71 results on '"Ryskalin L"'
Search Results
2. THE EFFECTS OF RAPAMYCIN ON THE OCCURRENCE OF PRIONOIDS IN GLIOBLASTOMA MULTIFORME
- Author
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Ryskalin, L, Biagioni, F, Gesi, M, Ruffoli, R, Giorgi, F. S., Lenzi, P, and Forna, i. F.
- Published
- 2021
3. Author Correction: A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling (Scientific Reports, (2017), 7, 1, (9706), 10.1038/s41598-017-10341-x)
- Author
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Vecchione C., Villa F., Carrizzo A., Spinelli C. C., Damato A., Ambrosio M., Ferrario A., MADONNA, MARTINA, Uccellatore A., Lupini S., Maciag A., Ryskalin L., Milanesi L., Frati G., Sciarretta S., BELLAZZI, RICCARDO, Genovese S., Ceriello A., Auricchio A., Malovini A., Puca A. A., Vecchione, C., Villa, F., Carrizzo, A., Spinelli, C. C., Damato, A., Ambrosio, M., Ferrario, A., Madonna, Martina, Uccellatore, A., Lupini, S., Maciag, A., Ryskalin, L., Milanesi, L., Frati, G., Sciarretta, S., Bellazzi, Riccardo, Genovese, S., Ceriello, A., Auricchio, A., Malovini, A., and Puca, A. A.
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
- Published
- 2019
4. NOVEL INSIGHT ON THE FINE MECHANISMS OF THE ACTION OF METHAMPHETAMINE WITHIN CATECHOLAMINERGIC NEURONS
- Author
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Fulceri, F, Ruffoli, R, Ryskalin, L, Soldani, P, and Fornai, F
- Published
- 2018
5. Methamphetamine and prion protein bridging drugs of abuse and neurodegeneration
- Author
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Limanaqi, F, Ryskalin, L, Ferrucci, M, Lazzeri, G, Falleni, A, Biagioni, F, Gambardella, S, and Fornai, F.
- Published
- 2017
6. Systematic Morphometry of Catecholamine Nuclei in the Brainstem Reticular Formation
- Author
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Bucci, D, Busceti, Cl, Calierno, Mt, Di Pietro, P, Madonna, M, Biagioni, F, Ryskalin, L, Limanaqi, F, Nicoletti, F, and Fornai, F.
- Subjects
reticular formation ,catecholamine ,tyrosine hydroxylase ,stereology ,catecholamine, dopamine, norepinephrine, epinephrine, tyrosine hydroxylase, reticular formation, brainstem, stereology ,epinephrine ,dopamine ,norepinephrine ,brainstem - Published
- 2017
7. The neuroanatomical features of the locus coeruleus in neurodegeneration
- Author
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Giorgi, Fs, Lazzeri, G., Lenzi, P., Busceti, C. L., Limanaqi, F., Ryskalin, L., and Fornai, F.
- Published
- 2017
8. PCR-based approach for qualitative molecular analysis of six neurotropic pathogens
- Author
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FERESE, R., primary, SCORZOLINI, L., additional, CAMPOPIANO, R., additional, ALBANO, V., additional, GRIGUOLI, A. M., additional, GIARDINA, E., additional, SCALA, S., additional, RYSKALIN, L., additional, D'ALESSIO, C., additional, ZAMPATTI, S., additional, FANTOZZI, R., additional, STORTO, M., additional, FORNAI, F., additional, and GAMBARDELLA, S., additional
- Published
- 2017
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9. Retraction Note: Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis.
- Author
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D'Antongiovanni V, Pellegrini C, Benvenuti L, Fornai M, Di Salvo C, Natale G, Ryskalin L, Bertani L, Lucarini E, Di Cesare Mannelli L, Ghelardini C, Nemeth ZH, Haskó G, and Antonioli L
- Published
- 2024
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10. The pharmacological blockade of P2X4 receptor as a viable approach to manage visceral pain in a rat model of colitis.
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Di Salvo C, D'Antongiovanni V, Benvenuti L, Fornai M, Valdiserra G, Natale G, Ryskalin L, Lucarini E, Mannelli LDC, Ghelardini C, Colucci R, Haskó G, Pellegrini C, and Antonioli L
- Subjects
- Animals, Rats, Male, Humans, Dexamethasone pharmacology, Interleukin-1beta metabolism, Visceral Pain drug therapy, Colitis drug therapy, Purinergic P2X Receptor Antagonists pharmacology, Purinergic P2X Receptor Antagonists therapeutic use, Receptors, Purinergic P2X4 metabolism, Disease Models, Animal
- Abstract
Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1β levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In in vitro studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1β axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1β axis inhibition.
- Published
- 2024
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11. Ultrasonographic measurements of gastro-soleus fascia thickness in midportion Achilles tendinopathy: A case-control study.
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Ryskalin L, Fulceri F, Morucci G, Busoni F, Soldani P, and Gesi M
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- Humans, Female, Case-Control Studies, Adult, Male, Middle Aged, Achilles Tendon diagnostic imaging, Achilles Tendon pathology, Tendinopathy diagnostic imaging, Tendinopathy pathology, Ultrasonography, Fascia diagnostic imaging, Fascia pathology, Fascia anatomy & histology, Muscle, Skeletal diagnostic imaging, Muscle, Skeletal pathology, Muscle, Skeletal anatomy & histology
- Abstract
Background: The Achilles tendon is one of the thickest, largest, and strongest tendons in the human body. Biomechanically, the AT represents the conjoint tendon of the triceps surae muscle, placed in series with the plantar fascia (PF) to ensure force transmission from the triceps surae toward the toes during walking, running, and jumping. Commonly encountered in the diagnostic evaluation of heel pain, Achilles tendinopathy (AT) refers to a combination of pathological changes affecting the tendon itself often resulting from excessive repetitive stress and overuse. Nevertheless, increasing evidence demonstrates that structural alterations due to overuse or abnormal patterns of skeletal muscle activity are not necessarily restricted to the muscles or tendons but can also affect the fascial tissue. At the same time, there has been recent discussion regarding the role of the fascial tissue as a potential contributor to the pathophysiological mechanisms of the development of several musculoskeletal disorders including tendinopathies. To the best of our knowledge, ultrasound (US) imaging studies on the fascial structures related to the triceps surae complex, as well as their possible correlation with Achillodynia have never been presented in the current literature., Methods: In the present study, a comparative US imaging evaluation of textural features of the suro-Achilleo-plantar complex was performed in 14 healthy controls and 14 symptomatic subjects complaining of midportion AT. The thickness of the Achilles tendon, paratenon, intermuscular fascia, and PF has been assessed with US. In addition, both groups underwent the Victorian Institute of Sport Assessment-Achilles (VISA-A), a disease-specific questionnaire that measures the severity of symptoms of AT. Correlations between quantitative ultrasound measures and VISA-A scores were determined through Pearson or Spearman's rho correlations., Results: Our ultrasonographic findings revealed statistically significant differences (p<0.05) in Achilles tendon and paratenon thicknesses between AT patients and controls. No significant differences were observed between groups in PF at the calcaneal insertion as all mean measures were within the expected range of a normal PF on US imaging. In contrast, in tendinopathic subjects, the deep intermuscular fascia between medial gastrocnemius (MG) and soleus (SOL) muscles is significantly (p<0.01) and considerably thickened compared to those of healthy subjects. Moderate correlations exist between tendon and paratenon thicknesses (r= 0.54, p= 0.04) and between MG-SOL fascia and tendon thicknesses (r= 0.58, p= 0.03). Regarding symptom severity and US morphological findings, the Spearman ρ test showed no correlation., Conclusions: Our data demonstrate that, in symptomatic subjects, US alterations are not restricted to paratenon and intratendinous areas, but also affect upstream structures along the myofascial chain, resulting in thickening of the fascia interposed between MG and SOL muscles. Moreover, positive correlations were found between MG-SOL fascia thickening and abnormalities in AT, paratenon, and symptom severity. Thus, US alterations in the fascial system should be interpreted within the clinical context of patients with AT as they may in turn represent important predictors of subsequent clinical outcomes and could help healthcare professionals and clinicians to refine non-operative treatment strategies and rehabilitation protocols for this disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)
- Published
- 2024
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12. Do the fasciae of the soleus have a role in plantar fasciitis?
