Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study.

Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.

Head and Neck Squamous Cell Carcinoma Vaccine: Current Landscape and Perspectives.

The treatment of unresectable or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has traditionally relied on chemotherapy or radiotherapy, yielding suboptimal outcomes. The introduction of immunotherapy has significantly improved HNSCC treatment, even if the long-term results cannot be defined as satisfactory. Its mechanism of action aims to counteract the blockade of tumor immune escape. This result can also be obtained by stimulating the immune system with vaccines. This review scope is to comprehensively gather existing evidence and summarize ongoing clinical trials focused on therapeutic vaccines for HNSCC treatment. The current landscape reveals numerous promising drugs in the early stages of experimentation, along with a multitude of trials that have been suspended or abandoned for years. Nonetheless, there are encouraging results and ongoing experiments that instill hope for potential paradigm shifts in HNSCC therapy.

Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome.

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia with consequent immune deficiency, cardiac malformations, hypoparathyroidism, facial and palatine abnormalities, variable degrees of cognitive impairment and psychiatric disorders. The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction. Neuroinflammation in DGS individuals could be directly related to the development of the syndrome's characteristic psychiatric and cognitive disorders. In patients with psychotic disorders, the most frequent psychiatric manifestation in DGS, Th-17, Th-1 and Th-2 cells are increased with consequent elevation of proinflammatory cytokine IL-6 and IL1ß. In patients with anxiety disorders, both CD3 and CD4 are increased. Some patients with autism spectrum disorders (ASDs) have an augmented level of proinflammatory cytokines IL-12, IL-6 and IL-1ß, while IFNγ and the anti-inflammatory cytokine IL-10 seem to be reduced. Other data proposed that altered synaptic plasticity could be directly involved in DGS cognitive disorders. In conclusion, the use of antioxidants for restoring mitochondrial functionality in DGS could be a useful tool to protect cortical connectivity and cognitive behavior.

Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea.

Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions.

Neurons, Nose, and Neurodegenerative Diseases: Olfactory Function and Cognitive Impairment.

Olfactory capacity declines with aging, but increasing evidence shows that smell dysfunction is one of the early signs of prodromal neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The study of olfactory ability and its role in neurodegenerative diseases arouses much interest in the scientific community. In neurology, olfactory impairment is a potential early marker for the onset of neurodegenerative diseases, but the underlying mechanism is poorly understood. The loss of smell is considered a clinical sign of early-stage disease and a marker of the disease's progression and cognitive impairment. Highlighting the importance of biological bases of smell and molecular pathways could be fundamental to improve neuroprotective and therapeutic strategies. We focused on the review articles and meta-analyses on olfactory and cognitive impairment. We depicted the neurobiology of olfaction and the most common olfactory tests in neurodegenerative diseases. In addition, we underlined the close relationship between the olfactory and cognitive deficit due to nasal neuroepithelium, which is a direct extension of the CNS in communication with the external environment. Neurons, Nose, and Neurodegenerative diseases highlights the role of olfactory dysfunction as a clinical marker for early stages of neurodegenerative diseases when it is associated with molecular, clinical, and neuropathological correlations.

The RNA-Binding Protein SMN as a Novel Player in Laryngeal Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium in the oral cavity, pharynx, sino-nasal region, and larynx. Laryngeal squamous cell carcinoma (LSCC) represents one-third of all head and neck cancers. Dysregulated RNA-related pathways define an important molecular signature in this aggressive carcinoma. The Survival Motor Neuron (SMN) protein regulates fundamental aspects of the RNA metabolism but, curiously, its role in cancer is virtually unknown. For the first time, here, we focus on the SMN in the cancer context. We conducted a pilot study in a total of 20 patients with LSCC where the SMN was found overexpressed at both the protein and transcript levels. By a cellular model of human laryngeal carcinoma, we demonstrated that the SMN impacts cancer-relevant behaviors and perturbs key players of cell migration, invasion, and adhesion. Furthermore, in LSCC we showed a physical interaction between the SMN and the epidermal growth factor receptor (EGFR), whose overexpression is an important feature in these tumors. This study proposes the SMN protein as a novel therapeutic target in LSSC and likely in the whole spectrum of HNSCC. Overall, we provide the first analysis of the SMN in human cancer.

Serum prokineticin-2 in prepubertal and adult Klinefelter individuals.

