Sirtuins as Players in the Signal Transduction of Citrus Flavonoids.

Sirtuins (SIRTs) belong to the family of nicotine adenine dinucleotide (NAD+)-dependent class III histone deacetylases, which come into play in the regulation of epigenetic processes through the deacetylation of histones and other substrates. The human genome encodes for seven homologs (SIRT1-7), which are localized into the nucleus, cytoplasm, and mitochondria, with different enzymatic activities and regulatory mechanisms. Indeed, SIRTs are involved in different physio-pathological processes responsible for the onset of several human illnesses, such as cardiovascular and neurodegenerative diseases, obesity and diabetes, age-related disorders, and cancer. Nowadays, it is well-known that Citrus fruits, typical of the Mediterranean diet, are an important source of bioactive compounds, such as polyphenols. Among these, flavonoids are recognized as potential agents endowed with a wide range of beneficial properties, including antioxidant, anti-inflammatory, hypolipidemic, and antitumoral ones. On these bases, we offer a comprehensive overview on biological effects exerted by Citrus flavonoids via targeting SIRTs, which acted as modulator of several signaling pathways. According to the reported studies, Citrus flavonoids appear to be promising SIRT modulators in many different pathologies, a role which might be potentially evaluated in future therapies, along with encouraging the study of those SIRT members which still lack proper evidence on their support.

Inflammation and Obesity: The Pharmacological Role of Flavonoids in the Zebrafish Model.

A Mediterranean-style diet is highly encouraged thanks to its healthy food pattern, which includes valuable nutraceuticals such as polyphenols. Among these, flavonoids are associated with relevant biological properties through which they prevent or fight the onset of several human pathologies. Globally, the enhanced incidence of overweight and obese people has caused a dramatic increase in comorbidities, raising the need to provide better therapies. Therefore, the development of sophisticated animal models of metabolic dysregulation has allowed for a deepening of knowledge on this subject. Recent advances in using zebrafish (Danio rerio) as model for metabolic disease have yielded fundamental insights into the potential anti-obesity effects of flavonoids. Chronic low-grade inflammation and immune system activation seem to characterize the pathogenesis of obesity; thus, their reduction might improve the lipid profile of obese patients or prevent the development of associated metabolic illnesses. In this review, we highlight the beneficial role of flavonoids on obesity and related diseases linked to their anti-inflammatory properties. In light of the summarized studies, we suggest that anti-inflammatory therapies could have a relevant place in the prevention and treatment of obesity and metabolic disorders.

Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms.

Phytochemicals have long been effective partners in the fight against several diseases, including cancer. Among these, flavonoids are valuable allies for both cancer prevention and therapy since they are known to influence a large panel of tumor-related processes. Particularly, it was revealed that quercetin, one of the most common flavonoids, controls apoptosis and inhibits migration and proliferation, events essential for the development of cancer. In this review, we collected the evidence on the anti-cancer activity of quercetin exploring the network of interactions between this flavonol and the proteins responsible for cancer onset and progression focusing on breast, colorectal and liver cancers, owing to their high worldwide incidence. Moreover, quercetin proved to be also a potentiating agent able to push further the anti-cancer activity of common employed anti-neoplastic agents, thus allowing to lower their dosages and, above all, to sensitize again resistant cancer cells. Finally, novel approaches to delivery systems can enhance quercetin's pharmacokinetics, thus boosting its great potentiality even further. Overall, quercetin has a lot of promise, given its multi-target potentiality; thus, more research is strongly encouraged to properly define its pharmaco-toxicological profile and evaluate its potential for usage in adjuvant and chemoprevention therapy.