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Ryskalin L, Morucci G, Soldani P, and Gesi M
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- Humans, Muscle, Skeletal, Fascia, Foot, Pain, Fasciitis, Plantar therapy, Achilles Tendon
- Abstract
Plantar fasciitis is a chronic, self-limiting, and painful disabling condition affecting the inferomedial aspect of the heel, usually extending toward the metatarsophalangeal joints. There is compelling evidence for a strong correlation between Achilles tendon (AT) loading and plantar aponeurosis (PA) tension. In line with this, tightness of the AT is found in almost 80% of patients affected by plantar fasciitis. A positive correlation has also been reported between gastrocnemius-soleus tightness and heel pain severity in this condition. Despite its high prevalence, the exact etiology and pathological mechanisms underlying plantar heel pain remain unclear. Therefore, the aim of the present paper is to discuss the anatomical and biomechanical substrates of plantar fasciitis with special emphasis on the emerging, though largely neglected, fascial system. In particular, the relationship between the fascia, triceps surae muscle, AT, and PA will be analyzed. We then proceed to discuss how structural and biomechanical alterations of the muscle-tendon-fascia complex due to muscle overuse or injury can create the conditions for the onset of PA pathology. A deeper knowledge of the possible molecular mechanisms underpinning changes in the mechanical properties of the fascial system in response to altered loading and/or muscle contraction could help healthcare professionals and clinicians refine nonoperative treatment strategies and rehabilitation protocols for plantar fasciitis., (© 2023 The Authors. Clinical Anatomy published by Wiley Periodicals LLC on behalf of American Association of Clinical Anatomists and British Association of Clinical Anatomists.)
- Published
- 2024
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13. Efficacy of focused extracorporeal shock wave therapy for fabella syndrome.
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Ryskalin L, Fulceri F, Morucci G, Busoni F, Soldani P, and Gesi M
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- 2024
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14. Early post-surgical rehabilitation and functional outcomes of a traumatic ulnar nerve injury: a pediatric case report.
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Fulceri F, Marinelli C, Ghelarducci G, Nucci AM, Poggetti A, Ryskalin L, and Gesi M
- Abstract
Background: Peripheral nerve injuries (PNIs) of the upper limb are very common events within the pediatric population, especially following soft tissue trauma and bone fractures. Symptoms of brachial plexus nerve injuries can differ considerably depending on the site and severity of injury. Compared to median and radial nerves, the ulnar nerve (UN) is the most frequently and severely injured nerve of the upper extremity. Indeed, due to its peculiar anatomical path, the UN is known to be particularly vulnerable to traumatic injuries, which result in pain and substantial motor and sensory disabilities of the forearm and hand. Therefore, timely and appropriate postoperative management of UN lesions is crucial to avoid permanent sensorymotor deficits and claw hand deformities leading to lifelong impairments. Nevertheless, the literature regarding the rehabilitation following PNIs is limited and lacks clear evidence regarding a solid treatment algorithm for the management of UN lesions that ensures full functional recovery., Case Presentation: The patient is a 11-year-old child who experienced left-hand pain, stiffness, and disability secondary to a domestic accident. The traumatic UN lesion occurred about 8 cm proximal to Guyon's canal and it was surgically treated with termino-terminal (end-to-end) neurorrhaphy. One month after surgery, the patient underwent multimodal rehabilitative protocol and both subjective and functional measurements were recorded at baseline (T0) and at 3- (T1) and 5-month (T2) follow-up. At the end of the rehabilitation protocol, the patient achieved substantial reduction in pain and improvement in quality of life. Of considerable interest, the patient regained a complete functional recovery with satisfactory handgrip and pinch functions in addition with a decrease of disability in activities of daily living., Conclusion: A timely and intensive rehabilitative intervention done by qualified hand therapist with previous training in the rehabilitation of upper limb neuromuscular disorders is pivotal to achieve a stable and optimal functional recovery of the hand, while preventing the onset of deformities, in patients with peripheral nerve injuries of the upper limb., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fulceri, Marinelli, Ghelarducci, Nucci, Poggetti, Ryskalin and Gesi.)
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- 2024
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15. Pain-Relieving Effects of Shockwave Therapy for Ledderhose Disease: An Ultrasound-Based Study of an Unusual Bilateral Case.
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Fulceri F, Ryskalin L, Morucci G, Busoni F, Soldani P, and Gesi M
- Abstract
Ledderhose disease (LD, or plantar fibromatosis) is a rare, nodular, hyperproliferative condition affecting the plantar aponeurosis of the foot. At present, several conservative, non-surgical treatments have been documented, although with various degrees of success, with little evidence in the literature supporting their efficacy. In this scenario, extracorporeal shock wave therapy (ESWT) has emerged as a safe, effective, and less invasive approach for the successful treatment of several refractory musculoskeletal conditions and soft tissue injuries. Again, recent experimental evidence has shown that ESWT can exert beneficial effects on different fibroproliferative diseases, including Dupuytren's and Peyronie's disease. In contrast, the literature regarding the use of ESWT for LD is extremely limited, and no optimal application parameters have been defined to ensure its effectiveness for this disease. Therefore, in the present paper, we report a case of a 48-year-old male patient who developed bilateral foot LD, which was successfully treated with a novel ESWT protocol of treatment consisting of three sessions at 1-week intervals, with 2000 impulses at 5 Hz with an energy flux density of 0.20 mJ/mm
2 . Our data show that this ESWT treatment protocol was effective in completely relieving pain, restoring full functional activity, and thus, greatly improving the patient's quality of life.- Published
- 2024
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16. Use of Saccharomyces boulardii CNCM I-745 as therapeutic strategy for prevention of nonsteroidal anti-inflammatory drug-induced intestinal injury.
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D'Antongiovanni V, Antonioli L, Benvenuti L, Pellegrini C, Di Salvo C, Calvigioni M, Panattoni A, Ryskalin L, Natale G, Banni S, Carta G, Ghelardi E, and Fornai M
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- Male, Rats, Animals, Diclofenac, NF-kappa B, Occludin, Anti-Inflammatory Agents, Non-Steroidal, Butyrates, Saccharomyces boulardii physiology, Intestinal Diseases chemically induced, Intestinal Diseases prevention & control
- Abstract
Background and Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. This study examined the protective effects of the probiotic Saccharomyces boulardii CNCM I-745 in a rat model of diclofenac-induced enteropathy., Experimental Approach: Enteropathy was induced in 40-week-old male rats by intragastric diclofenac (4 mg·kg
-1 BID for 14 days). S. boulardii CNCM I-745 (3 g·kg-1 BID by oral gavage) was administered starting 14 days before (preventive protocol) or along with (curative protocol) diclofenac administration. Ileal damage, inflammation, barrier integrity, gut microbiota composition and toll-like receptors (TLRs)-nuclear factor κB (NF-κB) pathway were evaluated., Key Results: Diclofenac elicited intestinal damage, along with increments of myeloperoxidase, malondialdehyde, tumour necrosis factor and interleukin-1β, overexpression of TLR2/4, myeloid differentiation primary response 88 (Myd88) and NF-κB p65, increased faecal calprotectin and butyrate levels, and decreased blood haemoglobin levels, occludin and butyrate transporter monocarboxylate transporter 1 (MCT1) expression. In addition, diclofenac provoked a shift of bacterial taxa in both faecal and ileal samples. Treatment with S. boulardii CNCM I-745, in both preventive and curative protocols, counteracted the majority of these deleterious changes. Only preventive administration of the probiotic counteracted NSAID-induced decreased expression of MCT1 and increase in faecal butyrate levels. Occludin expression, after probiotic treatment, did not significantly change., Conclusions and Implications: Treatment with S. boulardii CNCM I-745 prevents diclofenac-induced enteropathy through anti-inflammatory and antioxidant activities. Such effects are likely to be related to increased tissue butyrate bioavailability, through an improvement of butyrate uptake by the enteric mucosa., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
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17. Management of a High-Level Breaststroke Swimmer with Celiac Disease: A Case Report.
