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Spinal cord injury (SCI) leads to long-term and permanent motor dysfunctions, and nervous system abnormalities. Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and l-carnosine (Car), (β-alanyl-l-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre–car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24 h, Tre–car, Car, Tre, and Tre + Car mixture treatments, cells were collected and used to investigate Zn2+ homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6–T8 levels. After treatments with Tre, Car and Tre–Car conjugate 1 and 6 h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of l-carnosine and its conjugate. In vivo, the Tre–car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre–car conjugate stimulated neurotrophic factors release, and influenced Zn2+ homeostasis. We demonstrated that Tre–car, Tre and Car treatments improved tissue recovery after SCI. Tre–car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn2+ homeostasis, suggesting that Tre–car may represent a promising therapeutic agent for counteracting the consequences of SCI.

Oral squamous cell carcinoma (OSCC) is a commonly occurring head and neck cancer and it is characterized by a high metastasis grade. The aim of this study was to evaluate for the first time the effect of BAY-117082, a selective NLRP3 inflammasome inhibitor, in an in vivo orthotopic model of OSCC and its role in the invasiveness and metastasis processes in neighbor organs such as lymph node, lung, and spleen tissues. Our results demonstrated that BAY-117082 treatment, at doses of 2.5 mg/kg and 5 mg/kg, was able to significantly reduce the presence of microscopic tumor islands and nuclear pleomorphism in tongue tissues and modulate the NLRP3 inflammasome pathway activation in tongue tissues, as well as in metastatic organs such as lung and spleen. Additionally, BAY-117082 treatment modulated the epithelial–mesenchymal transition (EMT) process in tongue tissue as well as in metastatic organs such as lymph node, lung, and spleen, also reducing the expression of matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, markers of cell invasion and migration. In conclusion, the obtained data demonstrated that BAY-117082 at doses of 2.5 mg/kg and 5 mg/kg were able to reduce the tongue tumor area as well as the degree of metastasis in lymph node, lung, and spleen tissues through the NLRP3 inflammasome pathway inhibition.

Inflammatory bowel diseases (IBDs) involving Crohn’s disease (CD) and ulcerative colitis (UC) are gastrointestinal (GI) disorders in which abdominal pain, discomfort, and diarrhea are the major symptoms. The immune system plays an important role in the pathogenesis of IBD and, as indicated by several clinical studies, both innate and adaptative immune response has the faculty to induce gut inflammation in UC patients. An inappropriate mucosal immune response to normal intestinal constituents is a main feature of UC, thus leading to an imbalance in local pro- and anti-inflammatory species. Ulva pertusa, a marine green alga, is known for its important biological properties, which could represent a source of beneficial effects in various human pathologies. We have already demonstrated the anti-inflammatory, antioxidant, and antiapoptotic effects of an Ulva pertusa extract in a murine model of colitis. In this study, we aimed to examine thoroughly Ulva pertusa immunomodulatory and pain-relieving properties. Colitis was induced by using the DNBS model (4 mg in 100 μL of 50% ethanol), whereas Ulva pertusa was administered daily at the dosage of 50 and 100 mg/kg by oral gavage. Ulva pertusa treatments have been shown to relieve abdominal pain while modulating innate and adaptative immune-inflammatory responses. This powerful immunomodulatory activity was specifically linked with TLR4 and NLRP3 inflammasome modulation. In conclusion, our data suggest Ulva pertusa as a valid approach to counteract immune dysregulation and abdominal discomfort in IBD.

Bacterial vaginosis (BV) is a common vaginal dysbiosis characterized by a malodorous discharge and irritation. The imbalance of the vaginal microbiota plays a key role in the development of BV. It has been demonstrated that Gardnerella vaginalis (GV), a facultative anaerobic bacillus, is involved in BV. Due to the rising number of antimicrobial-resistant species, recurrence of BV is becoming more frequent in women; thus, alternative treatments to antibiotics are needed. Natural substances have recently shown a great efficacy for the treatment of vaginal dysbiosis. Thus, this study aimed to investigate the beneficial effect of a product containing pea protein (PP), grape seed extract (GS) and lactic acid (LA) in an in vivo model of Gardnerella vaginalis-induced vaginosis by intravaginal administration of GV suspension (1 × 106 CFU/20 µL saline). Our results demonstrated that the product containing PP, GS and LA significantly reduced GV proliferation. More specifically, it significantly preserved tissue architecture and reduced neutrophil infiltration, inflammatory markers and sialidase activity when used both as a pre- or a post-treatment. Moreover, the product displayed strong bioadhesive properties. Therefore, our data suggested that the product containing PP, GS and LA could be used as alternative preventive or curative treatment for the management of BV.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal gene abnormalities, epidermal barrier defects and inflammation. Corticosteroids are considered to be standard treatments, but often come with side effects and lose efficacy with long-term use. Alternative treatments targeting the epidermal barrier defect are needed to manage the disease. Film-forming substances such as xyloglucan, pea protein and Opuntia ficus-indica extract (XPO) have generated interest for their ability to restore skin barrier integrity and may pose an alternative approach to disease management. Thus, the aim of this two-part study was to evaluate the barrier-protective properties of a topical cream containing XPO on the membrane permeability of keratinocytes exposed to inflammatory conditions and compare its efficacy to dexamethasone (DXM) in an in vivo model of psoriasis-like dermatitis. XPO treatment significantly reduced S. aureus adhesion, subsequent skin invasion and restored epithelial barrier function in keratinocytes. Furthermore, the treatment restored the integrity of keratinocytes, reducing tissue damage. In mice with psoriasis-like dermatitis, XPO significantly reduced erythema, inflammatory markers and epidermal thickening with a superior efficacy to dexamethasone. Given the promising results, XPO may represent a novel steroid-sparing therapeutic for epidermal-related diseases such as psoriasis, thanks to its ability to preserve skin barrier function and integrity.

