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Fibromyalgia is a syndrome characterized by chronic and widespread musculoskeletal pain, often accompanied by other symptoms, such as fatigue, intestinal disorders and alterations in sleep and mood. It is estimated that two to eight percent of the world population is affected by fibromyalgia. From a medical point of view, this pathology still presents inexplicable aspects. It is known that fibromyalgia is caused by a central sensitization phenomenon characterized by the dysfunction of neuro-circuits, which involves the perception, transmission and processing of afferent nociceptive stimuli, with the prevalent manifestation of pain at the level of the locomotor system. In recent years, the pathogenesis of fibromyalgia has also been linked to other factors, such as inflammatory, immune, endocrine, genetic and psychosocial factors. A rheumatologist typically makes a diagnosis of fibromyalgia when the patient describes a history of pain spreading in all quadrants of the body for at least three months and when pain is caused by digital pressure in at least 11 out of 18 allogenic points, called tender points. Fibromyalgia does not involve organic damage, and several diagnostic approaches have been developed in recent years, including the analysis of genetic, epigenetic and serological biomarkers. Symptoms often begin after physical or emotional trauma, but in many cases, there appears to be no obvious trigger. Women are more prone to developing the disease than men. Unfortunately, the conventional medical therapies that target this pathology produce limited benefits. They remain largely pharmacological in nature and tend to treat the symptomatic aspects of various disorders reported by the patient. The statistics, however, highlight the fact that 90% of people with fibromyalgia also turn to complementary medicine to manage their symptoms.

Glutamate is a fundamental excitatory neurotransmitter in the mammalian central nervous system (CNS), playing key roles in memory, neuronal development, and synaptic plasticity. Moreover, excessive glutamate release has been implicated in neuronal cell death. There are both ionotropic and metabotropic glutamate receptors (mGluRs), the latter of which can be divided into eight subtypes and three subgroups based on homology sequence and their effects on cell signaling. Indeed, mGluRs exert fine control over glutamate activity by stimulating several cell-signaling pathways the activation of G protein-coupled (GPC) or G protein-independent cell signaling. The involvement of specific mGluRs in different forms of synaptic plasticity suggests that modulation of mGluRs may aid in the treatment of cognitive impairments related to several neurodevelopmental/psychiatric disorders and neurodegenerative diseases, which are associated with a high economic and social burden. Preclinical and clinical data have shown that, in the CNS, mGluRs are able to modulate presynaptic neurotransmission by fine-tuning neuronal firing and neurotransmitter release in a dynamic, activity-dependent manner. Current studies on drugs that target mGluRs have identified promising, innovative pharmacological tools for the treatment of neurodegenerative and neuropsychiatric conditions, including chronic pain.

Neuropathic pain results from lesions or diseases of the somatosensory nervous system and it remains largely difficult to treat. Peripheral neuropathic pain originates from injury to the peripheral nervous system (PNS) and manifests as a series of symptoms and complications, including allodynia and hyperalgesia. The aim of this review is to discuss a novel approach on neuropathic pain management, which is based on the knowledge of processes that underlie the development of peripheral neuropathic pain; in particular highlights the role of glia and mast cells in pain and neuroinflammation. ALIAmides (autacoid local injury antagonist amides) represent a group of endogenous bioactive lipids, including palmitoylethanolamide (PEA), which play a central role in numerous biological processes, including pain, inflammation, and lipid metabolism. These compounds are emerging thanks to their anti-inflammatory and anti-hyperalgesic effects, due to the down-regulation of activation of mast cells. Collectively, preclinical and clinical studies support the idea that ALIAmides merit further consideration as therapeutic approach for controlling inflammatory responses, pain, and related peripheral neuropathic pain.

