DKK3 Expression in Glioblastoma: Correlations with Biomolecular Markers.

Glioblastoma is the most common malignant primary tumor of the CNS. The prognosis is dismal, with a median survival of 15 months. Surgical treatment followed by adjuvant therapies such as radiotherapy and chemotherapy characterize the classical strategy. The WNT pathway plays a key role in cellular proliferation, differentiation, and invasion. The DKK3 protein, capable of acting as a tumor suppressor, also appears to be able to modulate the WNT pathway. We performed, in a series of 40 patients, immunohistochemical and Western blot evaluations of DKK3 to better understand how the expression of this protein can influence clinical behavior. We used a statistical analysis, with correlations between the expression of DKK3 and overall survival, age, sex, Ki-67, p53, and MGMT and IDH status. We also correlated our data with information included in the cBioPortal database. In our analyses, DKK3 expression, in both immunohistochemistry and Western blot analyses, was reduced or absent in many cases, showing downregulation. To date, no clinical study exists in the literature that reports a potential correlation between IDH and MGMT status and the WNT pathway through the expression of DKK3. Modulation of this pathway through the expression of DKK3 could represent a new tailored therapeutic strategy in the treatment of glioblastoma.

Correction: Casili et al. Therapeutic Potential of BAY-117082, a Selective NLRP3 Inflammasome Inhibitor, on Metastatic Evolution in Human Oral Squamous Cell Carcinoma (OSCC). Cancers 2023, 15, 2796.

In the original publication [...].

Efficacy of an oral suspension containing xyloglucan and pea proteins on a murine model of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is the most common foregut disease, affecting about 20% of the adult population. Esophageal epithelial barrier plays a fundamental role in the pathophysiology of GERD; however, pharmacological therapies mainly aim to reduce the acidity of the gastroesophageal environment rather than to protect esophageal tissue integrity. This study aims to evaluate the efficacy of an oral solution containing xyloglucan and pea proteins (XP) in reestablishing gastroesophageal tissue integrity and biochemical markers. To induce GERD, C57BL/6 mice were alternatively overfed and fasted for 56 days and then treated with XP, sodium alginate, omeprazole, or omeprazole+XP twice daily for 7 days. Gastric pain and inflammatory markers were evaluated after 3 and 7 days of treatment. After sacrifice, the esophagi and stomachs were surgically removed for macroscopic and histological examination. Gastric pain was significantly reduced at days 3 and 7 by XP, omeprazole, and omeprazole+XP, while alginates were ineffective at day 3. XP was able to diminish gastric macroscopic damage and demonstrated the same efficacy as omeprazole in reducing esophageal damage. XP significantly reduced histological damage, with an efficacy comparable to that of omeprazole, but superior to alginates. Inflammatory markers were significantly reduced by XP, with superior efficacy compared with alginates at day 7. Interestingly, XP was also able to significantly increase gastric pH. This study demonstrated that XP restored gastric homeostasis, improved esophageal integrity, and decreased inflammation and pain with a similar efficacy to omeprazole and greater than alginates.

bFGF-like Activity Supported Tissue Regeneration, Modulated Neuroinflammation, and Rebalanced Ca2+ Homeostasis following Spinal Cord Injury.

