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The pathogenesis and management of eye diseases have seen significant advancements in recent years, driven by technological innovations, a deeper understanding of molecular mechanisms, and novel therapeutic approaches [...]

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

Objective: Breast cancer patients and survivors are increasing in the last years such as their mean age. A feasible and useful complementary intervention to improve physical and psychological health, and decrease some disease symptoms seems to be physical activity. Consequently, this umbrella review wanted to analyze the protocols of different physical activity interventions and to eventually propose a standard operating procedure for possible exercise training in breast cancer patients.Design, Data sources, Eligibility criteria. The electronic databases PubMed, Scopus, and Web of Science were searched till 25 March 2022 to detect all systematic review and meta-analysis of randomized controlled trials on this topic. The studies were analyzed narratively and evaluated with a scale to assess their quality. Results: The studies presented heterogeneity in their population included in terms of disease stage and treatments, intervention protocols and outcomes evaluated. This made difficult to synthesize the findings. Conclusion: It was not possible to propose a standard operating procedure but some indications were proposed to provide feedback for future studies. Ideally, an intervention should be composed of combined training (aerobic and resistance training) with a component of a mindfulness intervention, with an intensity from moderate to high, and 3 times a week. The intervention should be supervised in the first period and then it could be home-based. Exercise training should be personalized to the patients treated.

Glioblastoma multiforme (GBM) stands out as the most tremendous brain tumor, constituting 60% of primary brain cancers, accompanied by dismal survival rates. Despite advancements in research, therapeutic options remain limited to chemotherapy and surgery. GBM molecular heterogeneity, the intricate interaction with the tumor microenvironment (TME), and non-selective treatments contribute to the neoplastic relapse. Diagnostic challenges arise from GBM advanced-stage detection, necessitating the exploration of novel biomarkers for early diagnosis. Using data from the literature and a bioinformatic tool, the current manuscript delineates the molecular interplay between human GBM, astrocytes, and myeloid cells, underscoring selected protein pathways belonging to astroglia and myeloid lineage, which can be considered for targeted therapies. Moreover, the pivotal role of extracellular vesicles (EVs) in orchestrating a favorable microenvironment for cancer progression is highlighted, suggesting their utility in identifying biomarkers for GBM early diagnosis.

Diabetic keratopathy (DK) is a common ocular complication of diabetes, characterized by alteration of the normal wound-healing mechanism, reduction of epithelial hemidesmosomes, disruption of the basement membrane, impaired barrier function, reduced corneal sensitivity, corneal ulcers, and corneal edema. The limited number of clinical studies do not allow a full characterization of the pathophysiology of DK and, until now, effective therapeutic approaches have not been available. However, in recent years, neuropeptides gained great attention for their biochemical characteristics and therapeutic potential. This review focuses on the role of neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the eye and, in particular, in the cornea, in physiological conditions, or during DK, by providing an overview of this diabetes mellitus complication.

Recent studies have demonstrated that Sirtuin-1 (SIRT-1)-activating molecules exert a protective role in degenerative ocular diseases. However, these molecules hardly reach the back of the eye due to poor solubility in aqueous environments and low bioavailability after topical application on the eye’s surface. Such hindrances, combined with stability issues, call for the need for innovative delivery strategies. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for SIRT-1 delivery can represent a promising approach. The aim of the work was to design and optimize SNEDDS for the ocular delivery of two natural SIRT-1 agonists, resveratrol (RSV) and melatonin (MEL), with potential implications for treating diabetic retinopathy. Pre-formulation studies were performed by a Design of Experiment (DoE) approach to construct the ternary phase diagram. The optimization phase was carried out using Response Surface Methodology (RSM). Four types of SNEDDS consisting of different surfactants (Tween® 80, Tween® 20, Solutol® HS15, and Cremophor® EL) were optimized to achieve the best physico-chemical parameters for ocular application. Stability tests indicated that SNEDDS produced with Tween® 80 was the formulation that best preserved the stability of molecules, and so it was, therefore, selected for further technological studies. The optimized formulation was prepared with Capryol® PGMC, Tween® 80, and Transcutol® P and loaded with RSV or MEL. The SNEDDS were evaluated for other parameters, such as the mean size (found to be ˂50 nm), size homogeneity (PDI < 0.2), emulsion time (around 40 s), transparency, drug content (>90%), mucoadhesion strength, in vitro drug release, pH and osmolarity, stability to dilution, and cloud point. Finally, an in vitro evaluation was performed on a rabbit corneal epithelial cell line (SIRC) to assess their cytocompatibility. The overall results suggest that SNEDDS can be used as promising nanocarriers for the ocular drug delivery of RSV and MEL.