The Inhibition of Mitogen-Activated Protein Kinases (MAPKs) and NF-κB Underlies the Neuroprotective Capacity of a Cinnamon/Curcumin/Turmeric Spice Blend in Aß-Exposed THP-1 Cells.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by an increased level of ß-amyloid (Aß) protein deposition in the brain, yet the exact etiology remains elusive. Nowadays, treatments only target symptoms, thus the search for novel strategies is constantly stimulated, and looking to natural substances from the plant kingdom. The aim of this study was to investigate the neuroprotective effects of a spice blend composed of cinnamon bark and two different turmeric root extracts (CCSB) in Aß-exposed THP-1 cells as a model of neuroinflammation. In abiotic assays, CCSB demonstrated an antioxidant capacity up to three times stronger than Trolox in the ORAC assay, and it reduced reactive oxygen species (ROS) induced by the amyloid fragment in THP-1 cells by up to 39.7%. Moreover, CCSB lowered the Aß stimulated secretion of the pro-inflammatory cytokines IL-1ß and IL-6 by up to 24.9% and 43.4%, respectively, along with their gene expression by up to 25.2% and 43.1%, respectively. The mechanism involved the mitogen-activated protein kinases ERK, JNK and p38, whose phosphorylation was reduced by up to 51.5%, 73.7%, and 58.2%, respectively. In addition, phosphorylation of p65, one of the five components forming NF-κB, was reduced by up to 86.1%. Our results suggest that CCSB can counteract the neuroinflammatory stimulus induced by Aß-exposure in THP-1 cells, and therefore can be considered a potential candidate for AD management.

Pharmacology and toxicology of tannins.

Tannins are an interesting class of polyphenols, characterized, in almost all cases, by a different degree of polymerization, which, inevitably, markedly influences their bioavailability, as well as biochemical and pharmacological activities. They have been used for the process of tanning to transform hides into leather, from which their name derives. For several time, they have not been accurately evaluated, but now researchers have started to unravel their potential, highlighting anti-inflammatory, antimicrobial, antioxidant and anticancer activities, as well as their involvement in cardiovascular, neuroprotective and in general metabolic diseases prevention. The mechanisms underlying their activity are often complex, but the main targets of their action (such as key enzymes modulation, activation of metabolic pathways and changes in the metabolic fluxes) are highlighted in this review, without losing sight of their toxicity. This aspect still needs further and better-designed study to be thoroughly understood and allow a more conscious use of tannins for human health.

The chorioallantoic membrane: A novel approach to extrapolate data from a well-established method.

The chorioallantoic membrane (CAM) of the chicken embryo is a highly vascularized extra-embryonic structure that has been widely used as an in vivo model for the evaluation of angiogenesis. This study was designed to optimize data extrapolation from the most exploited experimental protocol to improve its efficiency and the reliability of the obtainable results. In our study, we followed the most common procedure for CAM assay, employing retinoic acid and vascular endothelial growth factor as standards. CAMs were photographed at t0 , t24 , and t48 ; then, the main parameters of the predefined vascular network/area were evaluated. Subsequently, their variations in each CAM were calculated comparing them within the same CAM over the course of the whole treatment (t24 and t48 ), also comparing the treated CAMs respect to the untreated ones. Thus, we provide a novel approach aimed at extrapolating data from CAM assay that allows to (i) have a greater reliability and richness of data; (ii) better estimate the potential pro- and anti-angiogenic activity of new candidate drugs; (iii) save both eggs and time for the experiments.

Molecular Pathways Involved in the Anti-Cancer Activity of Flavonols: A Focus on Myricetin and Kaempferol.

Natural compounds have always represented valuable allies in the battle against several illnesses, particularly cancer. In this field, flavonoids are known to modulate a wide panel of mechanisms involved in tumorigenesis, thus rendering them worthy candidates for both cancer prevention and treatment. In particular, it was reported that flavonoids regulate apoptosis, as well as hamper migration and proliferation, crucial events for the progression of cancer. In this review, we collect recent evidence concerning the anti-cancer properties of the flavonols myricetin and kaempferol, discussing their mechanisms of action to give a thorough overview of their noteworthy capabilities, which are comparable to those of their most famous analogue, namely quercetin. On the whole, these flavonols possess great potential, and hence further study is highly advised to allow a proper definition of their pharmaco-toxicological profile and assess their potential use in protocols of chemoprevention and adjuvant therapies.

Oleacein Attenuates Lipopolysaccharide-Induced Inflammation in THP-1-Derived Macrophages by the Inhibition of TLR4/MyD88/NF-κB Pathway.