A spinal cord injury (SCI) is a well-defined debilitating traumatic event to the spinal cord that usually triggers permanent changes in motor, sensory, and autonomic functions. Injured tissue becomes susceptible to secondary mechanisms caused by SCIs, which include pro-inflammatory cytokine release, the activation of astrocytes and microglia, and increased neuronal sensibility. As a consequence, the production of factors such as GFAP, IBA-1, TNF-α, IL-1ß, IFN-γ, and S100-ß slow down or inhibit central nervous system (CNS) regeneration. In this regard, a thorough understanding of the mechanisms regulating the CNS, and specifically SCI, is essential for the development of new therapeutic strategies. It has been demonstrated that basic fibroblast growth factor (bFGF) was successful in the modulation of neurotrophic activity, also promoting neurite survival and tissue repair, thus resulting in the valuable care of CNS disorders. However, bFGF therapeutic use is limited due to the undesirable effects developed following its administration. Therefore, the synthetic compound mimetic of bFGF, SUN11602 (with chemical name 4-[[4-[[2-[(4-Amino-2,3,5,6-tetramethylphenyl)amino]acetyl]methylamino]-1-piperidinyl]methyl]benzamide), has been reported to show neuroprotective activities similar to those of bFGF, also demonstrating a good pharmacokinetic profile. Here, we aimed to investigate the neuroprotective activity of this bFGF-like compound in modulating tissue regeneration, neuroinflammation, and Ca2+ overload by using a subacute mouse model of SCI. SUN11602 (1, 2.5, and 5 mg/kg) was administered orally to mice for 72 h daily following the in vivo model of SCI, which was generated by the extradural compression of the spinal cord. The data obtained demonstrated that SUN11602 treatment considerably decreased motor alteration and diminished the neuroinflammatory state through the regulation of glial activation, the NF-κB pathway, and kinases. Additionally, by controlling Ca2+-binding proteins and restoring neurotrophin expression, we showed that SUN11602 therapy restored the equilibrium of the neuronal circuit. Because of these findings, bFGF-like compounds may be an effective tool for reducing inflammation in SCI patients while enhancing their quality of life.

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro.

BACKGROUND: Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis. METHODS: The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 µg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 µM, 10 µM and 50 µM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses. RESULTS: The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis. CONCLUSION: In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways.

An RNAi-Mediated Reduction in Transcription Factor Nrf-2 Blocks the Positive Effects of Dimethyl Fumarate on Metabolic Stress in Alzheimer's Disease.

The prevalence of obesity is rapidly rising around the world, and this will have a significant impact on our society as it is believed to be one of the leading causes of death. One of the main causes of these occurrences is added sugar consumption, which is associated with a higher risk of obesity, heart disease, diabetes, and brain illnesses such as Alzheimer's disease (AD). To this purpose, excess sugar might worsen oxidative damage and brain inflammation: two neuropathological signs of AD. Dimethyl fumarate (DMF) is an orally accessible methyl ester of fumaric acid with putative neuroprotective and immunomodulatory properties. In addition, DMF stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2), a key regulator of the antioxidant response mechanism in cells. The aim of the current study was to assess the potential therapeutic benefits of DMF in an in vitro model of metabolic stress induced by high and low sugar levels. We discovered that DMF reversed the negative impacts of high and low glucose exposure on the viability and oxidative stress of SH-SY5Y cells. Mechanistically, DMF's actions were mediated by Nrf-2. To this end, we discovered that DMF boosted the expression of the Nrf-2-regulated genes heme-oxygenase-1 (HO1) and manganese superoxide dismutase (MnSOD). More importantly, we found that inhibiting Nrf-2 expression prevented DMF's positive effects. Our combined findings suggest that DMF may be a valuable support for treatments for metabolic diseases.

Neuroprotective effects of GSK-343 in an in vivo model of MPTP-induced nigrostriatal degeneration.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal neurons, which causes disabling motor disorders. Scientific findings support the role of epigenetics mechanism in the development and progression of many neurodegenerative diseases, including PD. In this field, some studies highlighted an upregulation of Enhancer of zeste homolog 2 (EZH2) in the brains of PD patients, indicating the possible pathogenic role of this methyltransferase in PD. The aim of this study was to evaluate the neuroprotective effects of GSK-343, an EZH2 inhibitor, in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration. Specifically, nigrostriatal degeneration was induced by MPTP intraperitoneal injection. GSK-343 was administered intraperitoneally daily at doses of 1 mg/kg, 5 mg/kg and 10 mg/kg, mice were killed 7 days after MPTP injection. Our results demonstrated that GSK-343 treatment significantly improved behavioral deficits and reduced the alteration of PD hallmarks. Furthermore, GSK-343 administration significantly attenuated the neuroinflammatory state through the modulation of canonical and non-canonical NF-κB/IκBα pathway as well as the cytokines expression and glia activation, also reducing the apoptosis process. In conclusion, the obtained results provide further evidence that epigenetic mechanisms play a pathogenic role in PD demonstrating that the inhibition of EZH2, mediated by GSK-343, could be considered a valuable pharmacological strategy for PD.