Multiple sclerosis is a disease that concerns a growing number of people, especially females. There are different interventions proposed for this population, and physical activity is one of them. A proper and well-structured physical activity program can be a cheap, feasible, and practical instrument to help this population improve their quality of life. Consequently, the present study aimed to analyze, through an umbrella review, published articles to evaluate the protocols and the effect of intervention on different types of multiple sclerosis and eventually to propose a standardized intervention for this population. Systematic reviews and meta-analyses of randomized controlled trials on multiple sclerosis and physical activity effects were searched for on the electronic databases PubMed, Web of Science, and Scopus up to 22 December 2022. The quality of the studies included was determined and the results were narratively analyzed. The included studies present heterogeneity in the population, in the study design and protocols, and in the outcomes evaluated. Most of the studies detected positive outcomes on the physical function of people with multiple sclerosis. This study highlights the necessity of future studies on a population with similar characteristics, adopting similar protocols to evaluate their feasibility and validity to make physical intervention prescribed as a medicine.

Introduction: To evaluate the pharmacological profile of ocular formulations based on cross-linked sodium hyaluronate (CL-SH), taurine (Tau), vitamin B6 (Vit B6) and vitamin B12 (Vit B12) using in vitro and in vivo paradigms.Methods: Rabbit corneal epithelial cells were used to assess wound healing and reactive oxygen species (ROS) formation by scratch assay and oxidative stress (0.3 mM H2O2; 30 min), respectively with or without ocular formulations exposure. In vivo studies were carried out on albino rabbits to evaluate corneal nerve regeneration and corneal wound healing with or without treatment with six different formulations. Animals were anesthetized, the corneal epithelium was removed, and formulations were topically administered (30 μL/eye; 3 times/day for 6 days). Slit-lamp observation was carried out at different time points. After 6 days the animals were killed, and corneas were collected to evaluate corneal re-innervation by immunohistochemistry of selective neuronal marker β-III tubulin.Results: Formulations containing the concentrations 0.16% or 0.32% of cross-linked sodium hyaluronate, taurine, vitamin B6 and vitamin B12 accelerated corneal wound healing. Cells exposed to H2O2 led to significant (p < 0.05) increase of reactive oxygen species concentration that was significantly (p < 0.05) counteract by formulations containing cross-linked sodium hyaluronate (0.32%) and taurine with or without vitamins. The extent of re-innervation, in terms of β-III tubulin staining, was 5-fold greater (p < 0.01) in the eye of rabbits treated with formulation containing 0.32% cross-linked sodium hyaluronate, taurine, vitamins (RenerviX®) compared with the control group (no treatment). Furthermore, re-innervation elicited by RenerviX® was significantly greater (p < 0.01) compared with the group treated with the formulation containing 0.32% cross-linked sodium hyaluronate and taurine without vitamins, and with the group treated with the formulation containing 0.5% linear sodium hyaluronate (SH), taurine, and vitamin B12, respectively.Discussion: In conclusion, among the formulations tested, the new ophthalmic gel RenerviX® was able to contrast oxidative stress, to accelerate corneal re-epithelization and to promote nerve regeneration.

