PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis.

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.

Evaluation of a Product Containing Xyloglucan and Pea Protein on Skin Barrier Permeability.

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.

Effect of a Product Containing Xyloglucan and Pea Protein on a Murine Model of Atopic Dermatitis.

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 µL 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 µL 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.

TBK1 Inhibitor Exerts Antiproliferative Effect on Glioblastoma Multiforme Cells.

Glioma are common malignant brain tumors, among which glioblastoma multiforme (GBM) has the worst prognosis. Different studies of GBM revealed that targeting nuclear factor B (NF-B) induced an attenuation tumor proliferation and prolonged cell survival. TBK1 {TANK [TRAF (TNF (tumor-necrosis-factor) receptor-associated factor)-associated NF-B activator]-binding kinase 1} is a serine/threonine protein kinase, and it is a member of the IB kinase (IKK) family involved in NF-B pathway activation. The aim of this study was to investigate the potential effect of BX795, an inhibitor of TBK1, in an in vitro and ex vivo model of GBM. GBM cell lines (U87 and U138) and primary GBM cells were treated with different concentrations of BX795 at different time points (24, 48, and 72h) to evaluate cell viability, autophagy, inflammation, and apoptosis. Our results demonstrated that BX795 10 M was able to reduce cell viability, showing antiproliferative effect in U87, U138, and primary GBM cells. Moreover, treatment with BX795 10 M increased the proapoptotic proteins Bax, p53, caspase 3, and caspase 9, whereas the antiapoptotic Bcl-2 expression was reduced. Additionally, our results showed a marked decrease in autophagy following BX795 treatment, reducing Atg 7, Atg 5/12, and AKT expression. The anti-inflammatory effect of BX795 was demonstrated by a significantly reduction in NIK, IKK, and TNF- expression, accompanied by a downregulation of angiogenesis. Furthermore, in primary GBM cell, BX795 10 M was able to reduce TBK1 pathway activation and SOX3 expression. In conclusion, these findings showed that TBK1 is involved in GBM proliferation, demonstrating that the inhibitor BX795, thanks to its abilities, could improve therapeutic strategies for GBM treatment.

Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.

Role of Fibroblast Growth Factors Receptors (FGFRs) in Brain Tumors, Focus on Astrocytoma and Glioblastoma.

Despite pharmacological treatments and surgical practice options, the mortality rate of astrocytomas and glioblastomas remains high, thus representing a medical emergency for which it is necessary to find new therapeutic strategies. Fibroblast growth factors (FGFs) act through their associated receptors (FGFRs), a family of tyrosine kinase receptors consisting of four members (FGFR1-4), regulators of tissue development and repair. In particular, FGFRs play an important role in cell proliferation, survival, and migration, as well as angiogenesis, thus their gene alteration is certainly related to the development of the most common diseases, including cancer. FGFRs are subjected to multiple somatic aberrations such as chromosomal amplification of FGFR1; mutations and multiple dysregulations of FGFR2; and mutations, translocations, and significant amplifications of FGFR3 and FGFR4 that correlate to oncogenesis process. Therefore, the in-depth study of these receptor systems could help to understand the etiology of both astrocytoma and glioblastoma so as to achieve notable advances in more effective target therapies. Furthermore, the discovery of FGFR inhibitors revealed how these biological compounds improve the neoplastic condition by demonstrating efficacy and safety. On this basis, this review focuses on the role and involvement of FGFRs in brain tumors such as astrocytoma and glioblastoma.