Therapeutic Potential of BAY-117082, a Selective NLRP3 Inflammasome Inhibitor, on Metastatic Evolution in Human Oral Squamous Cell Carcinoma (OSCC).

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.

The Transcription Factor Nrf2 Mediates the Effects of Antrodia camphorata Extract on Neuropathological Changes in a Mouse Model of Parkinson's Disease.

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.

Efficacy of the Radical Scavenger, Tempol, to Reduce Inflammation and Oxidative Stress in a Murine Model of Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronically relapsing inflammatory skin disease, predominantly common in children; it is characterized by an eczematous pattern generally referable to skin dryness and itchy papules that become excoriated and lichenified in the more advanced stages of the disease. Although the pathophysiology of AD is not completely understood, numerous studies have demonstrated the complex interaction between genetic, immunological, and environmental factors, which acts to disrupt skin barrier function. Free radicals play a key role by directly damaging skin structure, inducing inflammation and weakening of the skin barrier. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a membrane-permeable radical scavenger, known to be a stable nitroxide, which exhibits excellent antioxidant effects in several human disorders, such as osteoarthritis and inflammatory bowel diseases. Considering the few existing studies on dermatological pathologies, this study aimed to evaluate tempol, in a cream formulation, in a murine model of AD. Dermatitis was induced in mice via dorsal skin application of 0.5% Oxazolone, three times a week for two weeks. After induction, mice were treated with tempol-based cream for another two weeks at three different doses of 0.5%, 1% and 2%. Our results demonstrated the ability of tempol, at the highest percentages, to counteract AD by reducing the histological damage, decreasing mast cell infiltration, and improving the skin barrier properties, by restoring the tight junction (TJs) and filaggrin. Moreover, tempol, at 1% and 2%, was able to modulate inflammation by reducing the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, as well as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß expression. Topical treatment also attenuated oxidative stress by modulating nuclear factor erythroid 2-related factor 2 (Nrf2), manganese superoxide dismutase (MnSOD), and heme oxygenase I (HO-1) expression levels. The obtained results demonstrate the numerous advantages provided by the topical administration of a tempol-based cream formulation, in reducing inflammation and oxidative stress through modulation of the NF-κB/Nrf2 signaling pathways. Therefore, tempol could represent an alternative anti-atopic approach to treating AD, thereby improving skin barrier function.

Role of Basic Fibroblast Growth Factor in Cancer: Biological Activity, Targeted Therapies, and Prognostic Value.

Cancer is the leading cause of death worldwide; thus, it is necessary to find successful strategies. Several growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF, FGF2), and transforming growth factor beta (TGF-ß), are involved in the main processes that fuel tumor growth, i.e., cell proliferation, angiogenesis, and metastasis, by activating important signaling pathways, including PLC-γ/PI3/Ca2+ signaling, leading to PKC activation. Here, we focused on bFGF, which, when secreted by tumor cells, mediates several signal transductions and plays an influential role in tumor cells and in the development of chemoresistance. The biological mechanism of bFGF is shown by its interaction with its four receptor subtypes: fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3, and FGFR4. The bFGF-FGFR interaction stimulates tumor cell proliferation and invasion, resulting in an upregulation of pro-inflammatory and anti-apoptotic tumor cell proteins. Considering the involvement of the bFGF/FGFR axis in oncogenesis, preclinical and clinical studies have been conducted to develop new therapeutic strategies, alone and/or in combination, aimed at intervening on the bFGF/FGFR axis. Therefore, this review aimed to comprehensively examine the biological mechanisms underlying bFGF in the tumor microenvironment, the different anticancer therapies currently available that target the FGFRs, and the prognostic value of bFGF.

