disease progression (Farsalinos et al., 2020; Mesnage et al., 2020; 727 Tsatsakis et al., 2020) . A recent US study indicates that obesity is an underappreciated risk factor 728 for COVID-19 (Kass et al., 2020) . The authors found, in a cohort of 265 hospitalized patients, that 729 age and the body-mass index (BMI) were inversely correlated with risk, hence indicating that 730 younger obese patients were more likely to be admitted to hospital. Kass et al concluded that a 731 higher prevalence of obesity in each population will result in a higher COVID-19 incidence in 732 younger individuals than previously reported. In addition to a mechanical impediment of 733 ventilation, obesity was correlated with lower immune response to viral infection (Honce and 734 Schultz-Cherry, 2019) . Moreover, besides obesity, metabolic disarray and inflammation were 735 suggested to contribute to COVID-19 pathogenesis . Indeed, specific 736 fat-resident regulatory T cells (Treg) and enhancement of TH17 (T-cell sub-lineage)-biased 737 immunity (Poutahidis et al., 2013; Winer et al., 2009 ) could be positively correlated to COVID-19 738 prevalence and increased mortality risk in obese individuals Skalny et al., 739 2020) . The "obese" pattern of immune cells subtypes was correlated to increased secretion of pro-740 inflammatory mediators including IL-6, IL-23/IL-17, TNF-α and macrophage inflammatory 741 protein-1α (Sumarac-Dumanovic et al., 2009) . Importantly, these inflammatory mediators were 742 proved to disrupted tight junctions of the respiratory epithelium, which facilitates pathogen entry 743 (Wittekindt, 2017) . 744 COVID-19 is impacting to a greater extent the patients having underlying metabolic 745 impairments (diabetes mellitus and/or obesity), as WHO is pointing out. On the other hand, 746 increased levels of inflammatory markers cytokines with pro-inflammatory outcomes constitute 747 predictors of adverse outcome in COVID-19 patients (Skalny et al., 2020) . 748

Thus, reducing the inflammatory pathways, through the long-term employment of lifestyle 749 changes (dietary measures, smoking cessation, moderate but constant physical activity, etc) could 750 contribute to a better reaction of the immune system when affected by aggressive pathogens, such 751 as SarsCov2. Improving diet (such as adding polyphenols, PUFAs, fibres, etc) can contribute to a 752 reduction of inflammation, thus increasing the chances for a better response of patients affected by 753 the virus (Butler and Barrientos, 2020; Rajkumar, 2020; WHO, 2020) . 754

Diet can play a major part in regulating various cellular pathways, as one is simultaneously 756 and continually exposed to a myriad of ingested substances, which, in their minute doses can yield 757 important long-term effects and influence the development of certain maladies, with their 758 cumulative effects still being underestimated. Real-life risk simulation (RLRS) strategies are 759 powerful tools for assessing not only the toxicological implications of joint effects for several 760 molecules, but also their collective beneficial role as nutraceuticals in our diet intake. These kinds 761 of analyses are important, as studies which separately assess the cellular and metabolic effects of 762 certain compounds can posit their detrimental or protective actions and their potency, and thus can 763 lead to erroneous conclusions regarding their long-term habitual consumption in lower, non-764 pharmacological doses, but alongside numerous other chemicals (Hernandez et al., 2020; Margină 765 et al., 2019; Tsatsakis et al., 2019b) . This type of approach will certainly play an important part in 766 one of the most important health struggles nowadays, the prevention of NCD, and could prove itself 767 beneficial even in the context of the present viral outbreak, since inflammation is the key 768 component of the severe phenomena associated with the COVID-19 respiratory complications. 769

There is an intense need for RLRS studies integrating dietary information with the inflammatory 770 response in order to evaluate if the usual components of normal diet could contribute to regulating 771 the immune response and reduce the sensitivity to complications. 772

Randomized cross-over trial 50 Danish subjects with high risk of metabolic syndrome two 8-week periods of whole grain intake (179±50 g/day) / refined grain (maximum 13±10 g/day of whole grain), divided by a washout period of ≥6 weeks. Crossover study 33 healthy, middleaged adults Patients received either high or low in in wholegrain intervention for 6-week periods, separated by a 4-week washout.