The prokineticin-2 (PROK2) is a small peptide belonging to the prokineticin family. In humans and rodents this chemokine is primarily involved in the control of central and peripheral reproductive processes. Klinefelter's syndrome (KS) is the first cause of male genetic infertility, due to an extra X chromosome, which may occur with a classical karyotype (47, XXY) or mosaic forms (46, XY/47, XXY). In affected subjects, pubertal maturation usually begins at an adequate chronological age, but when development is almost complete, they display a primary gonadal failure, with early spermatogenesis damage, and later onset of testosterone insufficiency. Thus, the main aim of the present study was to investigate the serum levels of PROK2 in prepubertal and adult KS patients, comparing them with healthy subjects. We showed for the first time the presence of PROK2 in the children serum but with significant changes in KS individuals. Indeed, compared with healthy subjects characterized by PROK2 serum elevation during the growth, KS individuals showed constant serum levels during the sexual maturation phase (higher during the prepubertal phase but lower during the adult age). In conclusion, these data indicate that in KS individuals PROK2 may be considered a biomarker for investigating the SK infertility process.

Antioxidant Intervention to Improve Cognition in the Aging Brain: The Example of Hydroxytyrosol and Resveratrol.

Both physiological and pathological aging processes induce brain alterations especially affecting the speed of processing, working memory, conceptual reasoning and executive functions. Many therapeutic approaches to reduce the impact of brain aging on cognitive functioning have been tested; unfortunately, there are no satisfactory results as a single therapy. As aging is partly contributed by free radical reactions, it has been proposed that exogenous antioxidants could have a positive impact on both aging and its associated manifestations. The aim of this report is to provide a summary and a subsequent review of the literature evidence on the role of antioxidants in preventing and improving cognition in the aging brain. Manipulation of endogenous cellular defense mechanisms through nutritional antioxidants or pharmacological compounds represents an innovative approach to therapeutic intervention in diseases causing brain tissue damage, such as neurodegeneration. Coherently with this notion, antioxidants, especially those derived from the Mediterranean diet such as hydroxytyrosol and resveratrol, seem to be able to delay and modulate the cognitive brain aging processes and decrease the occurrence of its effects on the brain. The potential preventive activity of antioxidants should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability, able to bypass the blood-brain barrier limitation, and that are well standardized.

Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies.

Aberrant expression of the programmed cell death protein ligand 1 (PD-L1) constitutes one of the main immune evasion mechanisms of cancer cells. The approval of drugs against the PD-1-PD-L1 axis has given new impetus to the chemo-therapy of many malignancies. We performed a literature review from 1992 to August 2022, summarizing evidence regarding molecular structures, physiological and pathological roles, mechanisms of PD-L1 overexpression, and immunotherapy evasion. Furthermore, we summarized the studies concerning head and neck squamous cell carcinomas (HNSCC) immunotherapy and the prospects for improving the associated outcomes, such as identifying treatment response biomarkers, new pharmacological combinations, and new molecules. PD-L1 overexpression can occur via four mechanisms: genetic modifications; inflammatory signaling; oncogenic pathways; microRNA or protein-level regulation. Four molecular mechanisms of resistance to immunotherapy have been identified: tumor cell adaptation; changes in T-cell function or proliferation; alterations of the tumor microenvironment; alternative immunological checkpoints. Immunotherapy was indeed shown to be superior to traditional chemotherapy in locally advanced/recurrent/metastatic HNSCC treatments.

NGF and the Male Reproductive System: Potential Clinical Applications in Infertility.

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. In recent studies, the potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p-ERK1/2/p-CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus-pituitary-gonadal axis (HPG) with the secretion of GnRH. Lastly, it has been shown that the physiology of mature sperm is affected by both exogenous and endogenous NGF. The NGF impact on the HPG axis and its effect on GnRH neurons might be exploited in the therapy of male hypogonadism or used as a protective strategy against gonadal dysfunction related to chemotherapeutic agents. Moreover, the improving effect of NGF on sperm motility and vitality could be useful to enhance assisted reproduction outcomes. NGF could be supplemented to cryopreserved sperm samples to counteract the oxidative stress induced by the frozen and thawing processes. Indeed, the potential clinical applications of NGF in male infertility treatment have been discussed.