It is known that plant phenolic compounds exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory factors. Recently, Olea europaea has been studied as a natural source of bioactive molecules; however, few studies have focused on the biological effect of oleacein (OLC), the most abundant secoiridoid. Therefore, the aim of this study was to investigate the potential anti-oxidant activity of OLC, as well as to study its anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated THP-1-derived macrophages. LPS brought a dramatic increase of both release and gene expression of pro-inflammatory cytokines (IL-6, IL-1ß and TNF-α), as well as a decrease of anti-inflammatory ones (IL-10), the effects of which are reverted by OLC. Moreover, it reduced the levels of COX-2, NO and PGE2 elicited by LPS exposure in THP-1 macrophages. Interestingly, OLC modulated inflammatory signaling pathways through the inhibition of CD14/TLR4/CD14/MyD88 axis and the activation of NF-κB. Finally, OLC showed relevant anti-oxidant capability, assessed by abiotic assays, and reduced the intracellular amount of ROS generated by LPS exposure in THP-1 macrophages. Overall, these results suggest that the anti-oxidant activity and anti-inflammatory effect of OLC may cooperate in its protective effect against inflammatory stressors, thus being a possible alternative pharmacological strategy aimed at reducing the inflammatory process.

Mediterranean Diet as a Shield against Male Infertility and Cancer Risk Induced by Environmental Pollutants: A Focus on Flavonoids.

The role of environmental factors in influencing health status is well documented. Heavy metals, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, dioxins, pesticides, ultrafine particles, produced by human activities put a strain on the body's entire defense system. Therefore, together with public health measures, evidence-based individual resilience measures are necessary to mitigate cancer risk under environmental stress and to prevent reproductive dysfunction and non-communicable diseases; this is especially relevant for workers occupationally exposed to pollutants and/or populations residing in highly polluted areas. The Mediterranean diet is characterized by a high intake of fruits and vegetables rich in flavonoids, that can promote the elimination of pollutants in tissues and fluids and/or mitigate their effects through different mechanisms. In this review, we collected evidence from pre-clinical and clinical studies showing that the impairment of male fertility and gonadal development, as well as cancers of reproductive system, due to the exposure of organic and inorganic pollutants, may be counteracted by flavonoids.

Molecular Basis of Interactions between the Antibiotic Nitrofurantoin and Human Serum Albumin: A Mechanism for the Rapid Drug Blood Transportation.

Nitrofurantoin is an antimicrobial agent obtained through the addition of a nitro group and a side chain containing hydantoin to a furan ring. The interactions of the antibiotic with human serum albumin (HSA) have been investigated by fluorescence, UV-VIS, Fourier transform infrared spectroscopy (FTIR) spectroscopy, and protein-ligand docking studies. The fluorescence studies indicate that the binding site of the additive involves modifications of the environment around Trp214 at the level of subdomain IIA. Fluorescence and UV-VIS spectroscopy, displacement studies, and FTIR experiments show the association mode of nitrofurantoin to HSA, suggesting that the primary binding site of the antibiotic is located in Sudlow's site I. Molecular modeling suggests that nitrofurantoin is involved in the formation of hydrogen bonds with Trp214, Arg218, and Ser454, and is located in the hydrophobic cavity of subdomain IIA. Moreover, the curve-fitting results of the infrared Amide I' band indicate that the binding of nitrofurantoin induces little change in the protein secondary structure. Overall, these data clarify the blood transportation process of nitrofurantoin and its rapid transfer to the kidney for its elimination, hence leading to a better understanding of its biological effects and being able to design other molecules, based on nitrofurantoin, with a higher biological potential.

The Second Life of Citrus Fruit Waste: A Valuable Source of Bioactive Compounds.