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Cannataro R, Morucci G, Moni L, Malorgio M, Ryskalin L, Gesi M, Levi-Micheli M, and Cione E
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- Humans, Swimming, Celiac Disease complications, Celiac Disease diagnosis
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- 2023
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18. Treatment of delayed union of the forearm with extracorporeal shockwave therapy: a case report and literature review.
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Ryskalin L, Fulceri F, Morucci G, Dell'Agli S, Soldani P, and Gesi M
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- Humans, Forearm, Fracture Healing, Bone Regeneration, Extracorporeal Shockwave Therapy, Fractures, Ununited surgery, Forearm Injuries therapy, Fractures, Bone therapy
- Abstract
Compared to other long bones, forearm fractures are particularly challenging due to the high rate of complications. These include malunion, delayed/nonunion, wrist and elbow movement reduction, and pain. Surgical procedure is considered the gold standard for managing delayed union and nonunion of the long bones. However, in the last decades, extracorporeal shockwave therapy (ESWT) has emerged as an effective and less invasive approach to enhance bone regeneration and fracture healing, avoiding major complications of surgical procedures. In contrast to the broad literature reporting good clinical results of ESWT in the treatment of nonunions, there is currently limited evidence regarding the clinical application of shock waves on long bone delayed fractures, particularly those of the forearm. In the present paper, we report a case of delayed bone healing of the diaphyseal region of the ulna treated with focused ESWT. The successful case experienced bone healing at the fracture site in less than 3 months after initial ESWT treatment. Acknowledging the limitation of reporting a case report, however, the remarkable clinical results and the absence of side effects contribute valuable information in support of the use of ESWT as an effective alternative to standard surgery for forearm fractures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ryskalin, Fulceri, Morucci, Dell’Agli, Soldani and Gesi.)
- Published
- 2023
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19. Effects of a 24-Week Exercise Program on Functional Fitness, Oxidative Stress, and Salivary Cortisol Levels in Elderly Subjects.
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Morucci G, Ryskalin L, Pratesi S, Branca JJV, Modesti A, Modesti PA, Gulisano M, and Gesi M
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- Humans, Aged, Aged, 80 and over, Infant, Newborn, Reactive Oxygen Species, Quality of Life, Antioxidants, Exercise physiology, Exercise Therapy methods, Oxidative Stress, Oxygen, Physical Fitness physiology, Hydrocortisone
- Abstract
Background and Objectives: Aging is a biological and irreversible process characterized by physiological alterations resulting in a progressive decline in biological functions, decreased resistance or adaptability to stress, and increased disease susceptibility. A decline in functional fitness, imbalance between pro- and antioxidant capacity, and/or hormonal dysregulation adversely impact physical capacity, emotional status, and overall quality of life, especially within the elderly population. On the other hand, regular physical activity is considered an effective strategy to prevent and reduce those changes associated with primary aging and concurrent chronic disease, while slowing age-related physical degeneration. However, there is still limited evidence-based information regarding both the intensity and interval of effective interventions on physical functioning in older adults. Thus, the aim of the study was to assess the effects of a 24-week regular multimodal exercise program on functional fitness, oxidative stress, salivary cortisol level, and self-perceived quality of life in a group of eighteen physically active elderly subjects (mean age 72.8 ± 7.5 years). Materials and Methods: A set of anthropometric and physical measurements (grip strength, chair sit to stand, sit and reach and back scratch) assessing the functional fitness performance were evaluated. Moreover, biochemical markers (derived-reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) tests, and salivary cortisol levels) and the EuroQoL 5-Dimension 3-Level (EuroQoL 5-D 3-L) self-perceived questionnaire of quality of life were measured before and after the intervention program. All measurements were normally distributed as assessed by D'Agostino and Pearson's omnibus normality test. Student's t -tests were used to evaluate the differences in all the parameters measured at baseline (T0) and after the 24-week physical program (T1). Results: The results showed that an age-tailored structured intervention exercise program (1 h per session, twice per week, for 24 weeks) was effective in improving flexibility and other biomechanical parameters, such as muscle strength and the dynamic balance fitness component, which are key to performing daily tasks independently. Moreover, biochemical analyses demonstrate that the proposed intervention program has beneficial effects on the balance between plasma ROS production and their neutralization. Conclusions: The results confirm the benefits of regular physical activity in older adults resulting in improved physical strength and flexibility in the functional fitness parameters, and in regulating anti- and pro-oxidant activity and cortisol (stress hormone) levels.
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- 2022
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20. Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis.
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D'Antongiovanni V, Pellegrini C, Benvenuti L, Fornai M, Di Salvo C, Natale G, Ryskalin L, Bertani L, Lucarini E, Di Cesare Mannelli L, Ghelardini C, Nemeth ZH, Haskó G, and Antonioli L
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Azepines, Caspase 1, Disease Models, Animal, Inflammasomes metabolism, Inflammation drug therapy, Inflammation metabolism, Mice, Oxadiazoles, Purinergic P2X Receptor Antagonists, Colitis chemically induced, Colitis drug therapy, Colitis pathology, NLR Family, Pyrin Domain-Containing 3 Protein
- Abstract
The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1β levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective. The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1β release and NLRP3, caspase-1, caspase-5, and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways., (© 2022. The Author(s).)
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- 2022
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21. Molecular Mechanisms Underlying the Pain-Relieving Effects of Extracorporeal Shock Wave Therapy: A Focus on Fascia Nociceptors.
- Author
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Ryskalin L, Morucci G, Natale G, Soldani P, and Gesi M
- Abstract
In recent years, extracorporeal shock wave therapy (ESWT) has received increasing attention for its potential beneficial effects on various bone and soft-tissue pathologies, yielding promising outcomes for pain relief and functional recovery. In fact, ESWT has emerged as an alternative, non-invasive, and safe treatment for the management of numerous musculoskeletal disorders, including myofascial pain syndrome (MPS). In particular, MPS is a common chronic painful condition, accounting for the largest proportion of patients affected by musculoskeletal problems. Remarkably, sensory innervation and nociceptors of the fascial system are emerging to play a pivotal role as pain generators in MPS. At the same time, increasing evidence demonstrates that application of ESWT results in selective loss of sensory unmyelinated nerve fibers, thereby inducing long-lasting analgesia. The findings discussed in the present review are supposed to add novel viewpoints that may further enrich our knowledge on the complex interactions occurring between disorders of the deep fascia including changes in innervation, sensitization of fascial nociceptors, the pathophysiology of chronic musculoskeletal pain of MPS, and EWST-induced analgesia. Moreover, gaining mechanistic insights into the molecular mechanisms of pain-alleviating effects of ESWT may broaden the fields of shock waves clinical practice far beyond the musculoskeletal system or its original application for lithotripsy.
- Published
- 2022
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22. Spreading of Alpha Synuclein from Glioblastoma Cells towards Astrocytes Correlates with Stem-like Properties.