Whole grain: a slight decrease of IL-10 and CRP (Ampatzoglou et al., 2016) Observational study 8 subjects with impaired fasting glucose subjects received (1) high-fibre formula;

(2) high-monounsaturated fatty acid formula or (3) control formula

High fibre group: ↓ NF-κB in PBMCs (Kim et al., 2013) Randomized controlled clinical trial 60 females with T2DM

Patients received 10 g/d resistant starch or placebo for 8 weeks, respectively ↓TNF-α, no effect on IL-6 or CRP Crossover clinical trial 80 overweight subjects Subjects received two isocaloric breakfast interventions -one rich in saturated fat and one in unsaturated fatty acids and fibres for 4 weeks with a 2-weeks washout. (Youm et al., 2015) High fat high sucrose diet (HFD) C57BL/6 J (wild type; WT) male mice 8-week treatment: Young + normal diet (YND) Young + HFD (YHFD) Old + normal diet (OND) Old + HFD (OHFD) HFD led to β-cell failure in aged mice, enhanced expression of pro-inflammatory cytokines and macrophage transformation to a more pro-inflammatory phenotype (He et al., 2018) Low-carbohydrate diet + peanuts: 60 g for men, 50 g for women (LCD-P) LCD + almonds: 55 g for men, 45 g for women (LCD-A) Improved glycaemic profile versus baseline, no difference between groups regarding IL-5 serum levels (Hou et al., 2018) Group 2: a moderate-carbohydrate and low-GI diet (LGI), n=36

Group 3: a low-fat and high-GI diet (LF), n=31

LGI vs LF: ↓ fasting insulin, ↑ HOMA No significant differences among groups regarding lipid profiles, inflammatory and metabolic risk markers (IL-6, MCP-1, Leptin, ICAM-1).

(Juanol a-Falgaro na et al., 2014)

Randomised controlled trial 90 subjects 12-week diet intervention: isocaloric control diet (50% of energy from carbohydrate, 35% from fat, 15% from protein) low-glycaemic-index diet (LGI) (60% from carbohydrate, 25% from fat, and 15% from protein)

LGI, rich in functional foods (LGI + FF) (60% from carbohydrate, 25% from fat, and 15% from protein)

LGI + FF vs. control: ↓CRP, TNF-α

LGI + FF vs.

LGI ICAM -intercellular adhesion molecule-1; HOMA -homeostatic model assessment of β cell function; MCP-1 -Monocyte chemotactic protein-1; (Venturini et al., 2015) Inflammatory bowel disease 8-week intervention: 3400-3600 mg n-3 PUFA (as salmon)/day 12 ↓ CPR, ↑ anti-inflammatory fatty acid index ↑ n-3 PUFAs ,↑ n-3/n-6 ratio in plasma and rectal LDL -low-density lipoproteins; HDL -high-density lipoproteins; FBG -fasting blood glucose; LIF -leukocyte inhibitory factor. ↓ waist circumference and postprandial SBP, moderately increased levels of TNFα (Pfeuffer et al., 2013) Randomised, doubleblind, placebocontrolled, crossover trial 18 healthy volunteers One-tine administration of 51 mg of oleuropeine ↓of IL8 production (Lockyer et al., 2015) Cross-sectional study 1997 females Frequency questionnaires assessment of total intake of flavonoids Higher anthocyanin and flavone intake were associated with significantly lower peripheral insulin resistance Higher anthocyanin intake was also associated with lower CRP concentrations Higher anthocyanin-rich intake was associated with lower insulin and inflammation (Jennings et al., 2014) Randomized, controlled dietary study 27 subjects with metabolic syndrome 400 g fresh bilberries/days vs. control diet ↓ CRP, IL-6, IL-12, (Kolehmainen et al., 2012) 

Inflammation, a silent killer in cancer is not so silent!