Citrus fruits (CF) are among the most widely cultivated fruit crops throughout the world and their production is constantly increasing along with consumers' demand. Therefore, huge amounts of waste are annually generated through CF processing, causing high costs for their disposal, as well as environmental and human health damage, if inappropriately performed. According to the most recent indications of an economic, environmental and pharmaceutical nature, CF processing residues must be transformed from a waste to be disposed to a valuable resource to be reused. Based on a circular economy model, CF residues (i.e., seeds, exhausted peel, pressed pulp, secondary juice and leaves) have increasingly been re-evaluated to also obtain, but not limited to, valuable compounds to be employed in the food, packaging, cosmetic and pharmaceutical industries. However, the use of CF by-products is still limited because of their underestimated nutritional and economic value, hence more awareness and knowledge are needed to overcome traditional approaches for their disposal. This review summarizes recent evidence on the pharmacological potential of CF waste to support the switch towards a more environmentally sustainable society.

A White Grape Juice Extract Reduces Fat Accumulation through the Modulation of Ghrelin and Leptin Expression in an In Vivo Model of Overfed Zebrafish.

A caloric surplus and a sedentary lifestyle are undoubtedly known to be the leading causes of obesity. Natural products represent valuable allies to face this problematic issue. This study was planned to assess the effect of a white grape (Vitis vinifera) juice extract (WGJe) in diet-induced obese zebrafish (Danio rerio). Fish were divided into four different diet groups: (i) normally fed (NF); (ii) overfed (OF); (iii) WGJe-supplemented NF (5 mL/L in fish water); (iv) WGJe-supplemented OF. Body mass index (BMI) was extrapolated each week. After the fourth week, euthanized zebrafish were processed for both microscopic evaluations and gene expression analyses. OF zebrafish showed higher BMI values with respect to NF counterparts, an effect that was hindered by WGJe treatment. Moreover, histological analyses showed that the area of the adipose tissue, as well as the number, size, and density of adipocytes was significantly higher in OF fish. On the other hand, WGJe was able to avoid these outcomes both at the subcutaneous and visceral levels, albeit to different extents. At the gene level, WGJe restored the altered levels of ghrelin and leptin of OF fish both in gut and brain. Overall, our results support the anti-obesity property of WGJe, suggesting its potential role in weight management.

A flavonoid-rich extract from bergamot juice prevents carcinogenesis in a genetic model of colorectal cancer, the Pirc rat (F344/NTac-Apcam1137).

PURPOSE: To determine the potential of a flavonoid-rich extract from bergamot juice (BJe) to prevent colorectal carcinogenesis (CRC) in vivo. MAIN METHODS: Pirc rats (F344/NTac-Apcam1137), mutated in Apc, the key gene in CRC, were treated with two different doses of BJe (35 mg/kg or 70 mg/kg body weight, respectively) mixed in the diet for 12 weeks. Then, the entire intestine was surgically removed and dissected for histological, immunohistochemical and molecular analyses. RESULTS: Rats treated with BJe showed a significant dose-related reduction in the colon preneoplastic lesions mucin-depleted foci (MDF). Colon and small intestinal tumours were also significantly reduced in rats supplemented with 70 mg/kg of BJe. To elucidate the involved mechanisms, markers of inflammation and apoptosis were determined. Compared to controls, colon tumours from BJe 70 mg/kg-supplemented rats showed a significant down-regulation of inflammation-related genes (COX-2, iNOS, IL-1ß, IL-6 and IL-10 and Arginase 1). Moreover, in colon tumours from rats fed with 70 mg/kg BJe, apoptosis was significantly higher than in controls. Up-regulation of p53 and down-regulation of survivin and p21 genes was also observed. CONCLUSIONS: These data indicate a strong chemopreventive activity of BJe that, at least in part, is due to its pro-apoptotic and anti-inflammatory actions. This effect could be exploited as a strategy to prevent CRC in high-risk patients.

PPI adverse drugs reactions: a retrospective study.

Proton pump inhibitors (PPIs) are drugs capable of blocking the gastric pump H,K-ATPase in order to inhibit gastric acid secretion. Omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole belong to PPIs category. Although PPIs have a good safety profile, allergic reactions to these molecules can occur. The real rate of hypersensitive reactions to PPIs is unknown. The aim of this retrospective study is to evaluate the rate of hypersensitive reactions to PPIs in patients admitted to our Unit between 2008 and 2013 with a history of drug hypersensitivity. From a database of 1229 patients (921 women, 308 men) with adverse drug reaction we extrapolated the data about PPI reactions. Twelve patients (10 female, 2 men) had a positive history for hypersensitive reaction to PPI. Pantoprazole was the most frequently PPI involved. Based on patient personal history in some cases we performed an oral challenge test for an alternative anti-acid drug and none of them had adverse reactions. According to our experience and according to the literature and pharmacovigilance reports, ADR caused by PPIs are ever increasing. Adverse reactions to these drugs are still under-reported; however, considering the frequency of their prescription worldwide, the risk of severe allergic events is low. Further studies are needed to provide clearer data on the real incidence and prevalence about this matter. This should be useful to help physician in choosing the molecule to prescribe and, in case of hypersensitivity, the alternative molecule to test, also considering the possible cross-reactivity.

The link between the AMPK/SIRT1 axis and a flavonoid-rich extract of Citrus bergamia juice: A cell-free, in silico, and in vitro study.

A previous report indicated that the flavonoid-rich extract of bergamot juice (BJe) exerts an anti-inflammatory effect through the activation of SIRT1 in leukemic monocytes THP-1 exposed to lipopolysaccharide (LPS). In this study, we deeply investigate the mode of action of BJe, along with its major flavonoids on SIRT1 through cell-free, in silico, and in vitro experimental models. In the cell-free assay, all the tested compounds as well as the whole BJe inhibited the deacetylase activity of SIRT1. This finding was reinforced by the results of the in silico study. In THP-1 cells exposed to LPS, a reduction of SIRT1 activity was observed, effect that was reverted by the pre-incubation with either BJe or its major flavonoids. This effect was also observed at gene level. Employing an activator and an inhibitor of AMP-activated protein kinase (AMPK; AICAR and dorsomorphin, respectively), we discovered its involvement in the activation of SIRT1 elicited by BJe or its major flavonoids in whole cell. Our study indicates the dual role of BJe and its components, depending on the employed experimental model as well as reveals their mode of action on the AMPK/SIRT1 axis, suggesting their role as promising candidates in pathologies in which this axis is implied.

Moringin from Moringa Oleifera Seeds Inhibits Growth, Arrests Cell-Cycle, and Induces Apoptosis of SH-SY5Y Human Neuroblastoma Cells through the Modulation of NF-κB and Apoptotic Related Factors.

In the last decades, glucosinolates (GLs), precursors of isothiocyanates (ITCs), have been studied mostly for their chemopreventive and chemotherapeutic properties. The aim of our research was to study the antiproliferative effect of 4-(α-L-rhamnopyranosyloxy) benzyl glucosinolate (glucomoringin; GMG) bioactivated by myrosinase enzyme to form the corresponding isothiocyanate 4-(α-L-rhamnopyranosyloxy) benzyl C (moringin) in SH-SY5Y human neuroblastoma cells. We found that moringin significantly reduced SH-SY5Y cell growth in a time and concentration-dependent (p < 0.05, 0.01, and 0.001 vs. ctrl, after treatment with 16.4 µM moringin for 24, 48, and 72 h, respectively) manner through a mechanism involving the activation of apoptotic machinery. In addition, it altered the normal progression of cells through the cell cycle, increasing the cell population in both G2 and S phases, as well as decreasing that in the G1 phase. Studying the drug mechanism of action, we found that moringin was able to increase the expression of p53, p21, and Bax at both the protein and transcriptional level. Moreover, exposure of SH-SY5Y cells to moringin significantly increased the gene expression of both caspase 3 and 9 and enhanced their cleavage, thereby initiating an intrinsic apoptotic cascade. Finally, moringin inhibited nuclear translocation of NF-κB. Our study demonstrates the ability of moringin to reduce the growth of SH-SY5Y cells and reveals its mechanism of action, suggesting its promising role as an anticancer drug.

Effects of a Flavonoid-Rich Extract from Citrus sinensis Juice on a Diet-Induced Obese Zebrafish.

BACKGROUND: Obesity is a pathological condition that has reached epidemic proportions; hence, it is necessary to find novel strategies aimed at fighting this disease. The present study was designed to evaluate the effect of a flavonoid-rich extract of orange (Citrus sinensis) juice (OJe) in diet-induced obese zebrafish. METHODS: Adult zebrafish were divided into four diet groups: (i) normally fed (NF); (ii) overfed (OF); (iii) NF supplemented with OJe (5 mL/L in fish water; NF + OJe); and (iv) OF supplemented with OJe (OF + OJe). Each week, body weight (BW) and body mass index (BMI) were measured, and, at the end of the fifth week, euthanized zebrafish were processed for both microscopic evaluations and qPCR analyses. RESULTS: In OF zebrafish, OJe significantly decreased both BW and BMI values and lowered the visceral adipose tissue, while it had little effect in the NF group. Moreover, it significantly reduced adipocyte cell size in both NF and OF groups in both visceral and subcutaneous adipose tissues, as well as their number in OF fish. Finally, OJe modulated some obesity-related genes, such as leptin A, ghrelin, orexin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY), in both gut and brain. CONCLUSION: This study adds new insights into the anti-obesity properties of orange juice and its flavonoids, suggesting their role as weight management agents through a lipolytic action linked to a restoration of metabolism-regulating gene expression.

Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Bearing a Pyrazole Scaffold and a Cinnamoyl Linker.

Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N¹-aryl or N¹-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations.

Citrus fruits intake and oral cancer risk: A systematic review and meta-analysis.

OBJECTIVE: To quantify the relationship between Citrus intake and risk of cancer of the oral cavity and pharynx. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Ovid MEDLINE, EMBASE, and Web of Science were searched until September 2017. Search terms included Citrus, Citrus aurantifolia, Citrus sinensis, Citrus paradisi, Citrus fruits, Citrus fruits extract, Citrus oil, fruits, oral cancer, mouth cancer, mouth neoplasm. STUDY SELECTION: The selection of studies and the systematic review were carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A pre-defined inclusion checklist resulted in the inclusion of articles which were (i) published in peer-reviewed scientific journals; (ii) English language; (iii) and included a measure of Citrus fruit intake and risk of oral and pharyngeal cancer. Studies were excluded if (i) preparations derived from other fruits were used, (ii) Citrus intake was combined with intake of other fruits; (iii) in vitro or animal models were used. We also excluded reviews, systematic reviews, meta-analyses, letters, personal opinions, conference abstracts and book chapters. DATA EXTRACTION: Three reviewers independently performed the extraction of data from studies included. RESULTS: Seventeen studies met our inclusion criteria and were included in the final review. Pooled analyses showed that those with the highest Citrus fruit intake compared to the lowest intake had a 50% reduction in risk of oral cavity and pharyngeal cancer (OR 0.50; 95% CI 0.43-0.59). CONCLUSION: The studies included in this review and meta-analysis showed an inverse association between Citrus fruit intake and oral cancer.

IL-33/IL-31 Axis: A Potential Inflammatory Pathway.

Cytokines play an important role in the regulation of the immune system (adaptive and innate). Given their importance in proinflammatory processes, cytokines have been used for understanding the pathogenesis and as biomarkers in many diseases. IL-31 and IL-33 are still considered novel cytokines. IL-31 controls signalling and regulates a huge amount of biological functions: it induces proinflammatory cytokines, regulates cell proliferation, and is involved also in tissue remodelling. On the other hand, IL-33 has been identified as an "alarmin" released from the epithelial cells and from different human tissues and organs after a damage following, that is, an inflammatory process. The aim of this literature review is to strengthen the hypothesis about an IL-31/IL-33 axis by evaluating the most recent studies linking these two cytokines. Literature data showed that, in many cases, IL-31 and IL-33 are linked to each other and that their expression is correlated with disease severity. The presence of one interleukin might stimulate the induction of the other, amplifying inflammation and the consequent detrimental processes. In a near future, influencing their balance could be helpful in modulating the first responses of the immune system in order to prevent the development of many inflammation-related diseases.