Exploring Mitochondrial Localization of SARS-CoV-2 RNA by Padlock Assay: A Pilot Study in Human Placenta.

The ongoing COVID-19 pandemic dictated new priorities in biomedicine research. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is a single-stranded positive-sense RNA virus. In this pilot study, we optimized our padlock assay to visualize genomic and subgenomic regions using formalin-fixed paraffin-embedded placental samples obtained from a confirmed case of COVID-19. SARS-CoV-2 RNA was localized in trophoblastic cells. We also checked the presence of the virion by immunolocalization of its glycoprotein spike. In addition, we imaged mitochondria of placental villi keeping in mind that the mitochondrion has been suggested as a potential residence of the SARS-CoV-2 genome. We observed a substantial overlapping of SARS-CoV-2 RNA and mitochondria in trophoblastic cells. This intriguing linkage correlated with an aberrant mitochondrial network. Overall, to the best of our knowledge, this is the first study that provides evidence of colocalization of the SARS-CoV-2 genome and mitochondria in SARS-CoV-2 infected tissue. These findings also support the notion that SARS-CoV-2 infection can reprogram mitochondrial activity in the highly specialized maternal-fetal interface.

Proneurogenic and neuroprotective effect of a multi strain probiotic mixture in a mouse model of acute inflammation: Involvement of the gut-brain axis.

Neuroinflammation can severely affect brain homeostasis and adult hippocampal neurogenesis with detrimental effects on cognitive processes. Brain and gut are intimately connected via the "gut-brain axis", a bidirectional communication system, and the administration of live bacteria (probiotics) has been shown to represent an intriguing approach for the prevention or even the cure of several diseases. In the present study we evaluated the putative neuroprotective effect of 15-days consumption of a multi-strain probiotic formulation based on food-associated strains and human gut bacteria at the dose of 109 CFU/mouse/day in a mouse model of acute inflammation, induced by an intraperitoneal single injection of LPS (0.1 mg/kg) at the end of probiotic administration. The results indicate that the prolonged administration of the multi-strain probiotic formulation not only prevents the LPS-dependent increase of pro-inflammatory cytokines in specific regions of the brain (hippocampus and cortex) and in the gastrointestinal district but also triggers a potent proneurogenic response capable of enhancing hippocampal neurogenesis. This effect is accompanied by a potentiation of intestinal barrier, as documented by the increased epithelial junction expression in the colon. Our hypothesis is that pre-treatment with the multi-strain probiotic formulation helps to create a systemic protection able to counteract or alleviate the effects of LPS-dependent acute pro-inflammatory responses.

Alcohol binge-drinking damage on the vestibulo-oculomotor reflex.

PURPOSE: Binge drinking is associated with several adverse effects in multiple organs. This study aimed at evaluating the effects of a binge-like-drinking on the vestibulo-oculomotor reflex (VOR) using the video Head Impulse Test (vHIT) and the functional Head Impulse Test (fHIT). METHODS: Eleven healthy men (age range 32-35 years) with moderate drinking habits and no history of vestibular dysfunction were enrolled. A preliminary assessment of breath alcohol concentration (BrAC) to check for zero alcohol value and a pre-intake evaluation of VOR using the vHIT and the fHIT were carried on. Then, the subjects were asked to take drinks with different alcohol content (8-40% ethanol by volume) according to their choice, consuming at least 5 standard drinks. Volunteers stopped drinking after 3 h. After a further 30 min, post-intake BrAC measurements and VOR analysis were repeated. RESULTS: After alcohol intake, vHIT recorded an overall significant reduction of VOR gain (0.82 ± 0.07 on both sides) although the outcomes were below the normal range only in the four subjects with the highest blood alcohol levels. The post-intake fHIT outcomes were substandard in 9 participants, with a significant deterioration in performance (% of exact answers = 84.54 ± 11.05% on the left, 83.18 ± 14.53 on the right). CONCLUSIONS: Binge drinking severely affects VOR; fHIT seems more sensitive than vHIT in the assessment of VOR function for complex vestibular lesions, such as those determined by ethanol, suggesting that fHIT could support vHIT in vestibular dysfunction assessment.

Aberrant Early in Life Stimulation of the Stress-Response System Affects Emotional Contagion and Oxytocin Regulation in Adult Male Mice.