Alessia Filippone, Tiffany Smith, Domenico Pratico Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USACorrespondence: Domenico PraticoAlzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, MERB, suite 1160, Philadelphia, PA, 19140, USATel +1 215-707-9380Fax +1 215-707-2746Email praticod@temple.eduIntroduction: Transport through endothelial cells of the blood–brain barrier (BBB) involves a complex group of structures of the endo-lysosome system such as early and late endosomes, and the retromer complex system. Studies show that neuronal dysregulation of the vacuolar protein sorting 35 (VPS35), the main component of the retromer complex recognition core, results in altered protein trafficking and degradation and is involved in neurodegeneration. Since the functional role of VPS35 in endothelial cells has not been fully investigated, in the present study we aimed at characterizing the effect of its downregulation on these pathways.Methods: Genetic silencing of VPS35 in human brain endothelial cells; measurement of retromer complex system proteins, autophagy and ubiquitin-proteasome systems.Results: VPS35-downregulated endothelial cells had increased expression of LC3B2/1 and more ubiquitinated products, markers of autophagy flux and impaired proteasome activity, respectively. Additionally, compared with controls VPS35 downregulation resulted in significant accumulation of tau protein and its phosphorylated isoforms.Discussion: Our findings demonstrate that in brain endothelial cells retromer complex dysfunction by influencing endosome-lysosome degradation pathways results in altered proteostasis. Restoration of the retromer complex system function should be considered a novel therapeutic approach to rescue endothelial protein transport.Keywords: retromer complex, brain endothelial cells, endosomal trafficking, tau protein, autophagy, ubiquitin-proteasome, Alzheimer’s disease

Background: The vacuolar protein sorting 35 (VPS35) is the main component of the retromer recognition core complex system which regulates intracellular cargo protein sorting and trafficking. Downregulation of VPS35 has been linked to the pathogenesis of neurodegenerative disorders such Alzheimer’s and Parkinson’s diseases via endosome dysregulation. Objective: Here we show that the genetic manipulation of VPS35 affects intracellular degradation pathways. Methods: A neuronal cell line expressing human APP Swedish mutant was used. VPS35 silencing was performed treating cells with VPS35 siRNA or Ctr siRNA for 72 h. Results: Downregulation of VPS35 was associated with alteration of autophagy flux and intracellular accumulation of acidic and ubiquitinated aggregates suggesting that dysfunction of the retromer recognition core leads to a significant alteration in both pathways. Conclusion: Taken together, our data demonstrate that besides cargo sorting and trafficking, VPS35 by supporting the integral function of the retromer complex system plays an important role also as a critical regulator of intracellular degradation pathways.

New therapeutic approaches are needed to improve the outcome of patients with glioblastoma (GBM). Propionate, a short-chain fatty acid (SCFA), has a potent antiproliferative effect on various tumor cell types. Peroxisome proliferator-activated receptor (PPAR) ligands possess anticancer properties. We aimed to investigate the PPAR-γ/SCFAs interaction in in vitro and in vivo models of GBM. The U87 cell line was used in the in vitro study and was treated with sodium propionate (SP). U87 cells were silenced by using PPAR-γ siRNA or Ctr siRNA. In the in vivo study, BALB/c nude mice were inoculated in the right flank with 3 × 106 U-87 cells. SP (doses of 30 and 100 mg/kg) and GW9662 (1 mg/kg) were administered. In vitro exposure of GBM to SP resulted in prominent apoptosis activation while the autophagy pathway was promoted by SP treatments by influencing autophagy-related proteins. Knockdown of PPAR-γ sensitized GBM cells and blocked the SP effect. In vivo, SP was able to decrease tumor growth and to resolve GBM tissue features. SP promoted apoptosis and autophagy pathways and tumor cell proliferation leading to cell cycle arrest through a PPAR-γ-dependent mechanism suggesting that the PPAR-γ/SCFAs axis could be targeted for the management of GBM.

Irritable Bowel Syndrome is a gastrointestinal disorder that affects the large intestine, which encompasses several symptoms including, but not limited to, abdominal pain, bloating and dysmotility. In particular, IBS associated with constipation (IBS-C) is characterized by hard and dry stools and inadequate evacuation and difficulty in defecation. Although several drugs ameliorate intestinal modifications and constipation-associated features, management of IBS is still a challenge. Natural compounds including Xyloglucan and pea protein (XP) and Chia seed powder (CS) are widely known to possess beneficial effects in counteracting several gastrointestinal disorders. Here, we aimed to assess the combined effects of XP and CS to treat constipation-related alterations in an IBS-C rat model. IBS-C was induced by gastric instillation of 2 mL of cold water (0–4 °C) for 14 days and Xiloglucan, Pea protein and Chia seeds (XP + CS) treatment was orally administered for 7 days. On day 22, colon tissues were collected for histological analysis. Our results showed that XP + CS administration attenuated constipation-related parameters by increasing body weight and food and water intake. Upon XP + CS treatment, from day 14 to 22, stool moisture content was restored to physiological level. Colonic tissues from IBS-C rats depicted a disruption of the organ architecture accompanied by edema. Loss of colonic structure was reflected by the marked reduction of tight junction protein expression, Occludin and zona occludens-1 (ZO-1). Administration of XP + CS treatment in IBS-C rats significantly ameliorated the colonic histological parameters and exerted a positive effect on barrier integrity by restoring the expression of Occludin and zona occludens-1 (ZO-1). Our findings demonstrated that the efficacy of XP and CS in managing constipation in rats is due to the ability of these compounds to form a protective barrier fortifying intestinal integrity and gut functionality.

Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric Ser/Thr phosphatase that regulates many cellular processes. PP2A is dysregulated in several human diseases, including oncological pathology; interestingly, PP2A appears to be essential for controlling cell growth and may be involved in cancer development. The role of PP2A as a tumor suppressor has been extensively studied and reviewed. To leverage the potential clinical utility of combination PP2A inhibition and radiotherapy treatment, it is vital that novel highly specific PP2A inhibitors be developed. In this review, the existing literature on the role of PP2A in brain tumors, especially in gliomas and glioblastoma (GBM), was analyzed. Interestingly, the review focused on the role of PP2A inhibitors, focusing on CIP2A inhibition, as CIP2A participated in tumor cell growth by stimulating cell-renewal survival, cellular proliferation, evasion of senescence and inhibition of apoptosis. This review suggested CIP2A inhibition as a promising strategy in oncology target therapy.

Glioblastoma (GB) is a tumor of the central nervous system characterized by high proliferation and invasiveness. The standard treatment for GB includes radiotherapy and chemotherapy; however, new therapies are needed. Particular attention was given to the role of histone methyltransferase enhancer of zeste-homolog-2 (EZH2) in GB. Recently, several EZH2-inhibitors have been developed, particularly GSK343 is well-known to regulate apoptosis and autophagy processes; however, its abilities to modulate canonical/non-canonical NF-κB/IκBα pathways or an immune response in GB have not yet been investigated. Therefore, this study investigated for the first time the effect of GSK343 on canonical/non-canonical NF-κB/IκBα pathways and the immune response, by an in vitro, in vivo and ex vivo model of GB. In vitro results demonstrated that GSK343 treatments 1, 10 and 25 μM significantly reduced GB cell viability, showing the modulation of canonical/non-canonical NF-κB/IκBα pathway activation. In vivo GSK343 reduced subcutaneous tumor mass, regulating canonical/non-canonical NF-κB/IκBα pathway activation and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Ex vivo results confirmed the anti-proliferative effect of GSK343 and also demonstrated its ability to regulate immune response through CXCL9, CXCL10 and CXCL11 expression in GB. Thus, GSK343 could represent a therapeutic strategy to counteract GB progression, thanks to its ability to modulate canonical/non-canonical NF-κB/IκBα pathways and immune response.