Association of Total Flavonoid Intake with Hypo-HDL-Cholesterolemia among Korean Adults: Effect Modification by Polyunsaturated Fatty Acid Intake

Resistant dextrin, as a prebiotic, improves insulin resistance and inflammation in women with type 2 diabetes: a randomised controlled clinical trial

A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the Comparing EPA to DHA (ComparED) Study

Gene expression, synthesis and degradation of hyaluronan during differentiation of 3T3-L1 adipocytes

Anti-inflammatory effect of Capuli cherry against LPS-induced cytotoxic damage in RAW 264.7 macrophages

Sedentary Lifestyle and High-Carbohydrate Intake are Associated with Low-Grade Chronic Inflammation in Post-Menopause: A Cross-sectional Study

Effects of increased wholegrain consumption on immune and inflammatory markers in healthy low habitual wholegrain consumers

Red wine polyphenolics reduce the expression of inflammation markers in human colon-derived CCD-18Co myofibroblast cells: potential role of microRNA-126

Diets naturally rich in polyphenols improve fasting and postprandial dyslipidemia and reduce oxidative stress: a randomized controlled trial

Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice

Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation

Impact of Consuming Extra-Virgin Olive Oil or Nuts within a Mediterranean Diet on DNA Methylation in Peripheral White Blood Cells within the PREDIMED-Navarra Randomized Controlled Trial: A Role for Dietary Lipids

Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells

Diets along with interval training regimes improves inflammatory & anti-inflammatory condition in obesity with type 2 diabetes subjects

Effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: a randomized clinical trial

Effects of pure eicosapentaenoic and docosahexaenoic acids on oxidative stress, inflammation and body fat mass in patients with type 2 diabetes

Metabolism and functional effects of plant-derived omega-3 fatty acids in humans

A high-fish-oil diet prevents adiposity and modulates white adipose tissue inflammation pathways in mice

Eicosapentaenoic acid (EPA) vs. Docosahexaenoic acid (DHA): Effects in epididymal white adipose tissue of mice fed a high-fructose diet

Source and amount of carbohydrate in the diet and inflammation in women with polycystic ovary syndrome

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

Strawberries decrease circulating levels of tumor necrosis factor and lipid peroxides in obese adults with knee osteoarthritis

Sex differences in the impact of the Mediterranean diet on systemic inflammation

The Mediterranean diet adoption improves metabolic, oxidative, and inflammatory abnormalities in Algerian metabolic syndrome patients

Montmorency cherries reduce the oxidative stress and inflammatory responses to repeated days high-intensity stochastic cycling

Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis

Fish or n3-PUFA intake and body composition: a systematic review and meta-analysis

Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice

Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study

Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century

Effects of increase in fish oil intake on intestinal eicosanoids and inflammation in a mouse model of colitis

Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance

Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors

Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease

A Dietary Intervention of Bioactive Enriched Foods Aimed at Adults at Risk of Metabolic Syndrome: Protocol and Results from PATHWAY-27 Pilot Study

Introduction to fatty acids and lipids

The impact of nutrition on COVID-19 susceptibility and longterm consequences

Multiple anti-inflammatory and anti-atherosclerotic properties of red wine polyphenolic extracts: differential role of hydroxycinnamic acids, flavonols and stilbenes on endothelial inflammatory gene expression

Fatty acids and inflammation: the cutting edge between food and pharma

Long-chain fatty acids and inflammation

Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance

Omega-3 fatty acids and inflammatory processes: from molecules to man

Expression of proinflammatory, proatherogenic genes is reduced by the Mediterranean diet in elderly people

Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification

Epicatechin and catechin modulate endothelial activation induced by platelets of patients with peripheral artery disease

The effects of the mediterranean diet on biomarkers of vascular wall inflammation and plaque vulnerability in subjects with high risk for cardiovascular disease. A randomized trial

Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota

Dietary n-3 PUFA May Attenuate Experimental Colitis

Resveratrol down-regulates interferon-gamma-inducible inflammatory genes in macrophages: molecular mechanism via decreased STAT-1 activation

Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: a parallel randomised controlled trial

Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease Study

Interplay between NADH oxidation by complex I, glutathione redox state and sirtuin-3, and its role in the development of insulin resistance