Results over the last decades have provided evidence suggesting that HPA axis dysfunction is a major risk factor predisposing to the development of psychopathological behaviour. This susceptibility can be programmed during developmental windows of marked neuroplasticity, allowing early-life adversity to convey vulnerability to mental illness later in life. Besides genetic predisposition, also environmental factors play a pivotal role in this process, through embodiment of the mother's emotions, or via nutrients and hormones transferred through the placenta and the maternal milk. The aim of the current translational study was to mimic a severe stress condition by exposing female CD-1 mouse dams to abnormal levels of corticosterone (80 µg/mL) in the drinking water either during the last week of pregnancy (PreCORT) or the first one of lactation (PostCORT), compared to an Animal Facility Rearing (AFR) control group. When tested as adults, male mice from PostCORT offspring and somewhat less the PreCORT mice exhibited a markedly increased corticosterone response to acute restraint stress, compared to perinatal AFR controls. Aberrant persistence of adolescence-typical increased interest towards novel social stimuli and somewhat deficient emotional contagion also characterised profiles in both perinatal-CORT groups. Intranasal oxytocin (0 or 20.0 µg/kg) generally managed to reduce the stress response and restore a regular behavioural phenotype. Alterations in density of glucocorticoid and mineralocorticoid receptors, oxytocin and µ- and κ-opioid receptors were found. Changes differed as a function of brain areas and the specific age window of perinatal aberrant stimulation of the HPA axis. Present results provided experimental evidence in a translational mouse model that precocious adversity represents a risk factor predisposing to the development of psychopathological behaviour.

The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V.

Nerve growth factor (NGF) is a key mediator of nociception, acting during the development and differentiation of dorsal root ganglion (DRG) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF also has central actions in the brain, where it regulates the phenotypic maintenance of cholinergic neurons. The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), caused by the 661C>T transition in the Ngf gene, resulting in the R100W missense mutation in mature NGF. Homozygous HSAN V patients present with congenital pain insensitivity, but are cognitively normal. This led us to hypothesize that the R100W mutation may differentially affect the central and peripheral actions of NGF. To test this hypothesis and provide a mechanistic basis to the HSAN V phenotype, we generated transgenic mice harboring the human 661C>T mutation in the Ngf gene and studied both males and females. We demonstrate that heterozygous NGFR100W/wt mice display impaired nociception. DRG neurons of NGFR100W/wt mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGFR100W protein has reduced capability to activate pain-specific signaling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGFR100W/wt mice, unlike heterozygous mNGF+/- mice, show no learning or memory deficits, despite a reduction in secretion and brain levels of NGF. The results exclude haploinsufficiency of NGF as a mechanistic cause for heterozygous HSAN V mice and demonstrate a specific effect of the R100W mutation on nociception.SIGNIFICANCE STATEMENT The R100W mutation in nerve growth factor (NGF) causes Hereditary Sensory and Autonomic Neuropathy type V, a rare disease characterized by impaired nociception, even in apparently clinically silent heterozygotes. For the first time, we generated and characterized heterozygous knock-in mice carrying the human R100W-mutated allele (NGFR100W/wt). Mutant mice have normal nociceptor populations, which, however, display decreased activation of pain transduction pathways. NGFR100W interferes with peripheral and central NGF bioavailability, but this does not impact on CNS function, as demonstrated by normal learning and memory, in contrast with heterozygous NGF knock-out mice. Thus, a point mutation allows neurotrophic and pronociceptive functions of NGF to be split, with interesting implications for the treatment of chronic pain.

The trophic effect of nerve growth factor in primary cultures of rat hippocampal neurons is associated to an anti-inflammatory and immunosuppressive transcriptional program.

Nerve growth factor, the prototype of a family of neurotrophins, elicits differentiation and survival of peripheral and central neuronal cells. Although its neural mechanisms have been studied extensively, relatively little is known about the transcriptional regulation governing its effects. We have previously observed that in primary cultures of rat hippocampal neurons treatment with nerve growth factor for 72 hr increases neurite outgrowth and cell survival. To obtain a comprehensive view of the underlying transcriptional program, we performed whole-genome expression analysis by microarray technology. We identified 541 differentially expressed genes and characterized dysregulated pathways related to innate immunity: the complement system and neuro-inflammatory signaling. The exploitation of such genes and pathways may help interfering with the intracellular mechanisms involved in neuronal survival and guide novel therapeutic strategies for neurodegenerative diseases.