TBI (traumatic brain injury) is a major cause of death among youth in industrialized societies. Brain damage following traumatic injury is a result of direct and indirect mechanisms; indirect or secondary injury involves the initiation of an acute inflammatory response, including the breakdown of the blood–brain barrier (BBB), brain edema, infiltration of peripheral blood cells, and activation of resident immunocompetent cells, as well as the release of numerous immune mediators such as interleukins and chemotactic factors. TBI can cause changes in molecular signaling and cellular functions and structures, in addition to tissue damage, such as hemorrhage, diffuse axonal damages, and contusions. TBI typically disturbs brain functions such as executive actions, cognitive grade, attention, memory data processing, and language abilities. Animal models have been developed to reproduce the different features of human TBI, better understand its pathophysiology, and discover potential new treatments. For many years, the first approach to manage TBI has been treatment of the injured tissue with interventions designed to reduce the complex secondary-injury cascade. Several studies in the literature have stressed the importance of more closely examining injuries, including endothelial, microglia, astroglia, oligodendroglia, and precursor cells. Significant effort has been invested in developing neuroprotective agents. The aim of this work is to review TBI pathophysiology and existing and potential new therapeutic strategies in the management of inflammatory events and behavioral deficits associated with TBI.

The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease (PD). PD is characterized by the degeneration of dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequent neuroinflammatory response is increasingly recognized as a prominent neuropathological feature of PD. There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10 mg/kg, i.p.), initiated 24 hr after MPTP injection (20 mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra. Furthermore, chronic PEA reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated MPTP systemic toxicity, while PEA-induced neuroprotection seemed be partially PPARα-dependent. The effects of PEA on molecules typically involved in apoptotic pathways were also analyzed. Our results indicate that PEA protects against MPTP-induced neurotoxicity and the ensuing functional deficits even when administered once the insult has been initiated.

Gastric ulcer or peptic ulcer is a common disease worldwide. Basically, it develops when there is an imbalance between the protective and aggressive factors, especially at the luminal surface of epithelial cells. Thus, there is a constant interest in research new drugs for treatment of gastric ulcer. The snail secretion is a dense mucous, that covers the external surface of the snails, with important functions for the survival of snails. The biological proprieties of snail Helix Aspersa Muller mucus it has been known for centuries to treat human disorders in particular for skin disease. Recently the use of snail mucus has seen a worldwide increase, as a component in cosmetic product and it has been used in particular for the management of wound and skin disorders. In this study we use a murine model of ethanol intragastric administration which has been widely used to test the drugs efficacies and to explore the underlying mechanism for gastric ulcer development. The intragastric ethanol administration causes several mucosal damages and an induction of a severe inflammatory response. Our results show a significant protective effect of snail secretion filtrate in reducing macroscopic and histological lesions, as well the protective effect on mucus content, oxidative stress and inflammatory response. In conclusion this study demonstrate the protective effect of intragastrical snail secretion filtrate, in a model of ethanol-induced gastric ulcer in mice, suggesting its possible useful use in the treatment or prevention of gastric ulcer.

Ischemia/reperfusion injury is a severe disorder associated with a high mortality. Several antioxidant and pharmacological properties of cashew nuts (Anacardium occidentale L.) and its metabolites from different countries have recently been described. It is a medicinal plant with important therapeutic effects. This study aimed to verify the effect of an oral administration of cashew nuts in a rat model of ischemia/reperfusion (I/R). Adult male rats were subjected to intestinal I/R injury by clamping the superior mesenteric artery for 30 min and then allowing animals to 1 h of reperfusion. Rats subjected to I/R of the gut showed a significant increase in different biochemical markers. In particular, we evaluated lipid peroxidation, tissue myeloperoxidase activity, protein carbonyl content, reactive oxygen species generation and decreased antioxidant enzyme activities. Western blot analysis showed the activation of the NRF2 and NF-kB pathways. Increased immunoreactivity to nitrotyrosine, PARP, P-selectin, and ICAM-1 was observed in the ileum of rats subjected to I/R. Administration of cashew nuts (100 mg/kg) significantly reduced the mortality rate, the fall in arterial blood pressure, and oxidative stress and restored the antioxidant enzyme activities by a mechanism involving both NRF2 and NF-kB pathways. Cashew nuts treatments reduced cytokines plasma levels, nitrotyrosine, and PARP expression as well as adhesion molecules expressions. Additionally, cashew nuts decreased the intestinal barrier dysfunction and mucosal damage, the translocation of toxins and bacteria, which leads to systemic inflammation and associated organs injuries in particular of liver and kidney. Our study demonstrates that cashew nuts administration exerts antioxidant and pharmacological protective effects in superior mesenteric artery occlusion–reperfusion shock.

