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Aim: Fibromyalgia (FM) is a complex and long-lasting musculoskeletal disorder characterized by mood changes, fatigue, headache, and extensive musculoskeletal pain. Spirulina has potent antioxidant, antinociceptive, and neuroprotective properties. This study aimed to evaluate spirulina’s capacity to protect rats against FM caused by reserpine. Methods: Male Sprague-Dawley rats received a subcutaneous injection of reserpine (1 mg/kg) once a day for three days. Subsequently, they were administered an oral dose of 400 mg/kg of Spirulina for 21 days. Many molecular, biochemical, and behavioral tests have been evaluated. Results: Daily spirulina consumption was able to limit the increase in neuroinflammation, oxidative stress, and a reduction in biogenic amine levels as well as behavioral alterations. Significance: This study demonstrated for the first time that dietary integration with spirulina could be helpful to reduce the onset of pain, inflammation and mental disturbance in FM patients.

The journal retracts the article, “Assessment of 2-Pentadecyl-2-oxazoline Role on Lipopolysaccharide-Induced Inflammation on Early Stage Development of Zebrafish (Danio rerio)” [...]

Traumatic brain injury (TBI) is described as a structural damage or physiological disturbance of brain function that occurs after trauma and causes disability or death in people of all ages. New treatment targets for TBI are being explored because current medicines are frequently ineffectual and poorly tolerated. There is increasing evidence that following TBI, there are widespread changes in autophagy-related proteins in both experimental and clinical settings. The current study investigated if Boswellia Sacra Gum Resin (BSR) treatment (500 mg/kg) could modulate post-TBI neuronal autophagy and protein expression, as well as whether BSR could markedly improve functional recovery in a mouse model of TBI. Taken together our results shows for the first time that BSR limits histological alteration, lipid peroxidation, antioxidant, cytokines release and autophagic flux alteration induced by TBI.

IntroductionFeline idiopathic cystitis is a common, chronic-relapsing disorder of the lower urinary tract. In addition to environmental modification/enrichment, long-term and safe treatment targeting specific pathophysiological changes may be of help. In this context, effective dietary interventions hold clinical promise. Palmitoyl-glucosamine (PGA) and hesperidin (HSP) are safe and authorized feed ingredients for animal nutrition under European regulations.MethodsThe current study aimed to investigate whether a 3:1 mixture of micronized PGA and HSP could represent a novel mechanism-oriented approach to chronic cystitis management. A newly validated rat model of cyclophosphamide (CYP)-induced chronic cystitis was used (40 mg/kg, three intraperitoneal injections every 3rd day). Animals were randomized to orally receive either vehicle or PGA-HSP at a low (72 + 24 mg/kg) or high (doubled) dose for 13 days, starting 3 days before the chronic CYP protocol, with mesna (2-mercaptoethane-sulfonate) being used as a reference drug.ResultsHigher PGA-HSP dose was effective at relieving chronic visceral pain, as measured by mechanical allodynia test (von Frey test). The severity of cystitis was also significantly improved, as shown by the reduced sonographic thickening of the bladder wall, as well as the decrease in edema, bleeding and bladder to body weight ratio compared to the vehicle treated group. A significant decrease of MPO activity, MDA level and fibrosis at Masson’s trichrome staining was also observed in animals administered PGA-HSP in comparison to vehicle treated ones. The CYP-induced increase in bladder mRNA expression of pro-inflammatory cytokines was also significantly counteracted by the study mixture. Moreover, CYP-induced bladder mast cell accumulation and releasability were significantly decreased by PGA-HSP (even at the low dose), as determined by metachromatic staining, chymase and tryptase immunostaining as well as enzyme-linked immunosorbent assay for histamine and 5-hydoxytriptamine.DiscussionPGA-HSP is able to block CYP-induced decrease of tight junction proteins, claudin-1 and occludin, thus preserving the urothelial bladder function. Finally, neuroinflammatory changes were investigated, showing that dietary supplementation with PGA-HSP prevented the activation of neurons and non-neuronal cells (i.e., microglia, astrocytes and mast cells) at the spinal level, and counteracted CYP-induced increase of spinal mRNA encoding for pro-inflammatory cytokines. Altogether, the present findings confirm the uroprotective and pain-relieving effect of PGA-HSP and pave the way to potential and relevant clinical applications of the study supplement in feline idiopathic cystitis.