NGF/anti-VEGF combined exposure protects RCS retinal cells and photoreceptors that underwent a local worsening of inflammation.

PURPOSE: Our previous study highlighted the potential nerve growth factor (NGF) effect on damaged photoreceptors from a rat model of spontaneous Retinitis Pigmentosa (RP). Herein, we tested the combined NGF/anti-vascular endothelial growth factor (αVEGF) effect on cultured retinal cells isolated from Royal College of Surgeons (RCS) rats receiving an intravitreal VEGF injection (iv-VEGF) to exacerbate retinal inflammation/neovascularization. METHODS: RCS (n = 75) rats were equally grouped as untreated (n = 25), iv-saline (single saline intravitreal injection; n = 25) and iv-VEGF (single VEGF intravitreal injection; n = 25). Morphological and biochemical analysis or in vitro stimulations with the biomolecular investigation were carried out on explanted retinas. Isolated retinal cells were treated with NGF and αVEGF, either alone or in combination, for 6 days and cells were harvested for morphological and biomolecular analyses. RESULTS: Infiltrating inflammatory cells were detected in iv-VEGF exposed RCS retinas, indicative of exacerbated inflammation and neovascularization. In cell cultures, NGF/αVEGF significantly increased retinal cell survival as well as rhodopsin expression and neurite outgrowth in photoreceptors. Particularly, NGF/αVEGF upregulated Bcl-2 mRNA, downregulated Bax mRNA, upregulated trkANGFR mRNA and finally upregulated both NGF mRNA and protein. CONCLUSIONS: These data confirm and extend our previous findings on NGF-photoreceptor crosstalk, highlighting that the NGF/αVEGF combination might be an interesting approach for improving neuroprotection of RCS retinal cells and likewise photoreceptors in the presence of neovascularization. Further studies are required to translate this in vitro approach into clinical practice.

Taste and Smell Alterations (TSAs) in Cancer Patients.

Recently, smell and taste disorders have seen renewed interest, as these symptoms are frequent complications of SARS-CoV-2 infection, since approximately 60% of patients affected by COVID-19 have shown olfactory and gustatory alterations. Otolaryngology pays attention to taste and smell abnormalities (TSAs), especially when associated with oncology. TSAs are common symptoms in people affected by cancer, yet they are ignored and underestimated. The clinical outcome of TSAs in cancer evidences the importance of identifying them with chemotherapy or radiotherapy in general, and they are associated with many types of cancer. We recognize the findings of the literature on TSAs in cancer, evaluating how it is important to consider and identify these disorders concerning reduced food enjoyment or inappropriate nutrient intake, and modulating the nutritional status, quality of life, and impact of therapy. This review aims to critically evaluate and recognize the assessment and clinical perspectives of taste and smell disorders in a cancer population.

The Impact of ROS and NGF in the Gliomagenesis and their Emerging Implications in the Glioma Treatment.

Reactive oxygen species (ROS) are highly reactive molecules derived from molecular oxygen (O2). ROS sources can be endogenous, such as cellular organelles and inflammatory cells, or exogenous, such as ionizing radiation, alcohol, food, tobacco, chemotherapeutical agents and infectious agents. Oxidative stress results in damage of several cellular structures (lipids, proteins, lipoproteins, and DNA) and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging. A large body of studies showed that ROS plays an important role in carcinogenesis. Indeed, increased production of ROS causes accumulation in DNA damage leading to tumorigenesis. Various investigations demonstrated the involvement of ROS in gliomagenesis. The most common type of primary intracranial tumor in adults is represented by glioma. Furthermore, there is growing attention on the role of the Nerve Growth Factor (NGF) in brain tumor pathogenesis. NGF is a growth factor belonging to the family of neurotrophins. It is involved in neuronal differentiation, proliferation and survival. Studies were conducted to investigate NGF pathogenesis's role as a pro- or anti-tumoral factor in brain tumors. It has been observed that NGF can induce both differentiation and proliferation in cells. The involvement of NGF in the pathogenesis of brain tumors leads to the hypothesis of a possible implication of NGF in new therapeutic strategies. Recent studies have focused on the role of neurotrophin receptors as potential targets in glioma therapy. This review provides an updated overview of the role of ROS and NGF in gliomagenesis and their emerging role in glioma treatment.