Anti-atherogenic and anti-angiogenic activities of polyphenols from propolis

Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents

Decreased insulin secretion and incretin concentrations and increased glucagon concentrations after a high-fat meal when compared with a high-fruit and -fiber meal

Differential effects of low-carbohydrate and low-fat diets on inflammation and endothelial function in diabetes

Mediterranean meal versus Western meal effects on postprandial ox-LDL, oxidative and inflammatory gene expression in healthy subjects: a randomized controlled trial for nutrigenomic approach in cardiometabolic risk

New obesity classification criteria as a tool for bariatric surgery indication

A diet high in fatty fish, bilberries and wholegrain products improves markers of endothelial function and inflammation in individuals with impaired glucose metabolism in a randomised controlled trial: the Sysdimet study

Systemic Resolvin E1 (RvE1) Treatment Does Not Ameliorate the Severity of Collagen-Induced Arthritis (CIA) in Mice: A Randomized, Prospective, and Controlled Proof of Concept Study

Inulin controls inflammation and metabolic endotoxemia in women with type 2 diabetes mellitus: a randomized-controlled clinical trial

Oligofructose-enriched inulin improves some inflammatory markers and metabolic endotoxemia in women with type 2 diabetes mellitus: a randomized controlled clinical trial

Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases

Effect of Dietary Sugar Intake on Biomarkers of Subclinical Inflammation: A Systematic Review and Meta-Analysis of Intervention Studies

An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA

Beneficial effects of flaxseed oil and fish oil diet are through modulation of different hepatic genes involved in lipid metabolism in streptozotocin-nicotinamide induced diabetic rats

Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome

Immunological contributions to adipose tissue homeostasis

A new threat from an old enemy: Reemergence of coronavirus (Review)

The modulatory effects of prostaglandin-E on cytokine production by human peripheral blood mononuclear cells are independent of the prostaglandin subtype

Does Fish Oil Have an Anti-Obesity Effect in Overweight/Obese Adults? A Meta-Analysis of Randomized Controlled Trials

Strawberry anthocyanin and its association with postprandial inflammation and insulin

Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol

Long-term ketogenic diet causes glucose intolerance and reduced beta-and alpha-cell mass but no weight loss in mice

Effect of long chain omega-3 polyunsaturated fatty acids on inflammation and metabolic markers in hypertensive and/or diabetic obese adults: a randomized controlled trial

Do flavanols-rich natural products relieve obesity-related insulin resistance?

Could resistant starch supplementation improve inflammatory and oxidative stress biomarkers and uremic toxins levels in hemodialysis patients? A pilot randomized controlled trial

Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome

Inflammasome activation and IL-1beta target IL-1alpha for secretion as opposed to surface expression

Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice

Long-chain omega-3 fatty acids: time to establish a dietary reference intake

Effects of supplemental long-chain omega-3 fatty acids and erythrocyte membrane fatty acid content on circulating inflammatory markers in a randomized controlled trial of healthy adults

Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice

Cross-regulatory circuits linking inflammation, high-fat diet, and the circadian clock

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

Is there any place for resistant starch, as alimentary prebiotic, for patients with type 2 diabetes?

Anti-inflammatory effect of strawberry extract against LPS-induced stress in RAW 264.7 macrophages

Nonorganic hearing loss. Malingering, factitious or conversion disorder?

Nonorganic hearing loss. Malingering, factitious or conversion disorder?

Comparative antiinflammatory and lipid-normalizing effects of metformin and omega-3 fatty acids through modulation of transcription factors in diabetic rats

Effects of rye and whole wheat versus refined cereal foods on metabolic risk factors: a randomised controlled two-centre intervention study

High-refined carbohydrate diet consumption induces neuroinflammation and anxiety-like behavior in mice

Insulin-Leptin Axis, Cardiometabolic Risk and Oxidative Stress in Elderly with Metabolic Syndrome

Adiponectin: possible link between metabolic stress and oxidative stress in the elderly

Salmon diet in patients with active ulcerative colitis reduced the simple clinical colitis activity index and increased the anti-inflammatory fatty acid index--a pilot study

Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis

Adipose tissue depot-specific intracellular and extracellular cues contributing to insulin resistance in obese individuals