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Abstract 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.

Pulmonary arterial hypertension (PAH) is a chronic, progressive disease characterized by an increase in blood pressure in the lungs' arteries. It can occur in a variety of species, including humans, dogs, cats, and horses. To date, PAH has a high mortality rate in both veterinary and human medicine, often due to complications such as heart failure. The complex pathological mechanisms of PAH involve multiple cellular signalling pathways at various levels. IL-6 is a powerful pleiotropic cytokine that regulates several phases of immune response, inflammation, and tissue remodelling. The hypothesis of this study was that the use of an IL-6 antagonist in PAH could interrupt or mitigate the cascade of events that leads to the progression of the disease and the worsening of clinical outcome, as well as tissue remodelling. In this study, we used two pharmacological protocols with an IL-6 receptor antagonist in a monocrotaline-induced PAH model in rats. Our results showed that the use of an IL-6 receptor antagonist had a significant protective effect, ameliorating both haemodynamic parameters, lung and cardiac function, tissue remodelling, and the inflammation associated with PAH. The results of this study suggest that the inhibition IL-6 could be a useful pharmacological strategy in PAH, in both human and veterinary medicine.

In the original publication [...]

Dr [...]

Brain tumors represent a heterogeneous group of neoplasms involving the brain or nearby tissues, affecting populations of all ages with a high incidence worldwide. Among the primary brain tumors, the most aggressive and also the most common is glioblastoma (GB), a type of glioma that falls into the category of IV-grade astrocytoma. GB often leads to death within a few months after diagnosis, even if the patient is treated with available therapies; for this reason, it is important to continue to discover new therapeutic approaches to allow for a better survival rate of these patients. Immunotherapy, today, seems to be one of the most innovative types of treatment, based on the ability of the immune system to counteract various pathologies, including cancer. In this context, interleukin 21 (IL-21), a type I cytokine produced by natural killer (NK) cells and CD4+ T lymphocytes, appears to be a valid target for new therapies since this cytokine is involved in the activation of innate and adaptive immunity. To match this purpose, our review deeply evaluated how IL-21 could influence the progression of GB, analyzing its main biological processes and mechanisms while evaluating the potential use of the latest available therapies.

Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain–containing protein 3 inflammasomes, and increased IL-1β formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.

Long COVID is a recognized post-viral syndrome characterized by neurological, somatic and neuropsychiatric symptoms that might last for long time after SARS-CoV-2 infection. An ever-growing number of patients come to the observation of General Practitioners complaining of mild or moderate symptoms after the resolution of the acute infection. Nine General Practitioners from the Rome area (Italy) performed a retrospective analysis in order to evaluate the role of the supplementation with Palmitoylethanolamide co-ultramicronized with Luteolin (PEALUT) on neurologic and clinical symptoms reported by their patients after COVID-19 resolution. Supplementation with PEALUT helped to improve all patient-reported symptoms, especially pain, anxiety and depression, fatigue, brain fog, anosmia and dysgeusia, leading to an overall improvement in patients’ health status. To our knowledge these are the first data presented on Long COVID patients collected in a territorial setting. Despite their preliminary nature, these results highlight the pathogenetic role of “non-resolving” neuroinflammation in Long COVID development and consequently the importance of its control in the resolution of the pathology and put the focus on the General Practitioner as the primary figure for early detection and management of Long COVID syndrome in a real-life setting. Future randomized, controlled, perspective clinical trials are needed to confirm this preliminary observation.