In the area of drug discovery, repurposing strategies represent an approach to discover new uses of approved drugs besides their original indications. We used this approach to investigate the effects of dimethyl fumarate (DMF), a drug approved for relapsing–remitting multiple sclerosis and psoriasis treatment, on early injury associated with diabetic retinopathy (DR). We used an in vivo streptozotocin (STZ)-induced diabetic rat model. Diabetes was induced by a single injection of STZ in rats, and after 1 week, a group of animals was treated with a daily intraperitoneal injection of DMF or a vehicle. Three weeks after diabetes induction, the retinal expression levels of key enzymes involved in DR were evaluated. In particular, the biomarkers COX-2, iNOS, and HO-1 were assessed via Western blot and immunohistochemistry analysis. Diabetic rats showed a significant retinal upregulation of COX-2 and iNOS compared to the retina of normal rats (non-diabetic), and an increase in HO-1 was also observed in the STZ group. This latter result was due to a mechanism of protection elicited by the pathological condition. DMF treatment significantly induced the retinal expression of HO-1 in STZ-induced diabetic animals with a reduction in iNOS and COX-2 retinal levels. Taken together, these results suggested that DMF might be useful to counteract the inflammatory process and the oxidative response in DR. In conclusion, we believe that DMF represents a potential candidate to treat diabetic retinopathy and warrants further in vivo and clinical evaluation.

Spinal cord injury (SCI) is an irreversible disease resulting in partial or total loss of sensory and motor function. The pathophysiology of SCI is characterized by an initial primary injury phase followed by a secondary phase in which reactive oxygen species (ROSs) and associated oxidative stress play hallmark roles. Physical exercise is an indispensable means of promoting psychophysical well-being and improving quality of life. It positively influences the neuromuscular, cardiovascular, respiratory, and immune systems. Moreover, exercise may provide a mechanism to regulate the variation and equilibrium between pro-oxidants and antioxidants. After a brief overview of spinal cord anatomy and the different types of spinal cord injury, the purpose of this review is to investigate the evidence regarding the effect of exercise on oxidative stress among individuals with SCI.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.

Osteoarthritis is a degenerative joint disease that affects millions of people worldwide. Current guidelines emphasize the importance of regular physical activity as a preventive measure against disease progression and as a valuable strategy for pain and functionality management. Despite this, most patients with osteoarthritis are inactive. Modern technological advances have led to the implementation of digital devices, such as wearables and smartphones, showing new opportunities for healthcare professionals and researchers to monitor physical activity and therefore engage patients in daily exercising. Additionally, digital devices have emerged as a promising tool for improving frequent health data collection, disease monitoring, and supporting public health surveillance. The leveraging of digital data has laid the foundation for developing a new concept of epidemiological study, known as ''Digital Epidemiology''. Analyzing real-world data can change the way we observe human behavior and suggest health interventions, as in the case of physical exercise and osteoarthritic patients. Furthermore, large-scale data could contribute to personalized and precision medicine in the future. Herein, an overview of recent clinical applications of wearables for monitoring physical activity in patients with osteoarthritis and the benefits of exploiting real-world data in the context of digital epidemiology are discussed.

Transcriptional regulation is fundamental to most biological processes and reverse-engineering programs can be used to decipher the underlying programs. In this review, we describe how genomics is offering a systems biology-based perspective of the intricate and temporally coordinated transcriptional programs that control neuronal apoptosis and survival. In addition to providing a new standpoint in human pathology focused on the regulatory program, cracking the code of neuronal cell fate may offer innovative therapeutic approaches focused on downstream targets and regulatory networks. Similar to computers, where faults often arise from a software bug, neuronal fate may critically depend on its transcription program. Thus, cracking the code of neuronal life or death may help finding a patch for neurodegeneration and cancer.