Carbohydrate-restricted Diet and High-intensity Interval Training Exercise Improve Cardio-metabolic and Inflammatory Profiles in Metabolic Syndrome: A Randomized Crossover Trial. Cureus 11, e5596

Effects of Arabinoxylan and Resistant Starch on Intestinal Microbiota and Short-Chain Fatty Acids in Subjects with Metabolic Syndrome: A Randomised Crossover Study

The ω-3 polyunsaturated fatty acids prevented colitis-associated carcinogenesis through blocking dissociation of β-catenin complex, inhibiting COX-2 through repressing NF-κB, and inducing 15-prostaglandin dehydrogenase

The immune response in atherosclerosis: a double-edged sword

An α-linolenic acid-rich formula reduces oxidative stress and inflammation by regulating NF-κB in rats with TNBS-induced colitis

Carbohydrate-restricted diet alters the gut microbiota, promotes senescence and shortens the life span in senescenceaccelerated prone mice

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures

Application of novel technologies and mechanistic data for risk assessment under the real-life risk simulation (RLRS) approach

Human exposure to chemical mixtures: Challenges for the integration of toxicology with epidemiology data in risk assessment

Women With Gestational Diabetes Mellitus Randomized to a Higher-Complex Carbohydrate/Low-Fat Diet Manifest Lower Adipose Tissue Insulin Resistance, Inflammation, Glucose, and Free Fatty Acids: A Pilot Study

Impact of Obesity on Influenza A Virus Pathogenesis, Immune Response, and Evolution

A Randomized Controlled Trial to Compare the Effect of Peanuts and Almonds on the Cardio-Metabolic and Inflammatory Parameters in Patients with Type 2 Diabetes Mellitus

The Effects of a Low-Carbohydrate Diet vs. a Low-Fat Diet on Novel Cardiovascular Risk Factors: A Randomized Controlled Trial

Oxidative Stress and Inflammation: What Polyphenols Can Do for Us

Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells

The extracellular matrix: not just pretty fibrils

Omega-3 fatty acids in anti-inflammation (pro-resolution) and GPCRs

Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodiuminduced colitis

PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial

Effect of Low-Energy-Dense Diet Rich in Multiple Functional Foods on Weight-Loss Maintenance, Inflammation, and Cardiovascular Risk Factors: A Randomized Controlled Trial

A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children

Dietary flaxseed oil and fish oil ameliorates renal oxidative stress, protein glycation, and inflammation in streptozotocinnicotinamide-induced diabetic rats

A Mediterranean-like dietary pattern with vitamin D3 (10 microg/d) supplements reduced the rate of bone loss in older Europeans with osteoporosis at baseline: results of a 1-y randomized controlled trial

Intakes of anthocyanins and flavones are associated with biomarkers of insulin resistance and inflammation in women

Inhibition of adipogenesis in 3T3-L1 cells and suppression of abdominal fat accumulation in high-fat diet-feeding C57BL/6J mice after downregulation of hyaluronic acid

A high intake of dietary fiber influences C-reactive protein and fibrinogen, but not glucose and lipid metabolism, in mildly hypercholesterolemic subjects

Advice to follow a lowcarbohydrate diet has a favourable impact on low-grade inflammation in type 2 diabetes compared with advice to follow a low-fat diet

Effect of the glycemic index of the diet on weight loss, modulation of satiety, inflammation, and other metabolic risk factors: a randomized controlled trial

Dietary antioxidants in preventing atherogenesis

Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance

Effects of a Low-Calorie, Low-Carbohydrate Soy Containing Diet on Systemic Inflammation Among Patients with Nonalcoholic Fatty Liver Disease: A Parallel Randomized Clinical Trial

Obesity could shift severe COVID-19 disease to younger ages

Docosapentaenoic acid (22:5n-3): a review of its biological effects

HA metabolism in skin homeostasis and inflammatory disease

Contact allergen (PPD and DNCB)-induced keratinocyte sensitization is partly mediated through a low molecular weight hyaluronan (LMWHA)/TLR4/NF-kappaB signaling axis