Post-Covid Olfactory Dysfunction (PCOD) is characterized by olfactory abnormalities, hyposmia, and anosmia, which are among the most often enduring symptoms in individuals who have recovered from SARS-CoV-2 infection. This disorder has been reported to persist in subsets of patients well after 12 months following infection, significantly affecting their quality of life. Despite the high prevalence of PCOD among patients who suffered from SARS-CoV-2 infection, specific therapeutic strategies are still limited. Among these, emerging evidence seems to indicate the administration of CoUltraPEALut, a combination of micronized Palmitoylethanolamide (PEA), an endogenous fatty acid amide, and Luteolin, a natural antioxidant flavonoid, as a viable therapy, especially when given as an adjuvant to olfactory training. Based on the above, a systematic review and a meta-analysis of the literature were conducted, with the aim of evaluating the efficacy of CoUltraPEALut as an addition to olfactory training (OT), in treating PCOD symptoms. Pubmed (MEDLINE), Embase (OVID), and Web of Science scientific databases were screened from the inception until 31 May 2023, and a total of 407 articles were recovered; only five of these studies (441 total patients between treated and control groups) were included in the systematic review. CoUltraPEALut demonstrated significant efficacy in the overall recovery of the olfactory function, compared to the conventional therapy, suggesting that it could represent a possible future adjuvant treatment for PCOD.

Myocarditis is an inflammatory and oxidative disorder characterized by immune cell recruitment in the damaged tissue and organ dysfunction. In this paper, we evaluated the molecular pathways involved in myocarditis using a natural compound, Coriolus versicolor, in an experimental model of autoimmune myocarditis (EAM). Animals were immunized with an emulsion of pig cardiac myosin and complete Freund’s adjuvant supplemented with mycobacterium tuberculosis; thereafter, Coriolus versicolor (200 mg/Kg) was orally administered for 21 days. At the end of the experiment, blood pressure and heart rate measurements were recorded and the body and heart weights as well. From the molecular point of view, the Coriolus versicolor administration reduced the activation of the TLR4/NF-κB pathway and the levels of pro-inflammatory cytokines (INF-γ, TNF-α, IL-6, IL-17, and IL-2) and restored the levels of anti-inflammatory cytokines (IL-10). These anti-inflammatory effects were accompanied with a reduced lipid peroxidation and nitrite levels and restored the antioxidant enzyme activities (SOD and CAT) and GSH levels. Additionally, it reduced the histological injury and the immune cell recruitment (CD4+ and CD68+ cells). Moreover, we observed an antiapoptotic activity in both intrinsic (Fas/FasL/caspase-3) and extrinsic (Bax/Bcl-2) pathways. Overall, our data showed that Coriolus versicolor administration modulates the TLR4/NF-κB signaling in EAM.

Almond skins are known for their antioxidative and anti-inflammatory properties, which are mainly due to the presence of polyphenols. The aim of the present study was to evaluate the antioxidant and anti-inflammatory effects of almond skin extract (ASE) obtained from the Sicilian cultivar “Fascionello” and to evaluate the possible mechanisms of action using an in vitro model of human monocytic U937 cells as well as an in vivo model of carrageenan (CAR)-induced paw edema. The in vitro studies demonstrated that pretreatment with ASE inhibited the formation of ROS and apoptosis. The in vivo studies showed that ASE restored the CAR-induced tissue changes; restored the activity of endogenous antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione; and decreased neutrophil infiltration, lipid peroxidation, and the release of proinflammatory mediators. The anti-inflammatory and antioxidant effects of ASE could be associated with the inhibition of the pro-inflammatory nuclear NF-κB and the activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) antioxidant pathways. In conclusion, almond skin could reduce the levels of inflammation and oxidative stress and could be beneficial in the treatment of several disorders.