Endometriosis is a gynecological condition affecting patients in reproductive age. The aim of this paper was to assess the effects of the autophagy and mitophagy induction in a rat model of endometriosis. Endometriosis was induced by the injection of uterine fragments, and rapamycin (0. 5 mg/kg) was administered once per week. One week from the induction, rats were sacrificed, and laparotomy was performed to collect the endometriotic implants and to further process them for molecular analysis. Western blot analysis was conducted on explanted lesions to evaluate the autophagy pathway during the pathology. Elevated phospho-serine/threonine kinase (p-AKT) and mammalian target of rapamycin (mTOR) expressions were detected in vehicle-treated rats, while Beclin and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) expressions were low. Additionally, samples collected from vehicle groups indicated low Bnip3, Ambra1, and Parkin expressions, demonstrating impaired autophagy and mitophagy. Rapamycin administration reduced p-AKT and mTOR expressions and increased Beclin and LC3II, Bnip3, Ambra1, and Parkin expressions, activating both mechanisms. We also evaluated the impact of the impaired autophagy and mitophagy pathways on apoptosis and angiogenesis. Rapamycin was administered by activating autophagy and mitophagy, which increased apoptosis (assessed by Western blot analysis of Bcl-2, Bax, and Cleaved-caspase 3) and reduced angiogenesis (assessed by immunohistochemical analysis of vascular endothelial grow factor (VEGF) and CD34) in the lesions. All of these mechanisms activated by the induction of the autophagy and mitophagy pathways led to the reduction in the lesions’ volume, area and diameter.

Homocysteine (HCY), a physiological amino acid formed when proteins break down, leads to a pathological condition called hyperhomocysteinemia (HHCY), when it is over a definite limit. It is well known that an increase in HCY levels in blood, can contribute to arterial damage and several cardiovascular disease, but the knowledge about the relationship between HCY and brain disorders is very poor. Recent studies demonstrated that an alteration in HCY metabolism or a deficiency in folate or vitamin B12 can cause altered methylation and/or redox potentials, that leads to a modification on calcium influx in cells, or into an accumulation in amyloid and/or tau protein involving a cascade of events that culminate in apoptosis, and, in the worst conditions, neuronal death. The present review will thus summarize how much is known about the possible role of HHCY in neurodegenerative disease.

Diabetes causes various macrovascular and microvascular alterations, often culminating in major clinical complications (first of all, stroke) that lack an effective therapeutic intervention. N-palmitoylethanolamide-oxazoline (PEA-OXA) possesses anti-inflammatory and potent neuroprotective effects. Although recent studies have explained the neuroprotective properties of PEA-OXA, nothing is known about its effects in treating cerebral ischemia. Methods: Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAo) in the right hemisphere. Middle cerebral artery (MCA) occlusion was provided by introducing a 4–0 nylon monofilament (Ethilon; Johnson & Johnson, Somerville, NJ, USA) precoated with silicone via the external carotid artery into the internal carotid artery to occlude the MCA. Results: A neurological severity score and infarct volumes were carried out to assess the neuroprotective effects of PEA-OXA. Moreover, we observed PEA-OXA-mediated improvements in tissue histology shown by a reduction in lesion size and an improvement in apoptosis level (assessed by caspases, Bax, and Bcl-2 modulation and a TUNEL assay), which further supported the efficacy of PEA-OXA therapy. We also found that PEA-OXA treatment was able to reduce mast cell degranulation and reduce the MCAo-induced expression of NF-κB pathways, cytokines, and neurotrophic factors. Conclusions: based on these findings, we propose that PEA-OXA could be useful in decreasing the risk of impairment or improving function in ischemia/reperfusion brain injury-related disorders.