Dietary Crocin Inhibits Colitis and Colitis-Associated Colorectal Carcinogenesis in Male ICR Mice. Evid Based Complement Alternat Med

Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial

Postprandial glucose and NF-kappaB responses are regulated differently by monounsaturated fatty acid and dietary fiber in impaired fasting glucose subjects

N-3 polyunsaturated fatty acids restore Th17 and Treg balance in collagen antibody-induced arthritis

High-fat diet disrupts behavioral and molecular circadian rhythms in mice

Bilberries reduce low-grade inflammation in individuals with features of metabolic syndrome

Fiberrich diet with brown rice improves endothelial function in type 2 diabetes mellitus: A randomized controlled trial

Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Extracts from Brassica oleracea L. convar. acephala var. sabellica inhibit TNF-alpha stimulated neutrophil adhesion in vitro under flow conditions

Nordic Diet and Inflammation-A Review of Observational and Intervention Studies

A high linoleic acid diet exacerbates metabolic responses and gut microbiota dysbiosis in obese rats with diabetes mellitus

Critical Role of Matrix Metalloproteinase 14 in Adipose Tissue Remodeling during Obesity

Rosmarinic Acid Attenuates Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma

Inflammation in atherosclerosis

Inflammation and its resolution as determinants of acute coronary syndromes

The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats

Adipose extracellular matrix remodelling in obesity and insulin resistance

Secoiridoids delivered as olive leaf extract induce acute improvements in human vascular function and reduction of an inflammatory cytokine: a randomised, double-blind, placebo-controlled, cross-over trial

Consumption of chokeberry (Aronia mitschurinii) products modestly lowered blood pressure and reduced low-grade inflammation in patients with mildly elevated blood pressure

Mediterranean Diet Supplemented With Coenzyme Q10 Modulates the Postprandial Metabolism of Advanced Glycation End Products in Elderly Men and Women

Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-kappaB signaling pathways

Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes

Adipocytes and intestinal epithelium dysfunctions linking obesity to inflammation induced by high glycemic index pellet-diet in Wistar rats

Dietary guidelines in type 2 diabetes: the Nordic diet or the ketogenic diet?

Mediterranean diet cools down the inflammatory milieu in type 2 diabetes: the MEDITA randomized controlled trial

Efficacy of omega-3 fatty acid supplementation on serum levels of tumour necrosis factor-alpha, Creactive protein and interleukin-2 in type 2 diabetes mellitus patients

Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis

Quercetin and epigallocatechin gallate induce in vitro a dose-dependent stiffening and hyperpolarizing effect on the cell membrane of human mononuclear blood cells

Overview of the effects of chemical mixtures with endocrine disrupting activity in the context of real-life risk simulation (RLRS): An integrative approach (Review)

Green tea catechins alone or in combination alter functional parameters of human neutrophils via suppressing the activation of TLR-4/NFkappaB p65 signal pathway

Expression of inflammation-related miRNAs in white blood cells from subjects with metabolic syndrome after 8 wk of following a Mediterranean diet-based weight loss program

Extravirgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED

Mediterranean diet and inflammaging within the hormesis paradigm

Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation

Randomization to 6-month Mediterranean diet compared with a low-fat diet leads to improvement in Dietary Inflammatory Index scores in patients with coronary heart disease: the AUSMED Heart Trial

Origin and physiological roles of inflammation

Limitations in the evidential basis supporting health benefits from a decreased exposure to pesticides through organic food consumption

Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids

Low-grade inflammation, diet composition and health: current research evidence and its translation

Biological effects of add-on eicosapentaenoic acid supplementation in diabetes mellitus and co-morbid depression: a randomized controlled trial

Greater expression of postprandial inflammatory genes in humans after intervention with saturated when compared to unsaturated fatty acids

Characteristic expression of extracellular matrix in subcutaneous adipose tissue development and adipogenesis; comparison with visceral adipose tissue

MAG-EPA reduces severity of DSS-induced colitis in rats

Antioxidant action of fermented grain food supplement: Scavenging of peroxyl radicals and inhibition of plasma lipid oxidation induced by multiple oxidants

Fish oil supplementation does not lower C-reactive protein or interleukin-6 levels in healthy adults