Diet can modulate the different stages of inflammation due to the presence of bioactive compounds such as polyphenols. Apples are a great source of phenolic compounds that show anti-inflammatory and antioxidant properties, and these might be used as a dietary supplement and/or functional element in the treatment of chronic inflammatory illnesses. The aim of our study was to evaluate the anti-inflammatory and antioxidant actions of thinned apple polyphenol (TAP) extracts in a model of paw edema. The experimental model was induced in rats via subplantar injections of 1% λ-Carrageenan (CAR) in the right hind leg, and TAP extract was administered via oral gavage 30 min before and 1 h after the CAR injection at doses of 5 mg/kg and 10 mg/kg, respectively. The inflammatory response is usually quantified by the increase in the size of the paw (edema), which is maximal about 5 h after the injection of CAR. CAR-induced inflammation generates the release of pro-inflammatory mediators and reactive oxygen species (ROS). Furthermore, the inflammatory state induces the pain that involves the peripheral nociceptors, but above all it acts centrally at the level of the spinal cord. Our results showed that the TAP extracts reduced paw histological changes, neutrophil infiltration, mast cell degranulation, and oxidative stress. Additionally, the oral administration of TAP extracts decreased thermal and mechanical hyperalgesia, along with a reduction in spinal microglia and the markers of nociception. In conclusion, we demonstrate that TAP extract is able to modulate inflammatory, oxidative, and painful processes, and is also useful in the treatment of the symptoms associated with paw edema.

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.

Myocarditis is an inflammatory cardiac disorder and the primary cause of heart failure in young adults. Its origins can be attributed to various factors, including bacterial or viral infections, exposure to toxins or drugs, endocrine disruptors (EDs), and autoimmune processes. Tebuconazole (TEB), which is a member of the triazole fungicide family, is utilized to safeguard agricultural crop plants against fungal pathogens. Although TEB poses serious threats to mammal health, the information about how it induces toxic effects through various pathways, particularly in autoimmune diseases, are still limited. Thus, the aim of this paper was to evaluate the effect of TEB exposure in autoimmune myocarditis (AM). To induce AM, rats were immunized with porcine cardiac myosin and exposed to TEB for 21 days. Thereafter, animals were sacrificed, and histological, biochemical, and molecular analyses were performed. TEB exposure increased heart weight, systolic blood pressure and heart rate already augmented by AM. Additionally, it significantly increased creatine phosphokinase heart (CK-MB), creatine phosphokinase (CPK), cardiac troponin T (cTnT), and cardiac troponin I (cTnI), as compared to the control. From the histological perspective, TEB exacerbates the histological damage induced by AM (necrosis, inflammation and cell infiltration) and increased fibrosis and collagen deposition. TEB exposure strongly increased pro-inflammatory cytokines and prooxidant levels (O2−, H2O2, NO2−, lipid peroxidation) and reduced antioxidant enzyme levels, which were already dysregulated by AM. Additionally, TEB increased NOX-4 expression and the TGFβ1-Smads pathway already activated by AM. Overall, our results showed that TEB exposure strongly aggravated the cardiotoxicity induced by AM.

Perfluorinated and polyfluorinated alkyl substances (PFAS), more than 4700 in number, are a group of widely used man-made chemicals that accumulate in living things and the environment over time. They are known as “forever chemicals” because they are extremely persistent in our environment and body. Because PFAS have been widely used for many decades, their presence is evident globally, and their persistence and potential toxicity create concern for animals, humans and environmental health. They can have multiple adverse health effects, such as liver damage, thyroid disease, obesity, fertility problems, and cancer. The most significant source of living exposure to PFAS is dietary intake (food and water), but given massive industrial and domestic use, these substances are now punctually present not only domestically but also in the outdoor environment. For example, livestock and wildlife can be exposed to PFAS through contaminated water, soil, substrate, air, or food. In this review, we have analyzed and exposed the characteristics of PFAS and their various uses and reported data on their presence in the environment, from industrialized to less populated areas. In several areas of the planet, even in areas far from large population centers, the presence of PFAS was confirmed, both in marine and terrestrial animals (organisms). Among the most common PFAS identified are undoubtedly perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA), two of the most widely used and, to date, among the most studied in terms of toxicokinetics and toxicodynamics. The objective of this review is to provide insights into the toxic potential of PFAS, their exposure, and related mechanisms.