Inhibition of LRRK2 Attenuates Depression-Related Symptoms in Mice with Moderate Traumatic Brain Injury.

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.

Redox Imbalance in Neurological Disorders in Adults and Children.

Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus-Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.

The Role of miR-128 in Neurodegenerative Diseases.

Several neurodegenerative disorders are characterized by the accumulation of misfolded proteins and are collectively known as proteinopathies. Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) represent some of the most common neurodegenerative disorders whose steady increase in prevalence is having a major socio-economic impact on our society. Multiple laboratories have reported hundreds of changes in gene expression in selective brain regions of AD, PD, and HD brains. While the mechanisms underlying these changes remain an active area of investigation, alterations in the expression of noncoding RNAs, which are common in AD, PD, and HD, may account for some of the changes in gene expression in proteinopathies. In this review, we discuss the role of miR-128, which is highly expressed in mammalian brains, in AD, PD, and HD. We highlight how alterations in miR-128 may account, at least in part, for the gene expression changes associated with proteinopathies. Indeed, miR-128 is involved, among other things, in the regulation of neuronal plasticity, cytoskeletal organization, and neuronal death, events linked to various proteinopathies. For example, reducing the expression of miR-128 in a mouse model of AD ameliorates cognitive deficits and reduces neuropathology. Overall, the data in the literature suggest that targeting miR-128 might be beneficial to mitigate the behavioral phenotype associated with these diseases.

Effect of a combination of pea protein, grape seed extract and lactic acid in an in vivo model of bacterial vaginosis.

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.

Evaluation of the Efficacy of Xyloglucan, Pea Protein and Opuntia ficus-indica Extract in a Preclinical Model of Psoriasis.

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.

Therapeutic Potential of Dimethyl Fumarate in Counteract Oral Squamous Cell Carcinoma Progression by Modulating Apoptosis, Oxidative Stress and Epithelial-Mesenchymal Transition.

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.

The Role of Neuro-Inflammation and Innate Immunity in Pathophysiology of Brain and Spinal Cord Tumors.

Inflammation and innate immune system play a central role in cancers, including those affecting the central nervous system (CNS). Currently, classification of neoplasms, especially regarding gliomas, is established on molecular mutations in isocitrate dehydrogenase (IDH) genes and the presence of co-deletion 1p/19q. Treatment, in most of brain and spinal cord tumors, is centered on surgery, radiotherapy and pharmacological approaches with chemotherapeutic agents. However, the results of the treatments, after several decades, are not completely satisfactory. Cytokines and angiogenic factors are closely linked to the brain cancer behavior. Moreover, recent studies suggest a link between inflammation and tumorigenesis, underlying the complex nature of this topic, especially the anti- and pro-tumoral activities of inflammation and the two-way interactions between immune and tumor cells. The current understanding of the mechanisms by which CNS cancer cells modulate the immune system, especially how bi-directional communications between immune cells and tumor cells create an immunosuppressed microenvironment, gives important information about the promotion of tumor survival and growth. Here, we have briefly reviewed the current literature on this topic, focusing on the possible role of inflammation and innate immunity involved in the origin and in the development of CNS tumors.

Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation.

Significance: Oxygen (O2) sensing is the fundamental process through which organisms respond to changes in O2 levels. Complex networks exist allowing the maintenance of O2 levels through the perception, capture, binding, transport, and delivery of molecular O2. The brain extreme sensitivity to O2 balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases (NDs). In this study, we wish to review the most relevant advances in O2 sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recent Advances: Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O2 imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation. Critical Issues: There is still a gap in knowledge concerning how O2 sensing plays a role in the above indicated neurodegenerations. Specifically, O2 concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O2 sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained. Future Directions: Future studies should focus on the precise characterization of O2 level disruption and O2 sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O2 sensing dysfunctions in these diseases. There is also the need to develop innovative therapies targeting this precise mechanism rather than its secondary effects, as early intervention is necessary. Antioxid. Redox Signal. 38, 160-182.