Intestinal ischemia-reperfusion (II/R) develops when the blood flow to the intestines decreases, followed by the reestablishment of the blood supply to the ischemic tissue, resulting in intestinal mucosal barrier dysfunction, with consequent severe local and systemic inflammation. Acute lung injury (ALI) represents the most serious complication after II/R. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic and inflammatory molecules. The aim of the present study is to assess the effects of POP-inhibition mediated by KYP-2047 treatment in the pathophysiology of ALI following II/R. An in vivo model of II/R was performed and mice were subjected to KYP-2047 treatment (intraperitoneal, 1, 2.5 and 5 mg/kg). Histological analysis, Masson's trichrome staining, immunohistochemical, immunofluorescence, biochemical and western blots analysis were performed on ileum and lung samples. KYP-2047 treatment ameliorated histological alteration in ileum and lung, reduced collagen amount and lowered inflammatory protein levels. Moreover, TGF-β1, eNOS, VEGF and CD34 positive staining has been modulated; also, a reduction in apoptosis expression was confirmed. This research revealed the strong anti-inflammatory potential of KYP-2047 associated to its modulatory role on angiogenesis and apoptosis, suggesting POP as a novel therapeutic target for ALI after II/R.

Gliomas are relatively rare but fatal cancers, and there has been insufficient research to specifically evaluate the role of headache as a risk factor. Nowadays, gliomas are difficult to cure due to the infiltrative nature and the absence of specific adjuvant therapies. Until now, mutations in hundreds of genes have been identified in gliomas and most relevant discoveries showed specific genes alterations related to migraine as potential risk factors for brain tumor onset. Prognostic biomarkers are required at the time of diagnosis to better adapt therapies for cancer patients. In this review, we aimed to highlight the significant modulation of CLOCK, BMLA1 and NOTCH genes in glioma onset and development, praising these genes to be good as potentially attractive therapeutic markers for brain tumors. A improved knowledge regarding the role of these genes in triggering or modulating glioma maybe the key to early diagnosing brain tumor onset in patients affected by a simple headache. In addition, investigating on these genes we can suggest potential therapeutic targets for treating brain tumors. These considerations open up the possibility of personalized treatments that can target each brain tumor’s specific genetic abnormality.

Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson’s disease (PD), moreover, its kinase activity was found to be upregulated after instigated inflammation of the central nervous system (CNS). Here, we aimed to investigate the PF06447475 (abbreviated as PF-475) role as a pharmacological LRRK2 antagonist by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord, then mice were treated with PF0-475 (2.5–5 and 10 mg/kg i.p) 1 and 6 h after SCI. We found that PF-475 treatments at the higher doses (5 and 10 mg/kg) showed a great ability to significantly reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders.

Parkinson’s disease (PD) is a disorder that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. On this basis, many scientific articles have highlighted the anti-inflammatory and neuroprotective properties of Antrodia camphorata (AC), an edible fungus containing various bioactive compounds. This study aimed to evaluate the inhibitory effect of AC administration on neuroinflammation and oxidative stress in a murine model of MPTP-induced dopaminergic degeneration. AC (10, 30, 100 mg/kg) was administered daily by oral gavage starting 24 h after the first administration of MPTP, and mice were sacrificed 7 days after MPTP induction. In this study, treatment with AC significantly reduced the alteration of PD hallmarks, increasing tyrosine hydroxylase expression and reducing the number of alpha-synuclein-positive neurons. In addition, AC treatment restored the myelination process of neurons associated with PD and attenuated the neuroinflammatory state. Furthermore, our study demonstrated that AC was able to reduce the oxidative stress induced by MPTP injection. In conclusion, this study highlighted that AC could be a potential therapeutic agent for the treatment of neurodegenerative disorders such as PD.

The management of post-operative (PO) pain has generally been shown to be inadequate; therefore, acquiring a novel understanding of PO pain mechanisms would increase the therapeutic options available. There is accumulating evidence to implicate

Migraine is a common neuronal disorder characterized by recurrent episodes of headache associated with a higher prevalence in women than men. Several risk factors have been associated with migraine disease as genetic factors, gender, and age. Although understanding migraine pathophysiology is improved, it has been reported that NOD-like receptor protein 3 (NLRP3) inflammasome pathway overactivation can contribute to migraine progression. Therefore, the aim of this study was to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in a mouse model of nitroglycerin (NTG)-induced migraine. The in vivo model of migraine was induced by intraperitoneal (i.p) injection of NTG (dose of 10 mg/kg). Mice were treated intraperitoneally with BAY-117082 at doses of 1 mg/kg, 5 mg/kg, and 10 mg/kg, 5 min following NTG injection. After 4 h of NTG injection, the whole brain tissue with the rostral spinal cord were collected and used to perform further analysis. Our results demonstrated that BAY-117082 treatments (5 mg/kg and 10 mg/kg) reduced pain attacks, hyperalgesia and photophobia more in female mice NTG-induced. Moreover, the treatment with BAY-117082 significantly reduced histological damage in the trigeminal nerve nucleus in female mice accordingly to significantly decreased in NLRP3 complex components expression levels such as ASC, IL-1β, IL-18, caspase-1 and TNF-α levels. Additionally, the treatment with BAY-117082 at both higher doses significantly modulated CREB/Erk/Akt pathways strictly correlated to the expression of neurotrophic factors. Taken together, obtained results confer new insight into the role of the NLRP3 inflammasome pathway in migraine pathogenesis, suggesting that BAY-117082 could be considered a novel strategy therapeutics for migraine treatment despite unconventional drug use.