Effects of a beverage rich in (poly)phenols on established and novel risk markers for vascular disease in medically uncomplicated overweight or obese subjects: A four week randomized placebo-controlled trial

Simultaneous ultrasound-assisted water extraction and beta-cyclodextrin encapsulation of polyphenols from Mangifera indica stem bark in counteracting TNFalpha-induced endothelial dysfunction

The effect of a short-term low-carbohydrate, high-fat diet with or without postmeal walks on glycemic control and inflammation in type 2 diabetes: a randomized trial

Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control

Suppressive effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient mice

ROS-major mediators of extracellular matrix remodeling during tumor progression

Heparan sulfate proteoglycans and heparin regulate melanoma cell functions

Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response

Cancer microenvironment and inflammation: role of hyaluronan

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice

The Routine and Specialised Staining for the Histologic Evaluation of Autogenous Mandibular Bone Grafts An experimental study

Discovery of natural naphthoquinones as sortase A inhibitors and potential antiinfective solutions against Staphylococcus aureus

Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors

Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice

Profiling in resolving inflammatory exudates identifies novel antiinflammatory and pro-resolving mediators and signals for termination

Low-energy diets differing in fibre, red meat and coffee intake equally improve insulin sensitivity in type 2 diabetes: a randomised feasibility trial

GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects

Resolution of inflammation: an integrated view

NF-kappaB signaling as a driver of ageing

Allicin Alleviates Dextran Sodium Sulfate-(DSS-) Induced Ulcerative Colitis in BALB/c Mice

Effects of n-3 polyunsaturated fatty acids (omega-3) supplementation on some cardiovascular risk factors with a ketogenic Mediterranean diet

Efficacy of a Mediterranean diet supplemented with fatty fish in ameliorating inflammation in paediatric asthma: a randomised controlled trial

Effects of grape seed extract beverage on blood pressure and metabolic indices in individuals with pre-hypertension: a randomised, double-blinded, two-arm, parallel, placebo-controlled trial

Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response

Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion from a Meckel diverticulum neuroendocrine tumor: case report

Effect of 12 wk of resistant starch supplementation on cardiometabolic risk factors in adults with prediabetes: a randomized controlled trial

Obesity a risk factor for increased COVID 19 prevalence, severity and lethality (Review)

Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms

Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota

Experimental model for the study of autogenous mandibular bone grafts integration

Experimental model for the study of autogenous mandibular bone gras integration

Omega-3 fatty acid supplementation influences the whole blood transcriptome in women with obesity, associated with pro-resolving lipid mediator production

Treatment with high-dose n-3 PUFAs has no effect on platelet function, coagulation, metabolic status or inflammation in patients with atherosclerosis and type 2 diabetes

Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action

Short-term treatment with eicosapentaenoic acid improves inflammation and affects colonic differentiation markers and microbiota in patients with ulcerative colitis

Short-term effects of Mediterranean-type diet intervention on soluble cellular adhesion molecules in subjects with abdominal obesity

Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials

Doserelated effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men

Oxidative stress, inflammation, and cancer: how are they linked? Free Radic

Whole grain-rich diet reduces body weight and systemic low-grade inflammation without

Glucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet

The Impact of a Low Glycemic Index Diet on Inflammatory Markers and Serum Adiponectin Concentration in Adolescent Overweight and Obese Girls: A Randomized Clinical Trial

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases

The role of pro-resolution lipid mediators in infectious disease

Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects

Ellagic Acid, a Dietary Polyphenol, Inhibits Tautomerase Activity of Human Macrophage Migration Inhibitory Factor and Its Pro-inflammatory Responses in Human Peripheral Blood Mononuclear Cells

Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial

Adipose tissue-resident immune cells: key players in immunometabolism

Heterogeneity of adipose tissue in development and metabolic function

Effect of n-3 fatty acids supplementation during life style modification in women with overweight

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

Resolvins and protectins in inflammation resolution

Resolution of inflammation: the beginning programs the end

Redox modulatory protective effects of ω-3 fatty acids rich fish oil against experimental colitis