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Ryskalin L, Biagioni F, Morucci G, Busceti CL, Frati A, Puglisi-Allegra S, Ferrucci M, and Fornai F
- Abstract
Evidence has been recently provided showing that, in baseline conditions, GBM cells feature high levels of α-syn which are way in excess compared with α-syn levels measured within control astrocytes. These findings are consistent along various techniques. In fact, they are replicated by using antibody-based protein detection, such as immuno-fluorescence, immuno-peroxidase, immunoblotting and ultrastructural stoichiometry as well as by measuring α-syn transcript levels at RT-PCR. The present manuscript further questions whether such a high amount of α-syn may be induced within astrocytes, which are co-cultured with GBM cells in a trans-well system. In astrocytes co-cultured with GBM cells, α-syn overexpression is documented. Such an increase is concomitant with increased expression of the stem cell marker nestin, along with GBM-like shifting in cell morphology. This concerns general cell morphology, subcellular compartments and profuse convolutions at the plasma membrane. Transmission electron microscopy (TEM) allows us to assess the authentic amount and sub-cellular compartmentalization of α-syn and nestin within baseline GBM cells and the amount, which is induced within co-cultured astrocytes, as well as the shifting of ultrastructure, which is reminiscent of GBM cells. These phenomena are mitigated by rapamycin administration, which reverts nestin- and α-syn-related overexpression and phenotypic shifting within co-cultured astrocytes towards baseline conditions of naïve astrocytes. The present study indicates that: (i) α-syn increases in astrocyte co-cultured with GBM cells; (ii) α-syn increases in astrocytes along with the stem cell marker nestin; (iii) α-syn increases along with a GBM-like shift of cell morphology; (iv) all these changes are replicated in different GBM cell lines and are reverted by the mTOR inhibitor rapamycin. The present findings indicate that α-syn does occur in high amount within GBM cells and may transmit to neighboring astrocytes as much as a stem cell phenotype. This suggests a mode of tumor progression for GBM cells, which may transform, rather than merely substitute, surrounding tissue; such a phenomenon is sensitive to mTOR inhibition.
- Published
- 2022
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23. Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity.
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Ryskalin L, Ferese R, Morucci G, Biagioni F, Busceti CL, Michetti F, Lenzi P, Frati A, and Fornai F
- Abstract
Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.
- Published
- 2022
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24. Inhibition of Autophagy In Vivo Extends Methamphetamine Toxicity to Mesencephalic Cell Bodies.
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Ferrucci M, Biagioni F, Busceti CL, Vidoni C, Castino R, Isidoro C, Ryskalin L, Frati A, Puglisi-Allegra S, and Fornai F
- Abstract
Methamphetamine (METH) is a widely abused psychostimulant and a stress-inducing compound, which leads to neurotoxicity for nigrostriatal dopamine (DA) terminals in rodents and primates including humans. In vitro studies indicate that autophagy is a strong modulator of METH toxicity. In detail, suppressing autophagy increases METH toxicity, while stimulating autophagy prevents METH-induced toxicity in cell cultures. In the present study, the role of autophagy was investigated in vivo. In the whole brain, METH alone destroys meso-striatal DA axon terminals, while fairly sparing DA cell bodies within substantia nigra pars compacta (SNpc). No damage to either cell bodies or axons from ventral tegmental area (VTA) is currently documented. According to the hypothesis that ongoing autophagy prevents METH-induced DA toxicity, we tested whether systemic injection of autophagy inhibitors such as asparagine (ASN, 1000 mg/Kg) or glutamine (GLN, 1000 mg/Kg), may extend METH toxicity to DA cell bodies, both within SNpc and VTA, where autophagy was found to be inhibited. When METH (5 mg/Kg × 4, 2 h apart) was administered to C57Bl/6 mice following ASN or GLN, a frank loss of cell bodies takes place within SNpc and a loss of both axons and cell bodies of VTA neurons is documented. These data indicate that, ongoing autophagy protects DA neurons and determines the refractoriness of cell bodies to METH-induced toxicity.
- Published
- 2021
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25. The Autophagy-Related Organelle Autophagoproteasome Is Suppressed within Ischemic Penumbra.
- Author
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Biagioni F, Mastroiacovo F, Lenzi P, Puglisi-Allegra S, Busceti CL, Ryskalin L, Ferese R, Bucci D, Frati A, Nicoletti F, and Fornai F
- Subjects
- Animals, Biomarkers metabolism, Male, Mice, Autophagosomes metabolism, Autophagosomes ultrastructure, Autophagy, HSP70 Heat-Shock Proteins metabolism, Ischemic Stroke metabolism, Ischemic Stroke pathology, Microtubule-Associated Proteins metabolism
- Abstract
The peri-infarct region, which surrounds the irreversible ischemic stroke area is named ischemic penumbra . This term emphasizes the borderline conditions for neurons placed within such a critical region. Area penumbra separates the ischemic core, where frank cell loss occurs, from the surrounding healthy brain tissue. Within such a brain region, nervous matter, and mostly neurons are impaired concerning metabolic conditions. The classic biochemical marker, which reliably marks area penumbra is the over-expression of the heat shock protein 70 (HSP70). However, other proteins related to cell clearing pathways are modified within area penumbra . Among these, autophagy proteins like LC3 increase in a way, which recapitulates Hsp70. In contrast, components, such as P20S, markedly decrease. Despite apparent discrepancies, the present study indicates remarkable overlapping between LC3 and P20S redistribution within area penumbra . In fact, the amount of both proteins is markedly reduced within vacuoles. Specifically, a massive loss of LC3 + P20S immuno-positive vacuoles (autophagoproteasomes) is reported here. This represents the most relevant sub-cellular alteration here described in cell clearing pathways within area penumbra . The functional significance of these findings remains to be determined and it will take a novel experimental stream to decipher the fine-tuning of such a phenomenon.
- Published
- 2021
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26. Lactoferrin Protects against Methamphetamine Toxicity by Modulating Autophagy and Mitochondrial Status.
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Ryskalin L, Biagioni F, Busceti CL, Polzella M, Lenzi P, Frati A, Ferrucci M, and Fornai F
- Subjects
- Animals, Autophagosomes drug effects, Autophagosomes metabolism, Autophagosomes ultrastructure, Cathepsin D metabolism, Cell Line, Tumor, Cell Survival drug effects, Humans, Lactoferrin administration & dosage, Lysosomal-Associated Membrane Protein 1 metabolism, Lysosomes drug effects, Lysosomes metabolism, Membrane Fusion drug effects, Methamphetamine administration & dosage, Microtubule-Associated Proteins metabolism, Mitochondria drug effects, Mitochondria ultrastructure, PC12 Cells, Phenotype, Rats, Time Factors, Tubulin metabolism, Vacuoles drug effects, Vacuoles metabolism, Vacuoles ultrastructure, Autophagy drug effects, Lactoferrin pharmacology, Methamphetamine toxicity, Mitochondria metabolism, Protective Agents pharmacology
- Abstract
Lactoferrin (LF) was used at first as a vehicle to deliver non-soluble active compounds to the body, including the central nervous system (CNS). Nonetheless, it soon became evident that, apart from acting as a vehicle, LF itself owns active effects in the CNS. In the present study, the effects of LF are assessed both in baseline conditions, as well as to counteract methamphetamine (METH)-induced neurodegeneration by assessing cell viability, cell phenotype, mitochondrial status, and specific autophagy steps. In detail, cell integrity in baseline conditions and following METH administration was carried out by using H&E staining, Trypan blue, Fluoro Jade B, and WST-1. Western blot and immuno-fluorescence were used to assess the expression of the neurofilament marker βIII-tubulin. Mitochondria were stained using Mito Tracker Red and Green and were further detailed and quantified by using transmission electron microscopy. Autophagy markers were analyzed through immuno-fluorescence and electron microscopy. LF counteracts METH-induced degeneration. In detail, LF significantly attenuates the amount of cell loss and mitochondrial alterations produced by METH; and mitigates the dissipation of autophagy-related proteins from the autophagy compartment, which is massively induced by METH. These findings indicate a protective role of LF in the molecular mechanisms of neurodegeneration.
- Published
- 2021
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27. The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson's Disease.
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Natale G, Ryskalin L, Morucci G, Lazzeri G, Frati A, and Fornai F
- Abstract
The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota-gut-brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson's disease. In fact, although being defined as a movement disorder, Parkinson's disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson's disease.
- Published
- 2021
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28. Retinal Degeneration Following Chronic Administration of the Parkinsonism-Inducing Neurotoxin MPTP.