Background Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. PD etiopathogenesis is multifactorial and not yet fully known, however, the scientific world advised the establishment of neuroinflammation among the possible risk factors. In this field, basic fibroblast growth factor/fibroblast growth factor receptor-1 (bFGF/FGFR1) could be a promising way to treat CNS-mediated inflammation; unfortunately, the use of bFGF as therapeutic agent is limited by its side effects. The novel synthetic compound SUN11602 exhibited neuroprotective activities like bFGF. With this perspective, this study aimed to evaluate the effect of SUN11602 administration in a murine model of MPTP-induced dopaminergic degeneration. Methods Specifically, nigrostriatal degeneration was induced by intraperitoneal injection of MPTP (80 mg/kg). SUN11602 (1 mg/kg, 2.5 mg/kg, and 5 mg/kg) was administered daily by oral gavage starting from 24 h after the first administration of MPTP. Mice were killed 7 days after MPTP induction. Results The results obtained showed that SUN11602 administration significantly reduced the alteration of PD hallmarks, attenuating the neuroinflammatory state via modulation of glial activation, NF-κB pathway, and cytokine overexpression. Furthermore, we demonstrated that SUN11602 treatment rebalanced Ca2+ overload in neurons by regulating Ca2+-binding proteins while inhibiting the apoptotic cascade. Conclusion Therefore, in the light of these findings, SUN11602 could be considered a valuable pharmacological strategy for PD.

Migraine is a common brain-disorder that affects 15% of the population. Converging evidence shows that migraine is associated with gastrointestinal disorders. However, the mechanisms underlying the interaction between the gut and brain in patients with migraine are not clear. In this study, we evaluated the role of the short-chain fatty acids (SCFAs) as sodium propionate (SP) and sodium butyrate (SB) on microbiota profile and intestinal permeability in a mouse model of migraine induced by nitroglycerine (NTG). The mice were orally administered SB and SP at the dose of 10, 30 and 100 mg/kg, 5 min after NTG intraperitoneal injections. Behavioral tests were used to evaluate migraine-like pain. Histological and molecular analyses were performed on the intestine. The composition of the intestinal microbiota was extracted from frozen fecal samples and sequenced with an Illumina MiSeq System. Our results demonstrated that the SP and SB treatments attenuated hyperalgesia and pain following NTG injection. Moreover, SP and SB reduced histological damage in the intestine and restored intestinal permeability and the intestinal microbiota profile. These results provide corroborating evidence that SB and SP exert a protective effect on central sensitization induced by NTG through a modulation of intestinal microbiota, suggesting the potential application of SCFAs as novel supportive therapies for intestinal disfunction associated with migraine.

Defects in cellular functions related to altered protein homeostasis and associated progressive accumulation of pathological intracellular material is a critical process involved in the pathogenesis of many neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Autophagy is an essential mechanism that ensures neuronal health by removing long-lived proteins or defective organelles and by doing so prevents cell toxicity and death within the central nervous system. Abundant evidence has shown that neuronal autophagy pathways are altered in Alzheimer's disease, Parkinson's disease and traumas of the central nervous system including Spinal Cord Injury and Traumatic Brain Injury. In this review, we aimed to summarize the latest studies on the role that altered neuronal autophagy plays in brain health and these pathological conditions, and how this knowledge can be leveraged for the development of novel therapeutics against them.

Psoriasis is an inflammatory and auto-immune skin-disease characterized by uncontrolled keratinocyte proliferation. Its pathogenesis is not still fully understood; however, an aberrant and excessive inflammatory and immune response can contribute to its progression. Recently, more attention has been given to the anti-inflammatory and immunomodulators effects of melatonin in inflammatory diseases. The aim of this paper was to investigate the effect of melatonin on psoriatic phenotype and also in S. aureus infection-associated psoriasis, with an in vitro model using Skinethic Reconstructed Human Epidermis (RHE). An in vitro model was constructed using the RHE, a three-dimensional-model obtained from human primary-keratinocytes. RHE-cells were exposed to a mix of pro-inflammatory cytokines, to induce a psoriatic phenotype; cells were also infected with S. aureus to aggravate psoriasis disease, and then were treated with melatonin at the concentrations of 1 nM, 10 nM, and 50 nM. Our results demonstrated that melatonin at higher concentrations significantly reduced histological damage, compared to the cytokine and S. aureus groups. Additionally, the treatment with melatonin restored tight-junction expression and reduced pro-inflammatory cytokine levels, such as interleukin-1β and interleukin-12. Our results suggest that melatonin could be considered a promising strategy for psoriasis-like skin inflammation, as well as complications of psoriasis, such as S. aureus infection.

Moderate traumatic brain injury (mTBI) has been associated with emotional dysregulation such as loss of consciousness, post-traumatic amnesia and major depressive disorder. The gene Leucine-rich repeat kinase 2 (LRRK2) is involved in protein synthesis and degradation, apoptosis, inflammation and oxidative stress, processes that trigger mTBI. The aim of this study was to investigate the role of LRRK2 in reducing depression-related symptoms after mTBI and to determine whether inhibition of LRRK2 mediated by PF-06447475 could have antidepressant effects. Moderate traumatic brain injury was induced by controlled cortical impact (CCI) and mice were treated with PF-06447475 at doses of 1, 2.5 and 5 mg/kg once daily for 14 days. We performed histological, immunohistochemical and molecular analyses of brain tissue 24 days after mTBI. Furthermore, the tissue changes found in the hippocampus and amygdala confirmed the depression-like behavior. PF-treatment with 06447475 significantly reduced the histological damage and behavioral disturbances. Thus, this study has shown that mTBI induction promotes the development of depression-like behavioral changes. LRRK2 inhibition showed an antidepressant effect and restored the changes in the copper/glutamate/N-methyl-D-aspartic acid receptor (Cu/NMDAR) system.

Primary brain tumors are a leading cause of death worldwide and are characterized by extraordinary heterogeneity and high invasiveness. Current drug and radiotherapy therapies combined with surgical approaches tend to increase the five-year survival of affected patients, however, the overall mortality rate remains high, thus constituting a clinical challenge for which the discovery of new therapeutic strategies is needed. In this field, novel immunotherapy approaches, aimed at overcoming the complex immunosuppressive microenvironment, could represent a new method of treatment for central nervous system (CNS) tumors. Chemokines especially are a well-defined group of proteins that were so named due to their chemotactic properties of binding their receptors. Chemokines regulate the recruitment and/or tissue retention of immune cells as well as the mobilization of tumor cells that have undergone epithelial–mesenchymal transition, promoting tumor growth. On this basis, this review focuses on the function and involvement of chemokines and their receptors in primary brain tumors, specifically examining chemokine-targeting immunotherapies as one of the most promising strategies in neuro-oncology.