Endometriosis is a chronic disease characterized by pelvic inflammation. This study aimed at investigating the molecular mechanisms underlying the pathology and how they can be modulated by the administration of a natural compound, Actaea racemosa (AR). We employed an in vivo model of endometriosis in which rats were intraperitoneally injected with uterine fragments from donor animals. During the experiment, rats were monitored by abdominal high-frequency ultrasound analysis. AR was able to reduce the lesion’s size and histological morphology. From a molecular point of view, AR reduced hyperproliferation, as shown by Ki-67 and PCNA expression and MAPK phosphorylation. The impaired apoptosis pathway was also restored, as shown by the TUNEL assay and RT-PCR for Bax, Bcl-2, and Caspase levels. AR also has important antioxidant (reduced Nox expression, restored SOD activity and GSH levels, and reduced MPO activity and MDA levels) and anti-inflammatory (reduced cytokine levels) properties. Moreover, AR demonstrated its ability to reduce the pain-like behaviors associated with the pathology, the neuro-sensitizing mediators (c-FOS and NGF) expression, and the related central astrogliosis (GFAP expression in the spinal cord, brain cortex, and hippocampus). Overall, our data showed that AR was able to manage several pathways involved in endometriosis suppression.

The deadly interstitial lung condition known as idiopathic pulmonary fibrosis (IPF) worsens over time and for no apparent reason. The traditional therapy approaches for IPF, which include corticosteroids and immunomodulatory drugs, are often ineffective and can have noticeable side effects. The endocannabinoids are hydrolyzed by a membrane protein called fatty acid amide hydrolase (FAAH). Increasing endogenous levels of endocannabinoid by pharmacologically inhibiting FAAH results in numerous analgesic advantages in a variety of experimental models for pre-clinical pain and inflammation. In our study, we mimicked IPF by administering intratracheal bleomycin, and we administered oral URB878 at a dose of 5 mg/kg. The histological changes, cell infiltration, pro-inflammatory cytokine production, inflammation, and nitrosative stress caused by bleomycin were all reduced by URB878. Our data clearly demonstrate for the first time that the inhibition of FAAH activity was able to counteract not only the histological alteration bleomycin-induced but also the cascade of related inflammatory events.

Pharmaceuticals are widely recognized as potentially hazardous to aquatic ecosystems. In the last two decades, the constant intake of biologically active chemicals used in human healthcare has been related to the growing release of these agents into natural environments. As reported by several studies, various pharmaceuticals have been detected, mainly in surface water (seas, lakes, and rivers), but also in groundwater and drinking water. Moreover, these contaminants and their metabolites can show biological activity even at very low concentrations. This study aimed to evaluate the developmental toxicity of exposure to the chemotherapy drugs gemcitabine and paclitaxel in aquatic environments. Zebrafish (Danio rerio) embryos were exposed to doses of gemcitabine 15 μM in combination with paclitaxel 1 μM from 0 to 96 h post-fertilization (hpf) using a fish embryo toxicity test (FET). This study highlights that both gemcitabine and paclitaxel exposure at single non-toxic concentrations affected survival and hatching rate, morphology score, and body length after exposure in combination. Additionally, exposure significantly disturbed the antioxidant defense system and increased ROS in zebrafish larvae. Gemcitabine and paclitaxel exposure caused changes in the expression of inflammation-related, endoplasmic reticulum stress-related (ERS), and autophagy-related genes. Taken together, our findings underline that gemcitabine and paclitaxel increase developmental toxicity in zebrafish embryos in a time-dependent manner.

(1) Background: Vinclozolin is a popular fungicide used in fruit, ornamental plants, and vegetable crops. It has recently been seen that prolonged exposure to VZN can cause human or animal health damage to various organs, but little is known to date about its cardiovascular effects. In this study, we addressed the chronic effects of VZN on the myocardium and the enzymes involved in the cardiovascular function. (2) Methods: The animals were divided into four groups: group 1 served as the control, group 2 received 1 mg/kg of VZN by gavage, group 3 received 30 mg/kg of VZN by gavage, and group 4 received 100 mg/kg of VZN by gavage, for 30 days. (3) Results: Results showed that 100 mg/kg VZN markedly increased the plasma concentration of cardiac markers (CK-MB, cTnT, ANP, BNP). Moreover, compared to the control group, VZN treatment decreased the activity of SOD, CAT, and GPx, and downregulated the mRNA expression levels of Nrf2. Furthermore, collagen deposition was amplified owing to 100 mg/kg VZN cardiotoxicity. This harmful effect was confirmed by a histological study using hematoxylin and eosin (H&E) and Masson’s trichrome staining. (4) Conclusion: Overall, our results proved the cardiotoxicity caused by chronic exposure to VZN.