Peripheral nerve injury is a complex condition with a variety of signs and symptoms depending on the severity and nerves involved. Peripheral nerve damage may lead to sensory and motor functions deficits and even lifelong disability, causing important socioeconomic costs worldwide. Despite the increase in knowledge of the mechanisms of injury and regeneration, a full functional recovery is still unsatisfying in the majority of patients. It is well known that exercise promotes physical and psychological well-being, by ameliorating general health. In the last years, there has been a growing interest in evaluating the effects of exercise on the peripheral nervous system. Experimental works with rodent models showed the potential utility of exercise following peripheral nerve injuries, as evinced by increasing axon regeneration, muscle reinnervation, better recovery of strength, muscle mass and higher expression of neurotrophic factors. Moreover, clinical evidence showed positive trends in favour of physical therapy following peripheral nerve damage based on the improvement of range of motion (ROM), muscle power grade and pain. After a brief overview of peripheral nerve anatomy and the different types of nerve injury, the present review aims to summarize the impact of exercise on peripheral nerve regeneration. Some clinical evidence regarding the effect of exercise after peripheral nerve injury will also be discussed.

This editorial aims to summarize the contents of the six scientific papers included in the Special Issue “Advances in Neuropeptide Biology” [...]

Abstract Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.

This study aimed to investigate the high glucose damage on human retinal pigment epithelial (RPE) cells, the role of p38 MAPK signaling pathway and how dimethyl fumarate can regulate that. We carried out in vitro studies on ARPE-19 cells exposed to physiological and high glucose (HG) conditions, to evaluate the effects of DMF on cell viability, apoptosis, and expression of inflammatory and angiogenic biomarkers such as COX-2, iNOS, IL-1β, and VEGF. Our data have demonstrated that DMF treatment attenuated HG-induced apoptosis, as confirmed by reduction of BAX/Bcl-2 ratio. Furthermore, in RPE cells exposed to HG we observed a significant increase of iNOS, COX-2, and IL-1β expression, that was reverted by DMF treatment. Moreover, DMF reduced the VEGF levels elicited by HG, inhibiting p38 MAPK signaling pathway. The present study demonstrated that DMF provides a remarkable protection against high glucose-induced damage in RPE cells through p38 MAPK inhibition and the subsequent down-regulation of VEGF levels, suggesting that DMF is a small molecule that represents a good candidate for diabetic retinopathy treatment and warrants further in vivo and clinical evaluation.

Huntington’s disease (HD) is a rare, hereditary, and progressive neurodegenerative disease, characterized by involuntary choreatic movements with cognitive and behavioral disturbances. In order to mitigate impairments in motor function, physical exercise was integrated in HD rehabilitative interventions, showing to be a powerful tool to ameliorate the quality of life of HD-affected patients. This review aims to describe the effects of physical exercise on HD-related skeletal muscle disorders in both murine and human models. We performed a literature search using PubMed, Scopus, and Web of Science databases on the role of physical activity in mouse models of HD and human patients. Fifteen publications fulfilled the criteria and were included in the review. Studies performed on mouse models showed a controversial role played by exercise, whereas in HD-affected patients, physical activity appeared to have positive effects on gait, motor function, UHDMRS scale, cognitive function, quality of life, postural stability, total body mass, fatty acid oxidative capacity, and VO2 max. Physical activity seems to be feasible, safe, and effective for HD patients. However, further studies with longer follow-up and larger cohorts of patients will be needed to draw firm conclusions on the positive effects of exercise for HD patients.

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disorder, caused by the degeneration of upper and lower motor neurons for which there is no truly effective cure. The lack of successful treatments can be well explained by the complex and heterogeneous nature of ALS, with patients displaying widely distinct clinical features and progression patterns, and distinct molecular mechanisms underlying the phenotypic heterogeneity. Thus, stratifying ALS patients into consistent and clinically relevant subgroups can be of great value for the development of new precision diagnostics and targeted therapeutics for ALS patients. In the last years, the use and integration of high-throughput “omics” approaches have dramatically changed our thinking about ALS, improving our understanding of the complex molecular architecture of ALS, distinguishing distinct patient subtypes and providing a rational foundation for the discovery of biomarkers and new individualized treatments. In this review, we discuss the most significant contributions of omics technologies in unraveling the biological heterogeneity of ALS, highlighting how these approaches are revealing diagnostic, prognostic and therapeutic targets for future personalized interventions.