Oral squamous cell carcinoma (OSCC) is a common human tumor, that originates from buccal mucosa and the tongue, associated with a high mortality rate. Currently, the treatment for OSCC involves surgery, chemotherapy and radiotherapy; however, survival outcomes for OSCC patients remain poor. For this reason, it is necessary to investigate new therapeutic strategies to counteract the progression of OSCC. In this study, we aimed to evaluate the role of dimethyl fumarate (DMF) in modulation of OSCC progression, both in vitro and in an in vivo orthotopic xenograft model. In vitro results revealed that DMF was able to reduce the expression of anti-apoptotic factors as BCL-2 and increased the expression of pro-apoptotic factors as Bax, Caspase-3 and BID. DMF appears to be involved in the modulation of oxidative stress mediators, such as MnSOD and HO-1. Furthermore, DMF showed to reduce the migratory ability of tumor cells and to modulate the expression of markers of epithelial-mesenchymal transition (EMT), as N-cadherin and E-cadherin. The in vivo study confirmed the data obtained in vitro significantly decreasing tumor mass and also reducing oxidative stress and apoptosis. Therefore, based on these results, the use of DMF could be considered a promising strategy to counteract oral cancer progression.

High-grade brain tumors are malignant tumors with poor survival and remain the most difficult tumors to treat. An important contributing factor to the development and progression of brain tumors is their ability to evade the immune system. Several immunotherapeutic strategies including vaccines and checkpoint inhibitors have been studied to improve the effectiveness of the immune system in destroying cancer cells. Recent studies have shown that kinase inhibitors, capable of inhibiting signal transduction cascades that affect cell proliferation, migration, and angiogenesis, have additional immunological effects. In this review, we explain the beneficial therapeutic effects of novel small-molecule kinase inhibitors and explore how, through different mechanisms, they increase the protective antitumor immune response in high-grade brain tumors.

Background: There is a growing realization that the gut–brain axis signaling is critical for maintaining the health and homeostasis of the Central Nervous System (CNS) and the intestinal environment. The role of Short-Chain Fatty Acids (SCFAs), such as Sodium Propionate (SP) and Sodium Butyrate (SB), has been reported to counteract inflammation activation in the central and Enteric Nervous System (ENS). Methods: In this study, we evaluated the role of the SCFAs in regulating the pathophysiology of migraine and correlated dysregulations in the gut environment in a mouse model of Nitroglycerine (NTG)-induced migraine. Results: We showed that, following behavioral tests evaluating pain and photophobia, the SP and SB treatments attenuated pain attacks provoked by NTG. Moreover, treatments with both SCFAs reduced histological damage in the trigeminal nerve nucleus and decreased the expression of proinflammatory mediators. Ileum evaluation following NTG injection reported that SCFA treatments importantly restored intestinal mucosa alterations, as well as the release of neurotransmitters in the ENS. Conclusions: Taken together, these results provide evidence that SCFAs exert powerful effects, preventing inflammation through the gut–brain axis, suggesting a new insight into the potential application of SCFAs as novel supportive therapies for migraine and correlated intestinal alterations.

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and radiotherapy, however, the survival rate of patients with OSCC remains low, thus new therapies are needed. It has been proven that excessive NLRP3 inflammasome activation and apoptosis alteration may contribute to oral cancer progression. This study aimed to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in an in vitro and in vivo xenograft model of oral cancer. In vitro results revealed that BAY-117082 at concentrations of 5, 10, and 30 µM was able to reduce OSCC cell viability. BAY-117082 at higher concentrations significantly reduced NLRP3, ASC, caspase-1, IL-1β, and IL-18 expression. Moreover, Bax, Bad, and p53 expression were increased, whereas Bcl-2 expression was reduced. Furthermore, the in vivo study demonstrated that BAY-117082 at doses of 2.5 and 5 mg/kg significantly decreased subcutaneous tumor mass, and also reduced NLRP3 inflammasome pathway activation. Therefore, based on these results, the use of BAY-117082 could be considered a promising strategy to counteract oral cancer progression, thanks its ability to modulate the NLRP3 inflammasome and apoptosis pathways.

Background: Intestinal ischemia/reperfusion injury (IRI) remains a clinical event that contributes to high morbidity and mortality rates. Intestinal epithelium is exposed to histological and vascular changes following tissue ischemia. Prolyl endopeptidase (PREP), involved in inflammatory responses, could be targeted for recovery from the permanent consequences following intestinal ischemia. Our aim was to investigate the role of PREP inhibitor KYP-2047 in tissue damage, angiogenesis, and endothelial barrier permeability after intestinal IRI in mice. Methods: KYP-2047 treatments were performed 5 min prior to intestinal damage. Intestinal IRI was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by 1 h of reperfusion. Results: PREP inhibition by KYP-2047 treatment reduced intestinal IR-induced histological damage and neutrophil accumulation, limiting inflammation through decrease of NF-ĸB nuclear translocation and fibrotic processes. KYP-2047 treatment restored barrier permeability and structural alteration following intestinal IRI, attenuating neovascular processes compromised by ischemia/reperfusion. Additionally, loss of epithelial cells during intestinal ischemia occurring by apoptosis was limited by KYP-2047 treatment, which showed strong effects counteracting apoptosis and DNA damage. Conclusions: These findings provide the first evidence that PREP inhibition through KYP-2047 inhibitor use could be a validate strategy for resolving alterations of intestinal epithelium the pathophysiology of intestinal disease.

Objective: The skin acts as a mechanical and protective barrier against viral, fungal, and bacterial infections. Skin conditions such as atopic dermatitis and psoriasis are characterized by alterations of the skin barrier, often caused by injury and by bacterial infections. In the last years, non-pharmacological interventions have gained great importance in epidermis-related diseases. Xyloglucan (XG) is a polysaccharide that possesses a “mucin-like” molecular structure that confers mucoadhesive properties, allowing XG-containing formulations to act as a protective barrier for the management of different diseases. Moreover, there is also increasing interest in the use of proteins due to their film-forming features. This study aimed to evaluate the barrier-protective properties of a product containing XG and pea protein (PP) in an in vitro model, assessing its effects on the membrane permeability of keratinocytes infected by Staphylococcus aureus. Methods: HaCaT keratinocytes were pretreated with XG and PP for 3 h and then infected with S. aureus cells (106 bacteria/well) at a multiplicity of infection of 10 for 1 h. The number of bacterial colonies and membrane integrity were measured, respectively. Results: We observed that pretreatment with XG and PP in human HaCaT keratinocytes infected with S. aureus significantly increased trans-epithelial electrical resistance (a marker of skin barrier function) measurement, reduced lucifer yellow (a marker of membrane integrity) permeation across the monolayer, and released lactate dehydrogenase (a marker of tissue damage). Moreover, XG and PP pretreatment was able to reduce bacterial adherence, avoiding S. aureus infection. Conclusion: In summary, we demonstrated that the product containing XG and PP was able to maintain barrier permeability preserving its integrity, and therefore, it can be considered as an interesting approach for the management of epidermis-related diseases.