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.

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.

Alzheimer’s disease (AD) is the most common cause of dementia, and its prevalence rises with age. Inflammation and altered antioxidant systems play essential roles in the genesis of neurodegenerative diseases. In this work, we looked at the effects of MemophenolTM, a compound rich in polyphenols derived from French grape (Vitis vinifera L.) and wild North American blueberry (Vaccinium angustifolium A.) extracts, in a rat model of AD. Methods: For 60 days, the animals were administered with AlCl3 (100 mg/kg, orally) and D-galactose (60 mg/kg, intraperitoneally), while from day 30, MemophenolTM (15 mg/kg) was supplied orally for 30 consecutive days. AlCl3 accumulates mainly in the hippocampus, the main part of the brain involved in memory and learning. Behavioral tests were performed the day before the sacrifice when brains were collected for analysis. Results: MemophenolTM decreased behavioral alterations and hippocampus neuronal degeneration. It also lowered phosphorylated Tau (p-Tau) levels, amyloid precursor protein (APP) overexpression, and β-amyloid (Aβ) buildup. Furthermore, MemophenolTM reduced the pro-oxidative and pro-inflammatory hippocampus changes caused by AD. Our finding, relevant to AD pathogenesis and therapeutics, suggests that MemophenolTM, by modulating oxidative and inflammatory pathways and by regulating cellular brain stress response mechanisms, protects against the behavioral and histopathological changes associated with AD.

Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress, and neuronal depletion. They include selective malfunction and progressive loss of neurons, glial cells, and neural networks in the brain and spinal cord. There is an urgent need to develop new and more effective therapeutic strategies to combat these devastating diseases because, today, there is no treatment that can cure degenerative diseases; however, we have many symptomatic treatments. Current nutritional approaches are beginning to reflect a fundamental change in our understanding of health. The Mediterranean diet may have a protective effect on the neurodegenerative process because it is rich in antioxidants, fiber, and omega-3 polyunsaturated fatty acids. Increasing knowledge regarding the impact of diet on regulation at the genetic and molecular levels is changing the way we consider the role of nutrition, resulting in new dietary strategies. Natural products, thanks to their bioactive compounds, have recently undergone extensive exploration and study for their therapeutic potential for a variety of diseases. Targeting simultaneous multiple mechanisms of action and a neuroprotection approach with the diet could prevent cell death and restore function to damaged neurons. For these reasons, this review will be focused on the therapeutic potential of natural products and the associations between the Mediterranean-style diet (MD), neurodegenerative diseases, and markers and mechanisms of neurodegeneration.

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-β), 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.

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.

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.

In the original publication [...]

A chronic, painful, and inflammatory condition known as endometriosis is defined by the extra-uterine development of endometrial tissue. The aim of this study was to evaluate the beneficial effects of fisetin, a naturally occurring polyphenol that is frequently present in a variety of fruits and vegetables. Uterine fragments were injected intraperitoneally to cause endometriosis, and fisetin was given orally every day. At 14 days of treatment, laparotomy was performed, and the endometrial implants and peritoneal fluids were collected for histological, biochemical, and molecular analyses. Rats subjected to endometriosis presented important macroscopic and microscopic changes, increased mast cell (MC) infiltration, and fibrosis. Fisetin treatment reduced endometriotic implant area, diameter, and volumes, as well as histological alterations, neutrophil infiltration, cytokines release, the number of MCs together with the expression of chymase and tryptase, and diminished α smooth muscle actin (α-sma) and transforming growth factor beta (TGF β) expressions. In addition, fisetin was able to reduce markers of oxidative stress as well as nitrotyrosine and Poly ADP ribose expressions and increase apoptosis in endometrial lesions. In conclusion, fisetin could represent a new therapeutic strategy to control endometriosis perhaps by targeting the MC-derived NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway and oxidative stress.