- Author
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Pinelli R, Biagioni F, Bertelli M, Busceti CL, Scaffidi E, Ryskalin L, and Fornai F
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Dopamine, Mice, Neurotoxins toxicity, Parkinsonian Disorders chemically induced, Retinal Degeneration chemically induced
- Abstract
During late stages, retinal degenerative disorders affecting photoreceptors progress independently from the specific disease trigger. In fact, a number of detrimental consequences occur downstream of photoreceptors, which are triggered by the loss of photoreceptors themselves. Such downstream anatomical alterations were originally thought to be compensatory events aimed to restore retinal function. At present, these phenomena are deciphered as detrimental effects and the term retinal degeneration is used to indicate the loss of cells and architecture within the inner retina as a consequence of damage to photoreceptors. In the process of testing a photoreceptor-dependent downstream spreading of neurodegeneration we applied a neurotoxin mimicking Parkinson's disease (PD), 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP). Chronic MPTP administration produces degeneration within the mouse retina. This is evident by apoptosis quite circumscribed to photoreceptors, which is reminiscent of most phenotypes of retinal degeneration. Retinal pathology following plain HE histochemistry is more widespread with delamination and loss of neuronal packaging in the inner retina. The retinal damage is characterized by a marked synucleinopathy mostly within retinal ganglion cells. In contrast, dopamine-containing structures are intact while norepinephrine is significantly reduced. Despite the involvement of the retina in PD is documented, no study so far analyzed the onset of a synucleinopathy and a degenerative process mimicking what is now recognized in typical retinal degeneration. The present data provide a novel vista on the reciprocal role of the retina in neurodegenerative disorders.
- Published
- 2021
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29. Stoichiometric Analysis of Shifting in Subcellular Compartmentalization of HSP70 within Ischemic Penumbra.
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Mastroiacovo F, Biagioni F, Lenzi P, Ryskalin L, Puglisi-Allegra S, Nicoletti F, Frati A, and Fornai F
- Subjects
- Animals, Brain Ischemia pathology, Cell Death physiology, Cytosol pathology, Disease Models, Animal, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Microscopy, Electron, Scanning, Mitochondria pathology, Neurons pathology, Vacuoles pathology, Brain Ischemia metabolism, Cytosol metabolism, HSP70 Heat-Shock Proteins metabolism, Mitochondria metabolism, Neurons metabolism, Vacuoles metabolism
- Abstract
The heat shock protein (HSP) 70 is considered the main hallmark in preclinical studies to stain the peri-infarct region defined area penumbra in preclinical models of brain ischemia. This protein is also considered as a potential disease modifier, which may improve the outcome of ischemic damage. In fact, the molecule HSP70 acts as a chaperonine being able to impact at several level the homeostasis of neurons. Despite being used routinely to stain area penumbra in light microscopy, the subcellular placement of this protein within area penumbra neurons, to our knowledge, remains undefined. This is key mostly when considering studies aimed at deciphering the functional role of this protein as a determinant of neuronal survival. The general subcellular placement of HSP70 was grossly reported in studies using confocal microscopy, although no direct visualization of this molecule at electron microscopy was carried out. The present study aims to provide a direct evidence of HSP70 within various subcellular compartments. In detail, by using ultrastructural morphometry to quantify HSP70 stoichiometrically detected by immuno-gold within specific organelles we could compare the compartmentalization of the molecule within area penumbra compared with control brain areas. The study indicates that two cell compartments in control conditions own a high density of HSP70, cytosolic vacuoles and mitochondria. In these organelles, HSP70 is present in amount exceeding several-fold the presence in the cytosol. Remarkably, within area penumbra a loss of such a specific polarization is documented. This leads to the depletion of HSP70 from mitochondria and mostly cell vacuoles. Such an effect is expected to lead to significant variations in the ability of HSP70 to exert its physiological roles. The present findings, beyond defining the neuronal compartmentalization of HSP70 within area penumbra may lead to a better comprehension of its beneficial/detrimental role in promoting neuronal survival.
- Published
- 2021
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30. Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy.
- Author
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Fulceri F, Biagioni F, Limanaqi F, Busceti CL, Ryskalin L, Lenzi P, and Fornai F
- Subjects
- Animals, Denervation, Disease Models, Animal, Mice, Motor Neurons, Neuromuscular Junction, Muscular Atrophy, Spinal genetics, Spinal Muscular Atrophies of Childhood
- Abstract
Spinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.
- Published
- 2021
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31. Neuroprotective Effects of Curcumin in Methamphetamine-Induced Toxicity.
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Ryskalin L, Puglisi-Allegra S, Lazzeri G, Biagioni F, Busceti CL, Balestrini L, Fornasiero A, Leone S, Pompili E, Ferrucci M, and Fornai F
- Subjects
- Animals, Apoptosis drug effects, Curcuma chemistry, Curcumin chemistry, Humans, Methamphetamine toxicity, Neuroprotective Agents chemistry, Neurotoxicity Syndromes pathology, PC12 Cells, Plant Extracts chemistry, Plant Extracts pharmacology, Rats, Curcumin pharmacology, Neuroprotective Agents pharmacology, Neurotoxicity Syndromes drug therapy, Oxidative Stress drug effects
- Abstract
Curcumin (CUR), a natural polyphenol extracted from rhizome of the Curcuma longa L , has received great attention for its multiple potential health benefits as well as disease prevention. For instance, CUR protects against toxic agents acting on the human body, including the nervous system. In detail, CUR possesses, among others, strong effects as an autophagy activator. The present study indicates that CUR counteracts methamphetamine (METH) toxicity. Such a drug of abuse is toxic by disturbing the autophagy machinery. We profited from an unbiased, low variable cell context by using rat pheochromocytoma PC12 cell line. In such a system, a strong protection was exerted by CUR against METH toxicity. This was associated with increased autophagy flux, merging of autophagosomes with lysosomes and replenishment of autophagy vacuoles with LC3, which instead is moved out from the vacuoles by METH. This is expected to enable the autophagy machinery. In fact, while in METH-treated cells the autophagy substrates α-synuclein accumulates in the cytosol, CUR speeds up α-synuclein clearance. Under the effects of CUR LC3 penetrate in autophagy vacuoles to commit them to cell clearance and promotes the autophagy flux. The present data provide evidence that CUR counteracts the neurotoxic effects induced by METH by promoting autophagy.
- Published
- 2021
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32. The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer.
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Ryskalin L, Biagioni F, Busceti CL, Giambelluca MA, Morelli L, Frati A, and Fornai F
- Abstract
Cellular prion protein (PrP
C ) is seminal to modulate a variety of baseline cell functions to grant homeostasis. The classic role of such a protein was defined as a chaperone-like molecule being able to rescue cell survival. Nonetheless, PrPC also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrPSc ). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrPC in its folded conformation may foster tumor progression by acting at multiple levels. The present review focuses on such a cancer-promoting effect. The manuscript analyzes recent findings on the occurrence of PrPC in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrPC on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrPC and the epigenetic effects, which are induced in neighboring cells to activate cancer-related genes. These detrimental effects are further discussed in relation to the aberrancy of its physiological and beneficial role on cell homeostasis. A specific paragraph is dedicated to the role of PrPC beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.- Published
- 2021
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33. The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects.
- Author
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Ryskalin L, Biagioni F, Busceti CL, Lazzeri G, Frati A, and Fornai F
- Subjects
- Cell Differentiation drug effects, Cell Movement drug effects, Glioblastoma pathology, Humans, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Neoplastic Stem Cells drug effects, Signal Transduction drug effects, Autophagy drug effects, Cell Proliferation drug effects, Curcumin pharmacology, Glioblastoma drug therapy
- Abstract
The present review focuses on the multi-faceted effects of curcumin on the neurobiology glioblastoma multiforme (GBM), with a special emphasis on autophagy (ATG)-dependent molecular pathways activated by such a natural polyphenol. This is consistent with the effects of curcumin in a variety of experimental models of neurodegeneration, where the molecular events partially overlap with GBM. In fact, curcumin broadly affects various signaling pathways, which are similarly affected in cell degeneration and cell differentiation. The antitumoral effects of curcumin include growth inhibition, cell cycle arrest, anti-migration and anti-invasion, as well as chemo- and radio-sensitizing activity. Remarkably, most of these effects rely on mammalian target of rapamycin (mTOR)-dependent ATG induction. In addition, curcumin targets undifferentiated and highly tumorigenic GBM cancer stem cells (GSCs). When rescuing ATG with curcumin, the tumorigenic feature of GSCs is suppressed, thus counteracting GBM establishment and growth. It is noteworthy that targeting GSCs may also help overcome therapeutic resistance and reduce tumor relapse, which may lead to a significant improvement of GBM prognosis. The present review focuses on the multi-faceted effects of curcumin on GBM neurobiology, which represents an extension to its neuroprotective efficacy.
- Published
- 2020
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34. Role of proteinase-activated receptors 1 and 2 in nonsteroidal anti-inflammatory drug enteropathy.
- Author
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Fornai M, Colucci R, Pellegrini C, Benvenuti L, Natale G, Ryskalin L, Blandizzi C, and Antonioli L
- Subjects
- Animals, Caspase 3 metabolism, Ileum drug effects, Ileum metabolism, Indomethacin pharmacology, Intestinal Diseases drug therapy, Intestinal Diseases metabolism, Male, Malondialdehyde metabolism, Peroxidase metabolism, Rats, Rats, Wistar, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Protein Serine-Threonine Kinases metabolism, Receptor, PAR-2 metabolism
- Abstract
Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can promote lower gastrointestinal detrimental effects. Proteinase-activated receptors 1 (PAR1) and PAR2 are involved in the pathophysiology of several digestive disorders. This study examines the contribution of PAR1 and PAR2 in NSAID-induced small intestinal injury, and to investigate the underlying mechanisms., Methods: Male Wistar rats (40 weeks old) were treated with indomethacin (1.5 mg/kg BID) for 14 days. Subgroups of animals were treated intraperitoneally with TFFLR-NH2 (PAR1 agonist), AC55541 (PAR2 agonist), SCH79797 (PAR1 antagonist) or ENMD-1068 (PAR2 antagonist). After treatments, blood and feces were collected for the assessment of hemoglobin and calprotectin, respectively. The ileum was processed for the evaluation of myeloperoxidase (MPO), malondialdehyde (MDA), and the protein expression of occludin and activated caspase-3., Results: Indomethacin elicited a significant intestinal damage, associated with a decrease in blood hemoglobin and an increase in tissue MPO, MDA and fecal calprotectin. In this setting, either the PAR1 agonist or PAR2 antagonist counteracted these changes, with the exception of MDA, which was unaffected. By contrast, the PAR1 antagonist or PAR2 agonist did not exert any effect on all the parameters. Indomethacin also decreased occludin and increased activated caspase-3 expression in ileal tissues. The PAR1 agonist or PAR2 antagonist prevented the reduced occludin expression, while the PAR2 antagonist also decreased the levels of activated caspase-3., Conclusions: PAR2 is involved in the pathogenesis of indomethacin enteropathy, through pro-inflammatory mechanisms and an impairment of the intestinal epithelial barrier. PAR1 activation and PAR2 inhibition could represent suitable strategies for the prevention of NSAID enteropathy.
- Published
- 2020
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35. mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme.
- Author
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Ryskalin L, Biagioni F, Lenzi P, Frati A, and Fornai F
- Abstract
Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.
- Published
- 2020
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36. Protective effects of the combination Bifidobacterium longum plus lactoferrin against NSAID-induced enteropathy.
- Author
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Fornai M, Pellegrini C, Benvenuti L, Tirotta E, Gentile D, Natale G, Ryskalin L, Colucci R, Piccoli E, Ghelardi E, Blandizzi C, and Antonioli L
- Subjects
- Animals, Diclofenac adverse effects, Feces chemistry, Hemoglobins, Ileum microbiology, Intestinal Diseases chemically induced, Intestinal Diseases microbiology, Intestinal Mucosa, Leukocyte L1 Antigen Complex analysis, Male, Malondialdehyde metabolism, NF-kappa B, Peroxidase metabolism, Rats, Signal Transduction, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Bifidobacterium longum, Intestinal Diseases prevention & control, Lactoferrin administration & dosage, Prebiotics administration & dosage, Probiotics administration & dosage, Protective Agents administration & dosage
- Abstract
Objectives: Nonsteroidal anti-inflammatory drugs can exert detrimental effects in the lower digestive tract. The aim of this study was to examine the protective effects of a combination of the probiotic Bifidobacterium longum BB536 (Bifidobacterium) with the prebiotic lactoferrin in a rat model of diclofenac-induced enteropathy., Methods: Enteropathy was induced in 40-wk-old male rats by intragastric diclofenac (4 mg/kg twice daily for 14 d). Lactoferrin (100 mg/kg twice daily), Bifidobacterium (2.5 × 10
6 CFU/rat twice daily) or their combination were administered 1 h before diclofenac. At the end of treatments, the ileum was processed for the evaluation of histologic damage, myeloperoxidase (MPO) and malondialdehyde (MDA) levels, as well as the expression of Toll-like receptors 2 and 4 (TLR-2/-4) and the activation of downstream signaling molecules (MyD88 and nuclear factor [NF]-κB p65). Blood hemoglobin and fecal calprotectin were also assessed., Results: Diclofenac induced intestinal damage, along with increments of MPO and MDA, overexpression of TLR-2, TLR-4, MyD88, and NF-κB p65, increased fecal calprotectin and decreased blood hemoglobin levels. Lactoferrin or Bifidobacterium alone prevented diclofenac-induced enteric damage, and the changes in blood hemoglobin, MPO, MDA, fecal calprotectin, and NF-κB p65. Bifidobacterium, but not lactoferrin, decreased TLR-4 expression, although none of them affected MyD88 overexpression. TLR-2 expression was slightly enhanced by all treatments. The combined administration of lactoferrin and Bifidobacterium reduced further the intestinal damage, and restored MPO and blood hemoglobin levels., Conclusions: Diclofenac induced ileal mucosal lesions by activation of inflammatory and pro-oxidant mechanisms. These detrimental actions were prevented by the combination of lactoferrin with Bifidobacterium likely through the modulation of TLR-2/-4/NF-κB proinflammatory pathways., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2020
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37. Motor Neurons Pathology After Chronic Exposure to MPTP in Mice.
- Author
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Vivacqua G, Biagioni F, Busceti CL, Ferrucci M, Madonna M, Ryskalin L, Yu S, D'Este L, and Fornai F
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine adverse effects, Motor Neurons drug effects, Motor Neurons pathology, Parkinsonian Disorders chemically induced, Parkinsonian Disorders pathology
- Abstract
The neurotoxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism in rodents and primates. Among different administration protocols, continuous or chronic exposure to small amounts of MPTP is reported to better mimic cell pathology reminiscent of Parkinson's disease (PD). Catecholamine neurons are the most sensitive to MPTP neurotoxicity; however, recent studies have found that MPTP alters the fine anatomy of the spinal cord including motor neurons, thus overlapping again with the spinal cord involvement documented in PD. In the present study, we demonstrate that chronic exposure to low amounts of MPTP (10 mg/kg daily, × 21 days) significantly reduces motor neurons in the ventral lumbar spinal cord while increasing α-synuclein immune-staining within the ventral horn. Spinal cord involvement in MPTP-treated mice extends to Calbindin D28 KDa immune-reactive neurons other than motor neurons within lamina VII. These results were obtained in the absence of significant reduction of dopaminergic cell bodies in the Substantia Nigra pars compacta, while a slight decrease was documented in striatal tyrosine hydroxylase immune-staining. Thus, the present study highlights neuropathological similarities between dopaminergic neurons and spinal motor neurons and supports the pathological involvement of spinal cord in PD and experimental MPTP-induced parkinsonism. Remarkably, the toxic threshold for motor neurons appears to be lower compared with nigral dopaminergic neurons following a chronic pattern of MPTP intoxication. This sharply contrasts with previous studies showing that MPTP intoxication produces comparable neuronal loss within spinal cord and Substantia Nigra.
- Published
- 2020
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38. Prion Protein in Glioblastoma Multiforme.
- Author
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Ryskalin L, Busceti CL, Biagioni F, Limanaqi F, Familiari P, Frati A, and Fornai F
- Subjects
- Animals, Autophagy, Cell Communication, Cell Differentiation, Exosomes metabolism, Glioblastoma drug therapy, Glioblastoma pathology, Humans, Molecular Targeted Therapy, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Prion Proteins antagonists & inhibitors, Prion Proteins chemistry, Tumor Microenvironment, Disease Susceptibility, Glioblastoma etiology, Glioblastoma metabolism, Prion Proteins genetics, Prion Proteins metabolism
- Abstract
The cellular prion protein (PrPc) is an evolutionarily conserved cell surface protein encoded by the PRNP gene. PrPc is ubiquitously expressed within nearly all mammalian cells, though most abundantly within the CNS. Besides being implicated in the pathogenesis and transmission of prion diseases, recent studies have demonstrated that PrPc contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPc over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, breast cancer, gastric cancer, and primary brain tumors, mostly glioblastoma multiforme (GBM). Thus, PrPc is emerging as a key in maintaining glioblastoma cancer stem cells' (GSCs) phenotype, thereby strongly affecting GBM infiltration and relapse. In fact, PrPc contributes to GSCs niche's maintenance by modulating GSCs' stem cell-like properties while restraining them from differentiation. This is the first review that discusses the role of PrPc in GBM. The manuscript focuses on how PrPc may act on GSCs to modify their expression and translational profile while making the micro-environment surrounding the GSCs niche more favorable to GBM growth and infiltration.
- Published
- 2019
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39. Molecular Mechanisms Linking ALS/FTD and Psychiatric Disorders, the Potential Effects of Lithium.
- Author
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Limanaqi F, Biagioni F, Ryskalin L, Busceti CL, and Fornai F
- Abstract
Altered proteostasis, endoplasmic reticulum (ER) stress, abnormal unfolded protein response (UPR), mitochondrial dysfunction and autophagy impairment are interconnected events, which contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). In recent years, the mood stabilizer lithium was shown to potentially modify ALS/FTD beyond mood disorder-related pathology. The effects of lithium are significant in ALS patients carrying genetic variations in the UNC13 presynaptic protein, which occur in ALS/FTD and psychiatric disorders as well. In the brain, lithium modulates a number of biochemical pathways involved in synaptic plasticity, proteostasis, and neuronal survival. By targeting UPR-related events, namely ER stress, excitotoxicity and autophagy dysfunction, lithium produces plastic effects. These are likely to relate to neuroprotection, which was postulated for mood and motor neuron disorders. In the present manuscript, we try to identify and discuss potential mechanisms through which lithium copes concomitantly with ER stress, UPR and autophagy dysfunctions related to UNC13 synaptic alterations and aberrant RNA and protein processing. This may serve as a paradigm to provide novel insights into the neurobiology of ALS/FTD featuring early psychiatric disturbances., (Copyright © 2019 Limanaqi, Biagioni, Ryskalin, Busceti and Fornai.)
- Published
- 2019
- Full Text
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40. The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies.
- Author
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Ryskalin L, Gaglione A, Limanaqi F, Biagioni F, Familiari P, Frati A, Esposito V, and Fornai F
- Subjects
- Animals, Biomarkers, Brain Neoplasms diagnosis, Brain Neoplasms therapy, Cell Differentiation, Cell Transformation, Neoplastic metabolism, Disease Management, Glioblastoma diagnosis, Glioblastoma therapy, Humans, Molecular Targeted Therapy, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Autophagy, Brain Neoplasms etiology, Brain Neoplasms metabolism, Glioblastoma etiology, Glioblastoma metabolism, Neoplastic Stem Cells metabolism
- Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology.
- Published
- 2019
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41. Phytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism.
- Author
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Limanaqi F, Biagioni F, Busceti CL, Ryskalin L, Polzella M, Frati A, and Fornai F
- Subjects
- Animals, Humans, Neuroprotective Agents pharmacology, Parkinsonian Disorders metabolism, Parkinsonian Disorders physiopathology, Proteolysis, Autophagy, Parkinsonian Disorders drug therapy, Phytochemicals pharmacology, alpha-Synuclein metabolism
- Abstract
Among nutraceuticals, phytochemical-rich compounds represent a source of naturally-derived bioactive principles, which are extensively studied for potential beneficial effects in a variety of disorders ranging from cardiovascular and metabolic diseases to cancer and neurodegeneration. In the brain, phytochemicals produce a number of biological effects such as modulation of neurotransmitter activity, growth factor induction, antioxidant and anti-inflammatory activity, stem cell modulation/neurogenesis, regulation of mitochondrial homeostasis, and counteracting protein aggregation through modulation of protein-folding chaperones and the cell clearing systems autophagy and proteasome. In particular, the ability of phytochemicals in restoring proteostasis through autophagy induction took center stage in recent research on neurodegenerative disorders such as Parkinson's disease (PD). Indeed, autophagy dysfunctions and α-syn aggregation represent two interdependent downstream biochemical events, which concur in the parkinsonian brain, and which are targeted by phytochemicals administration. Therefore, in the present review we discuss evidence about the autophagy-based neuroprotective effects of specific phytochemical-rich plants in experimental parkinsonism, with a special focus on their ability to counteract alpha-synuclein aggregation and toxicity. Although further studies are needed to confirm the autophagy-based effects of some phytochemicals in parkinsonism, the evidence discussed here suggests that rescuing autophagy through natural compounds may play a role in preserving dopamine (DA) neuron integrity by counteracting the aggregation, toxicity, and prion-like spreading of α-syn, which remains a hallmark of PD.
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- 2019
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42. The effects of proteasome on baseline and methamphetamine-dependent dopamine transmission.
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Limanaqi F, Biagioni F, Busceti CL, Ryskalin L, and Fornai F
- Subjects
- Humans, Proteasome Endopeptidase Complex drug effects, Ubiquitins drug effects, Amphetamine-Related Disorders metabolism, Dopamine metabolism, Dopamine Agents pharmacology, Methamphetamine pharmacology, Neuronal Plasticity drug effects, Proteasome Endopeptidase Complex metabolism, Ubiquitins metabolism
- Abstract
The Ubiquitin Proteasome System (UPS) is a major multi-catalytic machinery, which guarantees cellular proteolysis and turnover. Beyond cytosolic and nuclear cell compartments, the UPS operates at the synapse to modulate neurotransmission and plasticity. In fact, dysregulations of the UPS are linked with early synaptic alterations occurring in a variety of dopamine (DA)-related brain disorders. This is the case of psychiatric conditions such as methamphetamine (METH) addiction. While being an extremely powerful DA releaser, METH impairs UPS activity, which is largely due to DA itself. In turn, pre- and post- synaptic neurons of the DA circuitry show a high vulnerability to UPS inhibition. Thus, alterations of DA transmission and UPS activity are intermingled within a chain of events underlying behavioral alterations produced by METH. These findings, which allow escaping the view of a mere implication of the UPS in protein toxicity-related mechanisms, indicate a more physiological role for the UPS in modulating DA-related behavior. This is seminal for those plasticity mechanisms which underlie overlapping psychiatric disorders such as METH addiction and schizophrenia., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
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43. Author Correction: A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling.
- Author
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Vecchione C, Villa F, Carrizzo A, Spinelli CC, Damato A, Ambrosio M, Ferrario A, Madonna M, Uccellatore A, Lupini S, Maciag A, Ryskalin L, Milanesi L, Frati G, Sciarretta S, Bellazzi R, Genovese S, Ceriello A, Auricchio A, Malovini A, and Puca AA
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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- 2019
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44. Corticosterone Upregulates Gene and Protein Expression of Catecholamine Markers in Organotypic Brainstem Cultures.