Natural approaches to conventional pharmaceutical treatments for urinary tract infections (UTIs) have focused attention toward reducing the colonization of intestinal Escheri­chia coli reservoirs, the cause of ascending and hematogenous UTIs. In this study, we evaluated the protective effect of xyloglucan and xyloglucan plus gelose on intestinal and urinary epithelia in an in vivo E. coli infection model. Preventative xyloglucan and xyloglucan plus gelose oral treatments were performed by gavage 2 days before E. coli administration and every day until day 7. In vitro, xyloglucan had no effect on bacterial growth, cell morphology, or integrity. The results clearly demonstrated the protective barrier effect of xyloglucan in the bladder and intestine, as evidenced by a reduction in histological changes, neutrophil infiltration, and tight junction permeability in the intestine following E. coli infection. The potential beneficial effect of xyloglucan in preventing UTIs was supported by a reduction of E. coli-positive colony-forming units in the urinary tract. We consider xyloglucan in association with gelose to be an effective oral medical device for the prevention of extraintestinal UTIs.

The management of post-operative (PO) pain has generally been shown to be inadequate; therefore, acquiring a novel understanding of PO pain mechanisms would increase the therapeutic options available. There is accumulating evidence to implicate N-methyl-d-aspartate (NMDA) receptors in the induction and maintenance of central sensitization during pain states by reinforcing glutamate sensory transmission. It is known that DMF protects from oxidative glutamate toxicity. Therefore, NMDA receptor antagonists have been implicated in peri-operative pain management. Recent advances demonstrated that dimethyl fumarate (DMF), a non-opioid and orally bioavailable drug, is able to resolve neuroinflammation through mechanisms that drive nociceptive hypersensitivity. Therefore, in this study, we evaluated the role of DMF on pain and neuroinflammation in a mouse model of PO pain. An incision of the hind paw was performed, and DMF at two different doses (30 and 100 mg/kg) was administered by oral gavage for five consecutive days. Mechanical allodynia, thermal hyperalgesia and locomotor dysfunction were evaluated daily for five days after surgery. Mice were sacrificed at day 7 following PO pain induction, and hind paw and lumbar spinal cord samples were collected for histological and molecular studies. DMF administration significantly reduced hyperalgesia and allodynia, alleviating motor disfunction. Treatment with DMF significantly reduced histological damage, counteracted mast cell activation and reduced the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) inflammatory pathway, in addition to downregulating tumor necrosis factor-α (TNF-α), Interleukin-1β (Il-1β) and Il-4 expression. Interestingly, DMF treatment lowered the activation of NMDA receptor subtypes (NR2B and NR1) and the NMDA-receptor-interacting PDZ proteins, including PSD93 and PSD95. Furthermore, DMF interfered with calcium ion release, modulating nociception. Thus, DMF administration modulated PO pain, managing NMDA signaling pathways. The results suggest that DMF positively modulated persistent nociception related to PO pain, through predominantly NMDA-receptor-operated calcium channels.

Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0–4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15–20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats, this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.

Intracellular protein trafficking via the endosomes plays a key role in the maintenance of normal neuronal function. Although many diseases of the central nervous system exhibit specific pathological hallmarks, abnormalities of the endosome system are common traits for several of them including Alzheimer's disease (AD). Three main routes originate from the endosomes: the recycling, the degradation and the retrograde pathway. Studies have shown that the majority of Down syndrome subjects develop AD pathology and manifest altered morphology and number of endosomes, abnormalities in lysosome acidification and exosome secretion suggesting that dysfunction of one of these pathways could play a functional role in the AD-like phenotype of the syndrome. Two of the major endosomal routes are mediated by the retromer complex, a multimeric system responsible for transport of cargo from the endosome to the trans-Golgi network or to the cell membrane. Recently, a new endosome system structurally related to the retromer, called "retriever', has been reported. While we know a lot about the neuropathophysiology of the retromer complex, no precise pathogenic role for the retriever has been identified yet. Here, we will review the neurobiology of the endosome system and its role as key player in the development of AD-like pathology in Down syndrome. Additionally, we will discuss current knowledge on these two main endosome systems, retromer and retriever, and their potential as novel therapeutic targets. This article is protected by copyright. All rights reserved.

Inflammatory bowel diseases (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) represent gastrointestinal (GI) disorders associated with varied responses to microbial and environmental agents. Natural compounds have been suggested as a valid approach to the management of various GI diseases, particularly the green alga Ulva pertusa, belonging to the Ulvaceae family, which showed powerful biological properties. Here, we aimed to evaluate the effect and the mechanism of Ulva pertusa treatments in a murine model of DNBS-induced colitis. Colitis was induced by DNBS intrarectal installation (4 mg in 100 μL of 50% ethanol), while Ulva pertusa treatments (doses of 10, 50 and 100 mg/kg) were administered orally daily. Ulva pertusa, at the higher doses of 50 and 100 mg/kg, significantly reduced tissue damage DNBS-induced and the consequent inflammatory cascade via NF-κB inhibition. Furthermore, we demonstrated, for the first time, Ulva pertusa action on the SIRT1/Nrf2 axis, enhancing antioxidant response and the modulation of the apoptosis pathway colitis-induced, regulating the expression of p53, Bax, Bcl-2, and Caspases. Taken together, Ulva pertusa could be considered a valid approach for counteracting and blocking the progression of IBDs through modulation of the NF-κB/SIRT1/Nrf2 axis.

Traumatic brain injury (TBI) provokes primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) manages numerous aspects of cellular growth, and it is up‐regulated after moderate to severe traumatic brain injury (TBI). Currently, the significance of this increased signalling event for the recovery of brain function is unclear; therefore, we used two different selective inhibitors of mTOR activity to discover the functional role of mTOR inhibition in a mouse model of TBI performed by a controlled cortical impact injury (CCI). Treatment with KU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin as well‐known inhibitor of mTOR, was performed 1 and 4 hours subsequent to TBI. Results proved that mTOR inhibitors, especially KU0063794, significantly improved cognitive and motor recovery after TBI, reducing lesion volumes. Also, treatment with mTOR inhibitors ameliorated the neuroinflammation associated with TBI, showing a diminished neuronal death and astrogliosis after trauma. Our findings propose that the involvement of selective mTORC1/2 inhibitor may represent a therapeutic strategy to improve recovery after brain trauma.