Endometriosis is an estrogen-dependent gynecologic illness that has long-term effects on a woman’s fertility, physical health, and overall quality of life. Growing evidence suggests that endocrine-disrupting chemicals (EDCs) may be etiologically involved in the development and severity of the disease. We consider the available human evidence on EDCs and endometriosis, limiting ourselves to studies that have individually assessed chemical amounts in women. Dioxins, BPA, Phthalates, and other endocrine disruptors, like DDT, are among the evidence indicating an environmental etiology for endometriosis. Collectively, this review describes how environmental toxins are linked to lower fertility in women, as well as a number of reproductive diseases, focusing on the pathology of endometriosis and its treatments. Importantly, this review can be used to investigate techniques for preventing the negative effects of EDC exposure.

Bacterial sepsis induces the production of excessive pro-inflammatory cytokines and oxidative stress, resulting in tissue injury and hyperinflammation. Patients recovering from sepsis have increased rates of central nervous system (CNS) morbidities, which are linked to long-term cognitive impairment, such as neurodegenerative pathologies. This paper focuses on the tissue injury and hyperinflammation observed in the acute phase of sepsis and on the development of long-term neuroinflammation associated with septicemia. Here we evaluate the effects of Coriolus versicolor administration as a novel approach to treat polymicrobial sepsis. Rats underwent cecal ligation and perforation (CLP), and Coriolus versicolor (200 mg/kg in saline) was administered daily by gavage. Survival was monitored, and tissues from vital organs that easily succumb to infection were harvested after 72 h to evaluate the histological changes. Twenty-eight days after CLP, behavioral analyses were performed, and serum and brain (hippocampus) samples were harvested at four weeks from surgery. Coriolus versicolor increased survival and reduced acute tissue injury. Indeed, it reduced the release of pro-inflammatory cytokines in the bloodstream, leading to a reduced chronic inflammation. In the hippocampus, Coriolus versicolor administration restored tight junction expressions, reduce cytokines accumulation and glia activation. It also reduced toll-like receptor 4 (TLR4) and neuronal nitric oxide synthase (nNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome components expression. Coriolus versicolor showed antioxidant activities, restoring glutathione (GSH) levels and catalase and superoxide dismutase (SOD) activities and reducing lipid peroxidation, nitrite and reactive oxygen species (ROS) levels. Importantly, Coriolus versicolor reduced amyloid precursor protein (APP), phosphorylated-Tau (p-Tau), pathologically phosphorylated tau (PHF1), phosphorylated tau (Ser202 and Thr205) (AT8), interferon-induced transmembrane protein 3 (IFITM3) expression, and β-amyloid accumulation induced by CLP. Indeed, Coriolus versicolor restored synaptic dysfunction and behavioral alterations. This research shows the effects of Coriolus versicolor administration on the long-term development of neuroinflammation and brain dysfunction induced by sepsis. Overall, our results demonstrated that Coriolus versicolor administration was able to counteract the degenerative process triggered by sepsis.