COVID-19 infection: the perspectives on immune responses

Lumican, a small leucine-rich proteoglycan substituted with keratan sulfate chains is expressed and secreted by human melanoma cells and not normal melanocytes

Zinc and respiratory tract infections: Perspectives for COVID19 (Review)

Evaluation of the Effects of Vaccinium arctostaphylos L. Fruit Extract on Serum Lipids and hs-CRP Levels and Oxidative Stress in Adult Patients with Hyperlipidemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Distinct transcriptional profiles of adipogenesis in vivo and in vitro

Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages

Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women

Cancer cell signaling pathways targeted by spice-derived nutraceuticals

Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study

Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4

Green tea polyphenol epigallocatechin-3-gallate attenuates TNF-alpha-induced intercellular adhesion molecule-1 expression and monocyte adhesion to retinal pigment epithelial cells

Influence of anti-inflammatory flavonoids on degranulation and arachidonic acid release in rat neutrophils

Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms

Dietary flavonoids increase plasma very long-chain (n-3) fatty acids in rats

Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity

A Low-Glycemic, Mediterranean Diet and Lifestyle Modification Program with Targeted Nutraceuticals Reduces Body Weight, Improves Cardiometabolic Variables and Longevity Biomarkers in Overweight Subjects: A 13-Week Observational Trial

Toxicology for reallife risk simulation -Editorial preface to this special issue

COVID-19, an opportunity to reevaluate the correlation between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence

The effect of chronic vitamin deficiency and long term very low dose exposure to 6 pesticides mixture on neurological outcomes -A real-life risk simulation approach

New challenges in risk assessment of chemicals when simulating real exposure scenarios; simultaneous multi-chemicals' low dose exposure

NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?

Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults

Targeted Metabolomic Analysis of Serum Fatty Acids for the Prediction of Autoimmune Diseases

Role of the extracellular matrix in cancer-associated epithelial to mesenchymal transition phenomenon

Proteoglycans and Immunobiology of Cancer-Therapeutic Implications

Lipoprotein redox status evaluation as a marker of cardiovascular disease risk in patients with inflammatory disease

Preclinical and clinical results regarding the effects of a plant-based antidiabetic formulation versus well established antidiabetic molecules

Spectrophotometric versus spectrofluorometric assessment in the study of the relationships between lipid peroxidation and metabolic dysregulation

Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome --a randomized study (SYSDIET)

Combined intervention with pioglitazone and n-3 fatty acids in metformin-treated type 2 diabetic patients: improvement of lipid metabolism

Effects of extra virgin olive oil and fish oil on lipid profile and oxidative stress in patients with metabolic syndrome

Inflammatory gene expression in whole blood cells after EPA vs. DHA supplementation: Results from the ComparED study

A mixture of trans-galactooligosaccharides reduces markers of metabolic syndrome and modulates the fecal microbiota and immune function of overweight adults

Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products

Molecular mechanisms of insulin resistance that impact cardiovascular biology

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in

Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway

Obesity is associated with macrophage accumulation in adipose tissue

Beneficial effects of polyphenol-rich olive oil in patients with early atherosclerosis

Obesity predisposes to Th17 bias

Tight junctions in pulmonary epithelia during lung inflammation

Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis

Fish-oil supplement has neutral effects on vascular and metabolic function but improves renal function in patients with Type 2 diabetes mellitus

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents

The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease

Mediterranean diet supplemented with coenzyme Q10 modifies the expression of proinflammatory and endoplasmic reticulum stress-related genes in elderly men and women

Anti-pain and anti-inflammation like effects of Neptune krill oil and fish oil against carrageenan induced inflammation in mice models: Current statues and pilot study

A review of the alleged health hazards of monosodium glutamate

Efficacy of Omega-3 Polyunsaturated Fatty Acids Supplementation in Managing Overweight and Obesity: A Meta-Analysis of Randomized Clinical Trials

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Dietary flaxseed oil rich in omega-3 suppresses severity of type 2 diabetes mellitus via antiinflammation and modulating gut microbiota in rats

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

• Inflammatory cues contribute to chronic and acute disease • Nutraceuticals are important in prevention and treatment of inflammation 

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: