Neuroinflammation is a common symptom in the onset of different neurodegenerative diseases and growing interest is directed towards the development of active drugs for the reduction or elimination of its negative effects. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), belonging to the class of ?-3 polyunsaturated fatty acids, have been largely investigated for their anti-inflammatory activity and their potential as neuroprotective agents has been evaluated on some neural cells1. Most of the observed biological activities of these fatty acids are maintained, and in some case enhanced, in the corresponding amide derivatives or oxygenated metabolites2. Our study aims to elucidate the protective effect of both EPA and DHA, as well as the corresponding N-ethanolamides EPA-EA and DHA-EA, on Olfactory Ensheathing Cells (OECs) exposed to lipopolysaccharide (LPS)-induced neuroinflammation. OECs are glial cells located in the olfactory system, which is the first to show a deficit in neurodegenerative diseases. To verify the anti-inflammatory effect of these compounds on OEC cultures and on cell morphological features, the expression of some cytoskeletal proteins, such as Vimentin and Glial Fibrillary Acid Protein (GFAP), was evaluated by immunocytochemical procedures. In addition, MTT test was carried out to establish the non-toxic concentrations and the optimal time of exposure. Our results show a decrease of GFAP and Vimentin expression in OECs treated with EPA or DHA acids or EPA-EA or DHA-EA and stressed with LPS when compared with OECs exposed to LPS alone. While a protective role on cell morphology is predominantly observed for EPA and DHA, the amides EPA-EA and DHA-EA mainly show anti-inflammatory effects, superior to those of free acids. These results highlight that all the tested compounds have anti-inflammatory activity on LPS-exposed OECs and may provide an innovative tool to contrast neuroinflammation, which plays a key role in several neurodegenerative diseases.

A vast literature strongly suggests that the endocannabinoid (eCB) system and related bioactive lipids (the paracannabinoid system) contribute to numerous physiological processes and are involved in pathological conditions such as obesity, type 2 diabetes, and intestinal inflammation. The gut paracannabinoid system exerts a prominent role in gut physiology as it affects motility, permeability, and inflammatory responses. Another important player in the regulation of host metabolism is the intestinal microbiota, as microorganisms are indispensable to protect the intestine against exogenous pathogens and potentially harmful resident microorganisms. In turn, the composition of the microbiota is regulated by intestinal immune responses. The intestinal microbial community plays a fundamental role in the development of the innate immune system and is essential in shaping adaptive immunity. The active interplay between microbiota and paracannabinoids is beginning to appear as potent regulatory system of the gastrointestinal homeostasis. In this context, oleoylethanolamide (OEA), a key component of the physiological systems involved in the regulation of dietary fat consumption, energy homeostasis, intestinal motility, and a key factor in modulating eating behavior, is a less studied lipid mediator. In the small intestine namely duodenum and jejunum, levels of OEA change according to the nutrient status as they decrease during food deprivation and increase upon refeeding. Recently, we and others showed that OEA treatment in rodents protects against inflammatory events and changes the intestinal microbiota composition. In this review, we briefly define the role of OEA and of the gut microbiota in intestinal homeostasis and recapitulate recent findings suggesting an interplay between OEA and the intestinal microorganisms.

Nutraceuticals are natural substances whose anti-oxidant and anti-inflammatory properties may be used to treat retinal pathologies. Their efficacy is limited by poor bioavailability, which could be improved using nanocarriers. Lisosan G (LG), a fermented powder from whole grains, protects the retina from diabetic retinopathy (DR)-induced damage. For this study, we tested whether the encapsulation of LG in liposomes (LipoLG) may increase its protective effects. Diabetes was induced in mice via streptozotocin administration, and the mice were allowed to freely drink water or a water dispersion of two different doses of LG or of LipoLG. Electroretinographic recordings after 6 weeks showed that only the highest dose of LG could partially protect the retina from diabetes-induced functional deficits, while both doses of LipoLG were effective. An evaluation of molecular markers of oxidative stress, inflammation, apoptosis, vascular endothelial growth factor, and the blood-retinal barrier confirmed that the highest dose of LG only partially protected the retina from DR-induced changes, while virtually complete prevention was obtained with either dose of LipoLG. These data indicate that the efficacy of LG in contrasting DR is greatly enhanced by its encapsulation in liposomes and may lay the ground for new dietary supplements with improved therapeutic effects against DR.

Introduction: Microencapsulation of probiotic bacteria is an efficient and innovative new technique aimed at preserving bacterial survival in the hostile conditions of the gastrointestinal tract. However, understanding whether a microcapsule preserves the effectiveness of the bacterium contained within it is of fundamental importance. Methods: Male Wistar rats aged 90 days were fed a control diet or a Western diet for 8 weeks, with rats fed the Western diet divided into three groups: one receiving the diet only (W), the second group receiving the Western diet and free L. reuteri DSM 17938 (WR), and the third group receiving the Western diet and microencapsulated L. reuteri DSM 17938 (WRM). After 8 weeks of treatment, gut microbiota composition was evaluated, together with occludin, one of the tight junction proteins, in the ileum and the colon. Markers of inflammation were also quantified in the portal plasma, ileum, and colon, as well as markers for gut redox homeostasis. Results: The Western diet negatively influenced the intestinal microbiota, with no significant effect caused by supplementation with free and microencapsulated L. reuteri. However, L. reuteri, in both forms, effectively preserved the integrity of the intestinal barrier, thus protecting enterocytes from the development of inflammation and oxidative stress. Conclusion: From these whole data, it emerges that L. reuteri DSM 17938 can be an effective probiotic in preventing the unhealthy consequences of the Western diet, especially in the gut, and that microencapsulation preserves the probiotic effects, thus opening the formulation of new preparations to be able to improve gut function independent of dietary habits.

A series of copper(II) complexes with the formula [Cu(2+)Hy(x)Car%] varying the molecular weight (MW) of Hyaluronic acid (Hy, x = 200 or 700 kDa) conjugated with carnosine (Car) present at different loading were synthesized and characterized via different spectroscopic techniques. The metal complexes behaved as Cu, Zn-superoxide dismutase (SOD1) mimics and showed some of the most efficient reaction rate values produced using a synthetic and water-soluble copper(II)-based SOD mimic reported to date. The increase in the percentage of Car moieties parallels the enhancement of the I50 value determined via the indirect method of Fridovich. The presence of the non-functionalized Hy OH groups favors the scavenger activity of the copper(II) complexes with HyCar, recalling similar behavior previously found for the copper(II) complexes with Car conjugated using fi-cyclodextrin or trehalose. In keeping with the new abilities of SOD1 to activate protective agents against oxidative stress in rheumatoid arthritis and osteoarthritis diseases, Cu2+ interaction with HyCar promotes the nuclear translocation of erythroid 2-related factor that regulates the expressions of target genes, including Heme-Oxigenase-1, thus stimulating an antioxidant response in osteoblasts subjected to an inflammatory/oxidative insult.

Air pollution exposure plays a key role in the alteration of gene expression profiles, which can be regulated by microRNAs, inducing the development of various diseases. Moreover, there is also evidence of sensitivity of miRNAs to environmental factors, including tobacco smoke. Various diseases are related to specific microRNA signatures, suggesting their potential role in pathophysiological processes; considering their association with environmental pollutants, they could become novel biomarkers of exposure. Therefore, the aim of the present work is to analyse data reported in the literature on the role of environmental stressors on microRNA alterations and, in particular, to identify specific alterations that might be related to the development of airway diseases so as to propose future preventive, diagnostic, and therapeutic strategies.

The negative socioeconomic impact of mental health disorders and skin diseases has increased in part due to the conflict between Russia and Ukraine, which has been a fertile ground for the emergence of psychopathologies. It is firmly established that there is a direct thread of etiopathogenetic communication between skin diseases and neuropsychiatric disorders, and the literature has tried to reveal the pathophysiological mechanisms governing such bidirectionality. This paper discusses this complex network of molecular pathways that are targeted by conventional and biological pharmacological agents that appear to impact two pathological spheres that previously seemed to have little connection. This molecular discussion is supplemented with a literature review, from a clinical viewpoint, regarding skin-brain etiopathogenetic bidirectionality. We focus on post-traumatic stress disorder (PTSD), which can be considered for all intents and purposes a systemic inflammatory disease that also affects the skin. A brief overview is also provided on the diagnostic-therapeutic and follow-up potential of oxidative and inflammatory markers potentially involved in the pathophysiological mechanisms treated. The aim is to clarify how these mechanisms may be useful in defining different stress-coping strategies and thus individual phenotypes of stress sensitivity/resistance in order to promote personalized medicine in the field of psychodermatology.

Most oropharyngeal squamous cell carcinomas (OPSCCs) are human papillomavirus (HPV)-associated, high-risk (HR) cancers that show a better response to chemoradiotherapy and are associated with improved survival. Nucleophosmin (NPM, also called NPM1/B23) is a nucleolar phosphoprotein that plays different roles within the cell, such as ribosomal synthesis, cell cycle regulation, DNA damage repair and centrosome duplication. NPM is also known as an activator of inflammatory pathways. An increase in NPM expression has been observed in vitro in E6/E7 overexpressing cells and is involved in HPV assembly. In this retrospective study, we investigated the relationship between the immunohistochemical (IHC) expression of NPM and HR-HPV viral load, assayed by RNAScope in situ hybridization (ISH), in ten patients with histologically confirmed p16-positive OPSCC. Our findings show that there is a positive correlation between NPM expression and HR-HPV mRNA (Rs = 0.70, p = 0.03), and a linear regression (r(2) = 0.55; p = 0.01). These data support the hypothesis that NPM IHC, together with HPV RNAScope, could be used as a predictor of transcriptionally active HPV presence and tumor progression, which is useful for therapy decisions. This study includes a small cohort of patients and, cannot report conclusive findings. Further studies with large series of patients are needed to support our hypothesis.

miRNAs are involved in the generation and progression of musculoskeletal pain, a condition that causes significant clinical, economic and social burden. In runners, the presence of musculoskeletal pain related to an inflammatory state or ongoing underlying tissue damage may result in poor training ability and performance. This study aims to evaluate the association between circulating and salivary miRNAs and pain in runners with and without musculoskeletal pain and to observe whether dysregulated miRNAs can distinguish between responders and nonresponders to a kinesiological intervention. The possible correlation between these miRNAs and inflammatory molecules, stress parameters and individual or behavioral characteristics will be evaluated. Finally, in silico analysis will be used to characterize miRNAs function. Ethics approval was obtained.

Ginger (Zingiber officinale) is commonly consumed as spice or herbal medicine with anti-inflammatory, antioxidant and anticancer properties. It is rich of many bioactive constituents, mainly gingerols and shogaols. Although the bioactive constituents have been identified, the molecular mechanisms of ginger action are still limited and the related signalling pathways not completely defined. Here, we used a simple ethanol/freeze-drying method to obtain a new ginger extract (GE), which was chemically characterised by Folin-Ciocalteu, antioxidant ORAC and HPLC assays. At cellular level, anti-inflammatory/antioxidant properties of GE, in addition to the commercial [6]-gingerol, were evaluated using RAW264.7 murine macrophages. Cell viability tests verified the non-toxic doses of GE and [6]-gingerol, and the glutathione assay confirmed the antioxidant property of GE. By quantitative PCR, we analysed the differential expression of various genes in LPS-treated cells, after GE/[6]-gingerol pre-treatments. The genes belonged to different categories: immune signalling, pro/anti-inflammatory cytokines, pro/anti-antioxidant enzymes, hallmarks of macrophage polarization and endoplasmic reticulum stress response. Results showed that pre-treatment with two doses of GE reduced the LPS-induced expression of TLR4, MyD88, Rel-A, IL-1?, IL-6, TNF-?, IL-10, iNOS and TRIB3 genes to varying degrees, whereas increased Jun, Light/Tnfsf14, HO-1 and Arg-1 gene expression. No effect was found on MIF expression in LPS-induced cells after GE pre-treatments. These results also suggested that GE pre-treatment promotes the expression of specific markers of macrophage polarization in LPS-stimulated cells, with a trend to activate an anti-inflammatory M2 phenotype. Further analyses will broaden the understanding of the role of individual GE components in cellular inflammation/ immunomodulation.

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04-4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08-9.40) and PTSD (OR = 2.38; 95% CI: 1.06-8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.

In the past decades, many studies have widely examined the effects of dietary polyphenols on human health. Polyphenols are well known for their antioxidant properties and for their chelating abilities, by which they can be potentially employed in cases of pathological conditions, such as iron overload. In this review, we have highlighted the chelating abilities of polyphenols, which are due to their structural specific sites, and the differences for each class of polyphenols. We have also explored how the dietary polyphenols and their iron-binding abilities can be important in inflammatory/immunomodulatory responses, with a special focus on the involvement of macrophages and dendritic cells, and how they might contribute to reshape the gut microbiota into a healthy profile. This review also provides evidence that the axes "polyphenol-iron metabolism-inflammatory responses" and "polyphenol-iron availability-gut microbiota" have not been very well explored so far, and the need for further investigation to exploit such a potential to prevent or counteract pathological conditions.

Bee pollen represents one of the most complete natural foods playing an important role in the diet for its health qualities and therapeutic properties. This work aimed to characterize a Tuscan bee pollen by evaluating its phytochemical profile and the in vitro and ex vivo antioxidant activities. The isolation and taxonomic and functional characterization of yeasts in the sample has been also conducted. Finally, the pollen anti-inflammatory potential has been assessed on a TNF alpha-inflamed human colorectal adenocarcinoma cell line (HT-29). Our results highlighted a good phytochemical composition in terms of polyphenols, flavonoids, flavonols, monomeric anthocyanins, and carotenoids. In addition, we detected good antioxidant activity and radical scavenging capacity by in vitro and ex vivo assays, as well as good antioxidant activity by isolated yeasts. Data showed no cytotoxic effects of bee pollen extracts, with average viability values >80% at each tested dose. Moreover, TNF alpha treatment did not affect HT-29 viability while upregulating IL-8, COX-2, and ICAM-1 gene expression, otherwise reduced by both doses of bee pollen. In conclusion, our sample represents an interesting functional food and a potential probiotic product, having high phytochemical compound levels and good antioxidant activities, as well as anti-inflammatory effects on the TNF alpha-inflamed HT-29 cell line.

The enhanced consumption of fructose as added sugar represents a major health concern. Due to the complexity and multiplicity of hypothalamic functions, we aim to point out early molecular alterations triggered by a sugar-rich diet throughout adolescence, and to verify their persistence until the young adulthood phase. Methods: Thirty days old rats received a high-fructose or control diet for 3 weeks. At the end of the experimental period, treated animals were switched to the control diet for further 3 weeks, and then analyzed in comparison with those that were fed the control diet for the entire experimental period. Results: Quantitative proteomics identified 19 differentially represented proteins, between control and fructose-fed groups, belonging to intermediate filament cytoskeleton, neurofilament, pore complex and mitochondrial respiratory chain complexes. Western blotting analysis confirmed proteomic data, evidencing a decreased abundance of mitochondrial respiratory complexes and voltage-dependent anion channel 1, the coregulator of mitochondrial biogenesis PGC-1?, and the protein subunit of neurofilaments ?-internexin in fructose-fed rats. Diet-associated hypothalamic inflammation was also detected. Finally, the amount of brain-derived neurotrophic factor and its high-affinity receptor TrkB, as well as of synaptophysin, synaptotagmin, and post-synaptic protein PSD-95 was reduced in sugar-fed rats. Notably, deregulated levels of all proteins were fully rescued after switching to the control diet. Conclusions: A short-term fructose-rich diet in adolescent rats induces hypothalamic inflammation and highly affects mitochondrial and cytoskeletal compartments, as well as the level of specific markers of brain function; above-reported effects are reverted after switching animals to the control diet.

Pathogenic mutations in the Gjb2 and Gjb6 genes, encoding connexin 26 (Cx26) and connexin 30 (Cx30), respectively, have been linked to the most frequent monogenic hearing impairment, nonsyndromic hearing loss, and deafness DFNB1. It is known that Cx26 plays an important role in auditory development, while the role of Cx30 in hearing remains controversial. Previous studies found that partial deletion of Cx26 can accelerate age-related hearing loss (ARHL), a multifactorial complex disorder, with both environmental and genetic factors contributing to the etiology of the disease. Here, we investigated the role of Cx30 in cochlear-aging processes using a transgenic mouse model with total deletion of Cx30 (Cx30 delta delta mice), in which Cx30 was removed without perturbing the surrounding sequences. We show that these mice are affected by exacerbated ARHL, with increased morphological cochlear damage, oxidative stress, inflammation, and vascular dysfunctions. Overall, our data demonstrate that Cx30 deletion can be considered a genetic risk factor for ARHL, making cochlear structures more susceptible to aging processes.

We previously showed that genotoxic stress induced an active extracellular release of nucleophosmin (NPM) in human cardiac mesenchymal progenitor cells, and that serum deprivation provokes NPM secretion from human endothelial cells, eliciting inflammation via nuclear factor kappa B (NF-kB) transcriptional activation. In this study, we wanted to determine whether NPM was similarly modulated in the skin and plasma of psoriatic patients (Pso). We found that NPM was induced in 6 skin biopsies compared to 6 normal skin biopsies and was markedly increased in lesional (LS) vs. non-lesional skin (NLS) biopsies. Moreover, NPM was also increased at the transcriptional levels in LS vs. NLS. Both the innate stimuli, such as lipopolysaccharides and Poly inositol-cytosine and adaptive stimuli, that is, cytokine mix, were able to induce the extracellular release of NPM in immortalized keratinocytes and human skin fibroblasts in the absence of cytotoxicity. Interestingly, NPM interacts with Toll-like receptor (TLR)4 in these cells and activates an NF-kB-dependent inflammatory pathway upregulating interleukin IL-6 and COX-2 gene expression. Finally, circulating NPM was increased in the plasma of 29 Pso compared to 29 healthy controls, and positively correlates with psoriasis area severity index (PASI) and with determinants of cardiovascular diseases (CVDs), such as pulse wave velocity, systolic pressure, and left ventricular mass. Furthermore, NPM positively correlates with miR-200c circulating levels, which we previously showed to increase in Pso and correlate with CVD progression. Our data show that circulating miR-200c is physically associated with extracellular NPM, which most probably is responsible for its extracellular release and protection upon cytokine mix via a TLR4-mechanism. In conclusion, NPM is increased in psoriasis both in the skin and plasma and might be considered a novel biologic target to counteract chronic inflammation associated with CVD risk.