A breached nasal epithelial barrier plays an important role in driving allergic rhinitis (AR). Corticosteroids remain the standard of care (SoC) but come with side effects, thus alternative safe and effective treatments able to avoid inflammation and restore barrier integrity are needed. The aim of the present study is to evaluate the barrier-forming capacity of a xyloglucan-based nasal spray (XG) and compare its efficacy to several SoC treatments (corticosteroid spray, oral mast-cell stabilizer and oral antihistamine) in reducing allergic responses in addition to its effect when concomitantly administered with an antihistamine. An ovalbumin (OVA)-induced mouse AR model was used. XG shows a significant efficacy in reducing histological damage in AR mice, improves nasal rubbing and histamine-induced hyper-responsiveness. Total and OVA-specific IgE as well as pro-inflammatory cytokines are significantly reduced compared to OVA challenged-mice, with im-proved efficacy when used as an add-on treatment. However, XG reduces mucous secreting cells (PAS-positive) and mucin mRNA expression similar to the corticosteroid-treated mice. XG-spray maintains tight junction protein expression (ZO-1) and conversely decreases HDAC1 significantly, the latter being highly expressed in AR patients. Moreover, the concomitant treatment showed in all of the endpoints a similar efficacy to the corticosteroids. This innovative approach may represent a novel therapeutic strategy for nasal respiratory diseases like AR, reducing undesirable side effects and improving the quality of life in patients.

Glioblastoma (GBM) is a brain tumor characterized by poor therapeutic response and overall survival. Despite relevant progress in conventional treatments represented by the clinical use of temozolomide (TMZ), a combination of approaches might be a possible future direction for treating GBM. Transforming growth factor-beta-activated kinase-1 (TAK1) is an essential component in genotoxic stresses-induced NF-&kappa, B-activation and mitogen-activated protein kinase (MAPK)-pathways, however, the role of TAK1 in GBM-chemoresistance remains unknown. This study aimed to verify, in GBM human cell lines, in an in vivo U87-xenograft model and in TMZ-treated-patients, the effect of TAK1 inhibition on the sensitivity of GBM cells to chemotherapy. In vitro model, using GBM cell lines, showed that 5Z-7-oxozeaenol augmented the cytotoxic effects of TMZ, blocking TMZ-induced NF-&kappa, B-activation, reducing DNA-damage and enhancing TMZ-induced apoptosis in GMB cell lines. We showed a reduction in tumor burden as well as tumor volume in the xenograft model following the treatment with 5Z-7-oxozaenol associated with TMZ. Our results showed a significant up-regulation in TAK1, p-p38, p-JNK and NF-&kappa, B in glioblastoma TMZ-treated-patients and denoted the role of 5Z-7-oxozeaenol in increasing the sensitivity of GBM cells to chemotherapy, proving to be an effective coadjuvant to current GBM chemotherapeutic regimens, suggesting a new option for therapeutic treatment of GBM.

Oral squamous cell-carcinoma (OSCC) is a common cancer which arises from the alveolar ridge, buccal mucosa, and tongue. Among OSCC, the incidence of tongue squamous cell-carcinoma (TSCC) is growing all over the world. Oral carcinogenesis has been linked to genetic mutations, chromosomal aberrations and viral factors. Apoptosis and angiogenesis play a key role in the development of oral cancer. Therefore, it is very important discover new therapeutic strategies to counteract oral cancer progression. This study aimed to investigate the effect of KYP-2047 in an in vitro model of TSCC and in vivo CAL27-xenograft model. Our results demonstrated that KYP-2047 was able to reduce TSCCs cell viability at the concentrations of 50 μM and 100 μM. Additionally, KYP-2047 was able to increase Bax, Bad and caspase-3 expression, whereas Bcl-2 and p53 expression were reduced. Moreover, KYP-2047 significantly reduced vascular-endothelial-growth-factor (VEGF) and endothelial-nitric-oxide-synthase (eNOS) expression. In the vivo xenograft model, KYP-2047 at doses of 1 and 5 mg/kg significantly reduced tumor burden and tumor weight, decreasing also angiogenesis markers VEGF and eNOS. Moreover, KYP-2047 increased Bax and reduced Bcl2 expressions. Thus, KYP-2047 could represent a potential therapeutic treatment to counteract tongue oral-cancer growth, thanks its abilities to modulate angiogenesis and apoptosis pathways.

Neuroinflammation and autoimmune mechanisms have a key part in the pathogenesis of Parkinson&rsquo, s disease (PD). Therefore, we evaluated the role of Toll-like receptors (TLRs) as a link between inflammation and autoimmunity in PD. An in vivo model of PD was performed by administration of 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) at the dose of 20 mg/kg every 2 h for a total administration of 80/kg, both in single Knock Out (KO) mice for TLR7, TLR 8, and TLR9 and in double KO mice for TLR 7/8-/-. All animals were compared with WT animals used as a control group. All animals were sacrificed after 7 days form the first administration of MPTP. The genetic absence of TLR 7 and 8 modified the PD pathway, increasing the immunoreactivity for TH and DAT compared to PD groups and decreasing microglia and astrocytes activation. Moreover, the deletion of TLR7 and TLR8 significantly reduced T-cell infiltration in the substantia nigra and lymph nodes, suggesting a reduction of T-cell activation. Therefore, our result highlights a possibility that an immunotherapy approach, by using a dual antagonist of TLR 7 and 8, could be considered as a possible target to develop new therapies for Parkinson diseases.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a multifactorial chronic gastrointestinal disorder characterized by inflammation and immune response. In this context, NLRP3 over-activation is associated with a breakdown of enteric-immune balance related to IBS-D. The aim of this study was to evaluate the effect of the inflammasome inhibitor, BAY 11-7082, in a rat model of IBS-D. Syndrome was induced by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and sacrificed 2 weeks after IBS-D induction. BAY 11-7082 (10 and 30 mg/kg) was administered daily by oral gavage. The results obtained showed that the treatment with BAY 11-7082 (30 mg/kg) significantly reduced tissue injury characterized by edema, neutrophil infiltration, and loss of colon structure. We demonstrated that BAY 11-7082 treatment inhibited NLRP3 inflammasome activation and NF-kB translocation, reducing inflammatory mediators. Moreover, treatment with BAY 11-7082 restored tight junction alteration following IBS-D induction and reduced the restraint stress. Taken together, our data demonstrate that IBS-D induced NLRP3 inflammasome pathway activation, accompanied by the production of proinflammatory response. The modulation of the inflammosome pathway with BAY 11-7082 inhibitor significantly reduced pathological signs of IBS-D, therefore, can be considered a valuable strategy to reduce the development of IBS-D.