Amyotrophic lateral sclerosis (ALS) is a progressive multifactorial disease characterized by the loss of motor neurons (MNs). Not all MNs undergo degeneration: neurons of the oculomotor nucleus, which regulate eye movements, are less vulnerable compared to hypoglossal nucleus MNs. Several molecular studies have been performed to understand the different vulnerability of these MNs. By analyzing postmortem samples from ALS patients to other unrelated decedents, the differential genomic pattern between the two nuclei has been profiled. Among identified genes, adenylate cyclase activating polypeptide 1 (ADCYAP1) gene, encoding for pituitary adenylate cyclase-activating polypeptide (PACAP), was found significantly up-regulated in the oculomotor versus hypoglossal nucleus suggesting that it could play a trophic effect on MNs in ALS. In the present review, some aspects regarding the different vulnerability of oculomotor and hypoglossal nucleus to degeneration will be summarized. The distribution and potential role of PACAP on these MNs as studied largely in an animal model of ALS compared to controls, will be discussed.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.

The worldwide spread of COVID-19 has upset the normality of Italian daily life, forcing population to social distancing and self-isolation. Since the containment precautions also concern sport-related activities, home workout remained the only possibility to play sports and stay active during the pandemic.The present study aimed to examine changes in the physical activity levels during self-quarantine in Italy, and the impact of exercise on psychological health.A total of 2974 Italian subjects has completed an online survey, but only 2524 subjects resulted eligible for this study. The questionnaire measured the total weekly physical activity energy expenditure before and during quarantine (i.e. the sum of walking, moderate-intensity physical activities, and vigorous-intensity physical activities) in Metabolic Equivalent Task minutes per week (MET–min/wk) using an adapted version of International Physical Activity Questionnaire and their psychological well-being using the Psychological General Well Being Index. Of the 2524 Italian subjects included in the study, 1426 were females (56.4%) and 1098 males (43.6%). Total physical activity significantly decreased between before and during COVID-19 pandemic (Mean: 2429 vs. 1577 MET–min/wk, ∗∗∗∗p < 0.0001), in all age groups and especially in men (Female, mean: 1994 vs. 1443 MET–min/wk, ∗∗∗∗p < 0.0001; Male, mean: 2998 vs. 1754 MET–min/wk, ∗∗∗∗p < 0.0001). Furthermore, a significant positive correlation was found between the variation of physical activity and mental well-being (r = 0.07541, ∗∗∗p = 0.0002), suggesting that the reduction of total physical activity had a profoundly negative impact on psychological health and well-being of population.Based on this scientific evidence, maintaining a regular exercise routine is a key strategy for physical and mental health during a forced rest period like the current coronavirus emergency.

PACAP is widely expressed throughout the body. It exerts a beneficial role in the eye, including the cornea. The corneal epithelium is regularly exposed to diverse types of insults, including ultraviolet B (UV-B) radiation. Previously, we showed the protective role played by PACAP in counteracting UV-B ray insults in human corneal endothelial cells; however, its involvement in corneal epithelium protection against ROS induced by UV-B radiation, and the underlying mechanisms, remain to be determined. Here, we demonstrated that the peptide treatment reduced UV-B-induced ROS generation by playing an anti-apoptotic role via JNK-signaling pathway inhibition. Overall, our results can provide guidance in the therapeutic use of PACAP for the treatment of epithelial corneal damage.

The corneal epithelium, the outermost layer of the cornea, acts as a dynamic barrier preventing access to harmful agents into the intraocular space. It is subjected daily to different insults, and ultraviolet B (UV-B) irradiation represents one of the main causes of injury. In our previous study, we demonstrated the beneficial effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against UV-B radiation damage in the human corneal endothelium. Some of its effects are mediated through the activation of the intracellular factor, known as the activity-dependent protein (ADNP). In the present paper, we have investigated the role of ADNP and the small peptide derived from ADNP, known as NAP, in the corneal epithelium. Here, we have demonstrated, for the first time, ADNP expression in human and rabbit corneal epithelium as well as its protective effect by treating the corneal epithelial cells exposed to UV-B radiations with NAP. Our results showed that NAP treatment prevents ROS formation by reducing UV-B-irradiation-induced apoptotic cell death and JNK signalling pathway activation. Further investigations are needed to deeply investigate the possible therapeutic use of NAP to counteract corneal UV-B damage.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide with widespread distribution throughout the central and peripheral nervous system as well as in many other peripheral organs. It plays cytoprotective effects mediated mainly through the activation of specific receptors. PACAP is known to play pleiotropic effects on the eye, including the cornea, protecting it against different types of insult. This review firstly provides an overview of the anatomy of the cornea and summarizes data present in literature about PACAP’s role in the eye and, in particular, in the cornea, either in physiological or pathological conditions.