Chronic activated microglia is correlated with neuronal cell death in several neurodegenerative diseases. Activated microglia has been classified in two states, classic (M1) and alternative (M2), considered a pro-inflammatory and an anti-inflammatory state, respectively. Thus, functional modulation of microglial phenotypes has been deemed as a potential therapeutic strategy. Recently, a novel non-natural chimeric sulfoglycolipid, named Sulfavant A (?-SQDG), has shown promising immunomodulant activity, as proved by its effect on both dendritic cell maturation in vitro and immune response in vivo (1). However, whether Sulfavant A has similar modulatory actions on microglia activation has not been investigated yet. Here, we studied whether Sulfavant A modulates M1 or M2 polarization by using BV2 microglial cell line. The effect of Sulfavant A was tested on lipopolysaccharide (LPS) (100 ng/mL)-induced microglia activation by evaluating the markers defining microglia phenotypes. Pre-incubation with Sulfavant A (10 ug/mL) for 30 minutes attenuated LPS-induced microglia activation, as demonstrated by reduction of Iba1 expression and M1 pro-inflammatory markers COX-2 and iNOS, whereas an upregulation of M2 markers, such as Arginase 1 , occurred. Accordingly, a reduction of the nitric oxide production was detected in supernatants of microglia cultures. Interestingly, Sulfavant A pre-incubation induced early (30 minutes) induction of ERK1/2 phosphorylation. Collectively, our data suggest that Sulfavant A may act as pro-homeostatic pharmacological tool for controlling neuroinflammation, interfering with M1 polarization but also rapidly activating intracellular pathways that may promote microglia phagocytosis without inflammation .

Lung cancer is one of the leading forms of cancer in developed countries. Interleukin-8 (IL-8), a pro-inflammatory cytokine, exerts relevant effects in cancer growth and progression, including angiogenesis and metastasis in lung cancer. Mesoporous silica particles, functionalized with newly extracted fish oil (Omeg@Silica), are more effective than the fish oil alone in anti-proliferative and pro-apoptotic effects in non-small cell lung cancer (NSCLC) cell lines. The mechanisms that explain this efficacy are not yet understood. The aim of the present study is therefore to decipher the anti-cancer effects of a formulation of Omeg@Silica in aqueous ethanol (FOS) in adenocarcinoma (A549) and muco-epidermoid (NCI-H292) lung cancer cells, evaluating cell migration, as well as IL-8, NF-?B, and miRNA-21 expression. Results show that in both cell lines, FOS was more efficient than oil alone, in decreasing cell migration and IL-8 gene expression. FOS reduced IL-8 protein release in both cell lines, but this effect was only stronger than the oil alone in A549. In A549, FOS was able to reduce miRNA-21 and transcription factor NF-?B nuclear expression. Taken together, these data support the potential use of the Omeg@Silica as an add-on therapy for NSCLC. Dedicated studies which prove clinical efficacy are needed.

Retinal pigment epithelium (RPE) is a specialized pigmented monolayer dedicated to retinal support and protection. Given the fact that photoreceptor outer segments are the primary energy resource of RPE metabolism, it follows that, when photoreceptor function is compromised, RPE cells are impaired and vice versa. In retinitis pigmentosa (RP), genetic mutations lead to a massive degeneration of photoreceptors but only few studies have addressed systematically the consequences of rod and cone death on RPE cells, which, among others, undergo an abnormal organization of tight junctions (TJs) and a compromised barrier function. The biological mechanisms driving these barrier reorganizations are largely unknown. Studies aimed at addressing general and mutation-independent changes of the RPE in RP are relevant to reveal new pathogenic mechanisms of this heterogeneous family of diseases and prospectively develop effective therapeutic strategies. Here, we take advantage of a mouse model of RP in which retinal degeneration is spatially restricted to investigate a possible involvement of inflammatory responses in RPE remodeling. By immunostaining for Zona Occludens-1 (ZO-1), a structural and functional marker of TJs with pleiotropic functions, we found a partial rescue of TJs organization following local restoration of retinal organization, revealing that TJs structure can recover. Since lack of ZO-1 from TJs can alter cell density, we counted RPE cells without finding any differences between degenerated and controls animals, indicating preservation of RPE cells. However, we found an increased number of immune cells adhering to the RPE apical surface and a spatial correlation with areas of abnormal ZO-1 distribution. This suggests that inflammatory processes following photoreceptor degeneration can be responsible for TJs alterations during RP progression and deserve further investigation.