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin, characterized by dryness and more or less severe itching. The etiology of AD is complex and has not been fully clarified, involving genetic susceptibility, immunological abnormalities, epidermal barrier dysfunction, and environmental factors. Xyloglucan (XG) and pea protein (PP) are two compounds of natural origin characterized by the ability to create a physical barrier that protects mucosae membranes, reducing inflammation. The aim of the present study was to evaluate the potential beneficial effects of XG + PP in both a mouse model of AD and Staphylococcus aureus (S.aureus) infection- associated AD. Mice were topically treated with 200 &mu, L of 0.5% oxazolone on the dorsal skin three times a week for AD induction. Mice received XG and PP by topical administration 1 h before oxazolone treatment. In S. aureus infection-associated AD, to induce a superficial superinfection of the skin, mice were also treated with 5 &mu, L of 108 of a culture of S. aureus for 2 weeks, mice superinfected received XG and PP by topical administration 1 h before oxazolone + S. aureus. Four weeks later, the skin was removed for histological and biochemical analysis. Our results demonstrated the protective barrier effects of XG and PP characterized by a reduction in histological tissue changes, mastocyte degranulation, and tight junction permeability in the skin following oxazolone treatment. Moreover, XG + PP was able to preserve filaggrin expression, a hallmark of AD. Our data also support the effectiveness of XG + PP to reduce the damage by superinfection post AD induced by S. aureus. In conclusion, a future product containing XG and PP could be considered as a potentially interesting approach for the treatment of AD.

Chronic venous insufficiency (CVI) is a common disorder associated with a variety of symptoms in later disease stages; despite the high prevalence of this pathology, suitable pharmaceutical therapies have not been explored to date. In this context, it was recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins. Recent evidence demonstrate that flavonoids are natural substances that convey the circulatory system functionality, playing a key role in blood flow. Particularly, troxerutin, diosmin and horse chestnut extract, appear protective for the management of vascular diseases. The aim of the present study was to evaluate the effect of a flavonoid compound, containing troxerutin, diosmin and horse chestnut extract on in vitro model on HUVECs cells, due to its production of vasculoregulatory and vasculotropic molecules, on an ex-vivo model on mesenteric vessel contraction, to regularize mesenteric microcirculation and on in vivo model of CVI-induced by saphene vein ligation. Furthermore, the flavonoid compound capacity of extensibility and compatibility with peripheral veins was investigated through a tissue block culture study. The degree of absorption, the contractile venous activity, the histological analysis, the immunoistochemical and immunofluorescence evaluation for VEGF and CD34 were performed, together with inflammatory mediators dosage. For the first time, this research revealed the therapeutic potential of a compound, enriched with flavonoids, to be a supportive treatment, suitable to reduce varicose vein pathophysiology and to regularize venous tone.

Traumatic brain injury (TBI) induce primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) mediates many aspects of cell growth and regeneration and is up-regulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signalling event for recovery of brain function is presently unclear, here we used two different selective inhibitors of mTOR activity to explore the functional role of mTOR inhibition in an validated model of TBI, the controlled cortical impact injury (CCI). We treated animals withKU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin a well-known inhibitor of mTOR, 1 and 4 hours after TBI. Our results demonstrated that mTOR inhibitors, especially KU0063794, significantly improve motor and cognitive recovery after TBI as well as reduce lesion volumes. Moreover we observed that mTOR inhibitors treatment ameliorate the neuroinflammation associated to TBI and showed that this acute treatment significantly diminished the extent of neuronal death, astrogliosis and apoptotic process after trauma. Our findings suggest that the neuronal mTORC1/2 activity after TBI is deleterious to brain function and acute intervention with selective mTORC1/2 inhibitor may represent an effective therapeutic strategy to improve recovery after brain trauma.

Rare diseases constitute a wide range of disorders thus defined for their low prevalence. However, taken together, rare diseases impact a considerable percentage of the world population, thus representing a public healthcare problem. In particular, neurofibromatoses are autosomal-dominant genetic disorders that include type 1 neurofibromatosis (NF1), type 2 neurofibromatosis (NF2) and schwannomatosis. Each of the three types is a genetically distinct disease with an unpredictable clinical course and for which there is still no resolutive cure. Therefore, a personalized therapeutic approach directed at improving the symptomatology as well as the search for new pharmacological strategies for the management of neurofibromatosis represents a priority for positive outcomes for affected patients. The coronavirus disease 2019 (COVID-19) pandemic has severely affected health systems around the world, impacting the provision of medical care and modifying clinical surveillance along with scientific research procedures. COVID-19 significantly worsened exchanges between healthcare personnel and neurofibromatosis patients, precluding continuous clinical monitoring in specialized clinic centers. In this new scenario, our article presents, for the first time, a comprehensive literature review on the clinical challenges for neurofibromatosis clinical care and research during the COVID-19 pandemic health emergency. The review was performed through PubMed (Medline) and Google Scholar databases until December 2021.

Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by blood circulation disorder caused by various factors, such as traumatic shock, surgery, organ transplantation, and thrombus. Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. The kidney is a highly perfused organ, sensitive to ischemia and reperfusion injury, and the incidence of renal IRI has high morbidity and mortality. Several studies showed that infiltration of inflammatory cells, apoptosis, and angiogenesis are important mechanisms involved in renal IRI. Despite advances in research, effective therapies for renal IRI are lacking. Recently it has been demonstrated the role of KYP2047, a selective inhibitor of prolyl oligopeptidase (POP), in the regulation of inflammation, apoptosis, and angiogenesis. Thus, this research focused on the role of POP in kidney ischemia/reperfusion (KI/R). An in vivo model of KI/R was performed and mice were subjected to KYP2047 treatment (intraperitoneal, 0.5, 1 and 5 mg/kg). Histological analysis, Masson’s trichrome and periodic acid shift (PAS) staining, immunohistochemical and Western blots analysis, real-time PCR (RT-PCR) and ELISA were performed on kidney samples. Moreover, serum creatinine and blood urea nitrogen (BUN) were quantified. POP-inhibition by KYP2047 treatment, only at the doses of 1 and 5 mg/kg, significantly reduced renal injury and collagen amount, regulated inflammation through canonical and non-canonical NF-κB pathway, and restored renal function. Moreover, KYP2047 modulated angiogenesis markers, such as TGF-β and VEGF, also slowing down apoptosis. Interestingly, treatment with KYP2047 modulated PP2A activity. Thus, these findings clarified the role of POP inhibition in AKI, also offering novel therapeutic target for renal injury after KI/R.