Neuronal apoptosis and survival are regulated at the transcriptional level. To identify key genes and upstream regulators primarily responsible for these processes, we overlayed the temporal transcriptome of cerebellar granule neurons following induction of apoptosis and their rescue by three different neurotrophic factors. We identified a core set of 175 genes showing opposite expression trends at the intersection of apoptosis and survival. Their functional annotations and expression signatures significantly correlated to neurological, psychiatric and oncological disorders. Transcription regulatory network analysis revealed the action of nine upstream transcription factors, converging pro-apoptosis and pro-survival-inducing signals in a highly interconnected functionally and temporally ordered manner. Five of these transcription factors are potential drug targets. Transcriptome-based computational drug repurposing produced a list of drug candidates that may revert the apoptotic core set signature. Besides elucidating early drivers of neuronal apoptosis and survival, our systems biology-based perspective paves the way to innovative pharmacology focused on upstream targets and regulatory networks.

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different effects in various human cancer. In glioblastoma (GBM), PACAP has been shown to interfere with the hypoxic micro-environment through the modulation of hypoxia-inducible factors via PI3K/AKT and MAPK/ERK pathways inhibition. Considering that hypoxic tumor micro-environment is strictly linked to angiogenesis and Epithelial–Mesenchymal transition (EMT), in the present study, we have investigated the ability of PACAP to regulate these events. Results have demonstrated that PACAP and its related receptor, PAC1R, are expressed in hypoxic area of human GBM colocalizing either in epithelial or mesenchymal cells. By using an in vitro model of GBM cells, we have observed that PACAP interferes with hypoxic/angiogenic pathway by reducing vascular-endothelial growth factor (VEGF) release and inhibiting formation of vessel-like structures in H5V endothelial cells cultured with GBM-conditioned medium. Moreover, PACAP treatment decreased the expression of mesenchymal markers such as vimentin, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) as well as CD44 in GBM cells by affecting their invasiveness. In conclusion, our study provides new insights regarding the multimodal role of PACAP in GBM malignancy.

Glioblastoma multiforme (GBM) is the deadliest form of brain tumors. To date, the GBM therapeutical approach consists of surgery, radiation-therapy and chemotherapy combined with molecules improving cancer responsiveness to treatments. In this review, we will present a brief overview of the GBM classification and pathogenesis, as well as the therapeutic approach currently used. Then, we will focus on the modulatory role exerted by pituitary adenylate cyclase-activating peptide, known as PACAP, on GBM malignancy. Specifically, we will describe PACAP ability to interfere with GBM cell proliferation, as well as the tumoral microenvironment. Considering its anti-oncogenic role in GBM, synthesis of PACAP agonist molecules may open new perspectives for combined therapy to existing gold standard treatment.

The multifold benefits of regular physical exercise have been largely demonstrated in human and animal models. Several studies have reported the beneficial effects of physical activity, both in peripheral tissues and in the central nervous system (CNS). Regular exercise improves cognition, brain plasticity, neurogenesis and reduces the symptoms of neurodegenerative diseases, making timeless the principle of “mens sana in corpore sano” (i.e., a healthy mind in a healthy body). Physical exercise promotes morphological and functional changes in the brain, acting not only in neurons but also in astrocytes, which represent the most numerous glial cells in the brain. The multiple effects of exercise on astrocytes comprise the increased number of new astrocytes, the maintenance of basal levels of catecholamine, the increase in glutamate uptake, the major release of trophic factors and better astrocytic coverage of cerebral blood vessels. The purpose of this review is to highlight the effects of exercise on brain function, emphasize the role of astrocytes in the healthy CNS, and provide an update for a better understanding of the effects of physical exercise in the modulation of astrocyte function.