Background: Fibromyalgia is a medical condition that affects a small percentage of the population, with no known effective treatment. There is evidence to suggest that inflammation is a key factor in the nerve sensitization that characterizes the disorder. Therefore, this paper concentrates on the role of IL-6 in fibromyalgia and the related pain-like symptoms. Methods: This work aimed to evaluate Sprague–Dawley rats, which were injected for three consecutive days with 1 mg/kg of reserpine; IL-6-R Ab was intraperitoneally injected at 1.5 mg/kg seven days after the first reserpine injection. Behavioral analyses were conducted at the beginning of the experiment and at seven and twenty-one days from the first reserpine injection. At this timepoint, the animals were sacrificed, and tissues were collected for molecular and histological analysis. Results: Our data showed the analgesic effect of IL-6-R-Ab administration on mechanical allodynia and thermal hyperalgesia. Additionally, the reserpine + IL-6-R-Ab group showed a reduced expression of the pain-related mediators cFOS and NFG and reduced levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokines (Cxcl5, Cxcl10 and Cx3cl1). From the molecular point of view, the IL-6-R-Ab administration reduced the gp130 phosphorylation and the activation of the Jak/STAT3 pathway. Additionally, the IL-6-R Ab reduced the activation of neuroinflammatory cells. Conclusions: Our study showed that IL-6 plays a crucial role in fibromyalgia by triggering the Jak/STAT3 pathway, leading to an increase in chemokine levels and activating glial cells.

Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. Its role in the mechanisms of cellular degeneration and protection is still unknown. The aim of our work is to investigate the endogenous activation of the DKK3 pathway in a model of transient occlusion of the middle cerebral artery in rats. In particular, the animals were subjected to 1 h of ischemia followed by different reperfusion times (1 h, 6 h, 12 h and 24 h) to evaluate the downstream pathway and the time course of its activation. Western blot analysis showed increased Dkk3 expression in animals with the highest time of reperfusion. The increased levels of Dkk3 were accompanied by reduced Wnt3a, Frz1 and PIWI1a expression in the cytosol while FOXM1 and β-catenin decreased in the nucleus. These molecular changes led to an increase in the apoptotic pathway, as showed by the increased expression of Caspase 3 and Bax and the reduced levels of Bcl-2, and to a decrease in neurogenesis, as shown by the decreased expression of Tbr2, Ngn2 and Pax6. In the second part of the study, we decided to employ curcumin, an activator of the Wnt/β-catenin signaling, to investigate its effect on Dkk3. In particular, curcumin was administered 1 and 6 h after ischemia, and animals were sacrificed 24 h later when the expression of Dkk3 was higher. Our data displayed that curcumin administration decreased Dkk3 expression, and increased Wnt3a, Frz1 and PIWI1a levels. Well in line with these data, curcumin administration increased nuclear β-catenin and FOXM1 expression. The down-regulation of Dkk3 by curcumin led to reduced apoptosis and increased neurogenesis. Summarizing, our results showed that Dkk3 acts as an inhibitor of Wnt/β-catenin signaling during cerebral ischemia. Additionally, its inhibition and the contextual activation of the Wnt/β-catenin pathway are protective against ischemic stroke.

Primary brain tumors are a leading cause of death worldwide and are characterized by extraordinary heterogeneity and high invasiveness. Current drug and radiotherapy therapies combined with surgical approaches tend to increase the five-year survival of affected patients, however, the overall mortality rate remains high, thus constituting a clinical challenge for which the discovery of new therapeutic strategies is needed. In this field, novel immunotherapy approaches, aimed at overcoming the complex immunosuppressive microenvironment, could represent a new method of treatment for central nervous system (CNS) tumors. Chemokines especially are a well-defined group of proteins that were so named due to their chemotactic properties of binding their receptors. Chemokines regulate the recruitment and/or tissue retention of immune cells as well as the mobilization of tumor cells that have undergone epithelial–mesenchymal transition, promoting tumor growth. On this basis, this review focuses on the function and involvement of chemokines and their receptors in primary brain tumors, specifically examining chemokine-targeting immunotherapies as one of the most promising strategies in neuro-oncology.

Abstract 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.

Abstract Background Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A3 adenosine receptor (A3AR) can provide antiinflammatory and neuroprotective effects. However, the role of A3AR in TBI has not been investigated. Methods Using the selective A3AR agonist, MRS5980, we evaluated the effects of A3AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. Results When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4+ and CD8+ T cell influx. Moreover, when measured 4–5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. Conclusion Our results provide support for the beneficial effects of small molecule A3AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.

Abstract Background Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine. Methods Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation. Results DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated. Conclusion These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.