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.

Studies on the effectiveness of physical exercise to treat and/or prevent mental disorders are essential and particularly appropriate, given the rapid growth of the elderly population and the consequent increase in the prevalence of neurodegenerative diseases. The onset of neurodegenerative diseases is subtle, and progression is irreversible, as there is still no cure capable of stopping them permanently. Therefore, we should not underestimate these diseases and should immediately begin to combine the treatment with physical activity adapted to specific needs. Indeed, it is well known that physical activity has positive effects on mobility, autonomy, and functional capacity, improving not only cognitive functions, but also reducing the risk of developing dementia. Despite several studies in this field, to date there are no specific and effective protocols that promote physical exercise in people with dementia. Based on this evidence, the aim of the present work was to verify whether an adapted physical exercise regimen could promote the maintenance of psychomotor functions in elderly subjects and, therefore, delay the irreversible effects of combinations of dementia and other pathologies associated with aging. Our results clearly show that exercise is very effective in improving psychomotor functions and delaying the progress of neurodegenerative diseases in humans, since we observed that the subjects maintained their cognitive skills after 8 months of physical activity, moreover, two patients presented an amelioration. Based on the results obtained, we recommend that the motor practice, in any chosen form, be considered an integral part of prevention programs based on an active lifestyle in older people. Future studies will be necessary to establish how long lasting the benefits of a specific physical activity are and whether they are enough to delay cognitive decline.

We are glad to introduce the Third Journal Club of Volume five, the third issue. This edition is focused on relevant studies published in the last years in the field of PhysioMechanics of Human Locomotion, chosen by our Editorial Board members and their colleagues. We hope to stimulate your curiosity in this field and to share with you the passion for the Sports Medicine and Movement Sciences seen also from the scientific point of view. The Editorial Board members wish you an inspiring lecture.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease characterized by the loss of upper and lower motor neurons. To date, no resolutive cure is available, and only two Food and Drug Administration-approved drugs are used to treat ALS without a resolutive outcome. In recent years, the study of the beneficial effects of physical activity on health has acquired special relevance. However, the relationship between ALS progression and physical exercise is still a hotly debated topic in medicine. Some studies have suggested higher risks to develop the disease that are associated with practicing intense physical activity, as seen in professional soccer or football players, for example. On the contrary, moderate training has been shown to exert several benefits in ALS-affected patients. Overall, more studies are needed to clarify whether physical activity is helpful or harmful for developing ALS.

We are glad to introduce the seventeenth Journal Club. This edition is focused on several relevant studies published in the last years in the field of Overtraining and Exercise Addiction, chosen by our Editorial Board members and their colleagues. We hope to stimulate your curiosity in this field and to share with you the passion for the sport seen also from the scientific point of view. The Editorial Board members wish you an inspiring lecture.

Fragile X syndrome is the most common inherited form of mental retardation. Although this syndrome originates from the absence of the RNA-binding protein FMRP, the molecular mechanisms underlying the cognitive deficits are unknown. The expression pattern of 6789 genes was studied in the brains of wild-type and FMR1 knockout mice, a fragile X syndrome animal model that has been associated with cognitive deficits. Differential expression of more than two-fold was observed for the brain mRNA levels of 73 genes. Differential expression of nine of these genes was confirmed by real-time quantitative reverse transcription-polymerase chain reaction and by in situ hybridization. In addition to corroborating the microarray data, the in situ hybridization analysis showed distinct spatial distribution patterns of microtubule-associated protein 2 and amyloid beta precursor protein. A number of differentially expressed genes associated with the fragile X syndrome phenotype have been previously involved in other memory or cognitive disorders.