- Author
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Busceti CL, Ferese R, Bucci D, Ryskalin L, Gambardella S, Madonna M, Nicoletti F, and Fornai F
- Subjects
- Animals, Brain Stem cytology, Brain Stem drug effects, Dopamine Plasma Membrane Transport Proteins genetics, Dopamine Plasma Membrane Transport Proteins metabolism, Dopamine beta-Hydroxylase genetics, Dopamine beta-Hydroxylase metabolism, Mice, Mice, Inbred C57BL, Organ Culture Techniques methods, Tyrosine 3-Monooxygenase genetics, Tyrosine 3-Monooxygenase metabolism, Up-Regulation, Brain Stem metabolism, Catecholamines metabolism, Corticosterone pharmacology
- Abstract
Glucocorticoids are produced by the adrenal cortex and regulate cell metabolism in a variety of organs. This occurs either directly, by acting on specific receptors in a variety of cells, or by stimulating catecholamine expression within neighbor cells of the adrenal medulla. In this way, the whole adrenal gland may support specific metabolic requirements to cope with stressful conditions from external environment or internal organs. In addition, glucocorticoid levels may increase significantly in the presence of inappropriate secretion from adrenal cortex or may be administered at high doses to treat inflammatory disorders. In these conditions, metabolic alterations and increased blood pressure may occur, although altered sleep-waking cycle, anxiety, and mood disorders are frequent. These latter symptoms remain unexplained at the molecular level, although they overlap remarkably with disorders affecting catecholamine nuclei of the brainstem reticular formation. In fact, the present study indicates that various doses of glucocorticoids alter the expression of genes and proteins, which are specific for reticular catecholamine neurons. In detail, corticosterone administration to organotypic mouse brainstem cultures significantly increases Tyrosine hydroxylase (TH) and Dopamine transporter (DAT), while Phenylethanolamine N-methyltransferase (PNMT) is not affected. On the other hand, Dopamine Beta-Hydroxylase (DBH) increases only after very high doses of corticosterone.
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- 2019
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45. The Effects of Amphetamine and Methamphetamine on the Release of Norepinephrine, Dopamine and Acetylcholine From the Brainstem Reticular Formation.
- Author
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Ferrucci M, Limanaqi F, Ryskalin L, Biagioni F, Busceti CL, and Fornai F
- Abstract
Amphetamine (AMPH) and methamphetamine (METH) are widely abused psychostimulants, which produce a variety of psychomotor, autonomic and neurotoxic effects. The behavioral and neurotoxic effects of both compounds (from now on defined as AMPHs) stem from a fair molecular and anatomical specificity for catecholamine-containing neurons, which are placed in the brainstem reticular formation (RF). In fact, the structural cross-affinity joined with the presence of shared molecular targets between AMPHs and catecholamine provides the basis for a quite selective recruitment of brainstem catecholamine neurons following AMPHs administration. A great amount of investigations, commentary manuscripts and books reported a pivotal role of mesencephalic dopamine (DA)-containing neurons in producing behavioral and neurotoxic effects of AMPHs. Instead, the present review article focuses on catecholamine reticular neurons of the low brainstem. In fact, these nuclei add on DA mesencephalic cells to mediate the effects of AMPHs. Among these, we also include two pontine cholinergic nuclei. Finally, we discuss the conundrum of a mixed neuronal population, which extends from the pons to the periaqueductal gray (PAG). In this way, a number of reticular nuclei beyond classic DA mesencephalic cells are considered to extend the scenario underlying the neurobiology of AMPHs abuse. The mechanistic approach followed here to describe the action of AMPHs within the RF is rooted on the fine anatomy of this region of the brainstem. This is exemplified by a few medullary catecholamine neurons, which play a pivotal role compared with the bulk of peripheral sympathetic neurons in sustaining most of the cardiovascular effects induced by AMPHs.
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- 2019
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46. Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity.
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Limanaqi F, Biagioni F, Busceti CL, Ryskalin L, Soldani P, Frati A, and Fornai F
- Subjects
- Animals, Autophagy, Biomarkers, Disease Susceptibility, Energy Metabolism, Humans, Immune System cytology, Immune System immunology, Immune System metabolism, Inflammation Mediators metabolism, Neurodegenerative Diseases etiology, Neurodegenerative Diseases metabolism, Proteasome Endopeptidase Complex metabolism, Synaptic Transmission, Neuroimmunomodulation, Neuronal Plasticity
- Abstract
In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease.
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- 2019
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47. Ambiguous Effects of Autophagy Activation Following Hypoperfusion/Ischemia.
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Ferrucci M, Biagioni F, Ryskalin L, Limanaqi F, Gambardella S, Frati A, and Fornai F
- Subjects
- Animals, Cell Survival physiology, Cerebrovascular Circulation physiology, Humans, Mitochondria metabolism, Mitophagy physiology, Neurodegenerative Diseases physiopathology, Autophagy physiology, Brain Ischemia physiopathology
- Abstract
Autophagy primarily works to counteract nutrient deprivation that is strongly engaged during starvation and hypoxia, which happens in hypoperfusion. Nonetheless, autophagy is slightly active even in baseline conditions, when it is useful to remove aged proteins and organelles. This is critical when the mitochondria and/or proteins are damaged by toxic stimuli. In the present review, we discuss to that extent the recruitment of autophagy is beneficial in counteracting brain hypoperfusion or, vice-versa, its overactivity may per se be detrimental for cell survival. While analyzing these opposite effects, it turns out that the autophagy activity is likely not to be simply good or bad for cell survival, but its role varies depending on the timing and amount of autophagy activation. This calls for the need for an appropriate autophagy tuning to guarantee a beneficial effect on cell survival. Therefore, the present article draws a theoretical pattern of autophagy activation, which is hypothesized to define the appropriate timing and intensity, which should mirrors the duration and severity of brain hypoperfusion. The need for a fine tuning of the autophagy activation may explain why confounding outcomes occur when autophagy is studied using a rather simplistic approach.
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- 2018
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48. Interdependency Between Autophagy and Synaptic Vesicle Trafficking: Implications for Dopamine Release.
- Author
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Limanaqi F, Biagioni F, Gambardella S, Ryskalin L, and Fornai F
- Abstract
Autophagy (ATG) and the Ubiquitin Proteasome (UP) are the main clearing systems of eukaryotic cells, in that being ultimately involved in degrading damaged and potentially harmful cytoplasmic substrates. Emerging evidence implicates that, in addition to their classic catalytic function in the cytosol, autophagy and the proteasome act as modulators of neurotransmission, inasmuch as they orchestrate degradation and turnover of synaptic vesicles (SVs) and related proteins. These findings are now defining a novel synaptic scenario, where clearing systems and secretory pathways may be considered as a single system, which senses alterations in quality and distribution (in time, amount and place) of both synaptic proteins and neurotransmitters. In line with this, in the present manuscript we focus on evidence showing that, a dysregulation of secretory and trafficking pathways is quite constant in the presence of an impairment of autophagy-lysosomal machinery, which eventually precipitates synaptic dysfunction. Such a dual effect appears not to be just incidental but it rather represents the natural evolution of archaic cell compartments. While discussing these issues, we pose a special emphasis on the role of autophagy upon dopamine (DA) neurotransmission, which is early affected in several neurological and psychiatric disorders. In detail, we discuss how autophagy is engaged not only in removing potentially dangerous proteins, which can interfere with the mechanisms of DA release, but also the fate of synaptic DA vesicles thus surveilling DA neurotransmission. These concepts contribute to shed light on early mechanisms underlying intersection of autophagy with DA-related synaptic disorders.
- Published
- 2018
- Full Text
- View/download PDF
49. mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders.
- Author
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Ryskalin L, Limanaqi F, Frati A, Busceti CL, and Fornai F
- Subjects
- Animals, Autophagy, Brain metabolism, Brain pathology, Humans, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Neuronal Plasticity, Schizophrenia metabolism, Schizophrenia pathology, Substance-Related Disorders metabolism, Substance-Related Disorders pathology, TOR Serine-Threonine Kinases analysis, Brain physiopathology, Neurodegenerative Diseases physiopathology, Schizophrenia physiopathology, Substance-Related Disorders physiopathology, TOR Serine-Threonine Kinases metabolism
- Abstract
The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.
- Published
- 2018
- Full Text
- View/download PDF
50. Anti-inflammatory effect of a novel locally acting A 2A receptor agonist in a rat model of oxazolone-induced colitis.
- Author
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Antonioli L, El-Tayeb A, Pellegrini C, Fornai M, Awwad O, Giustarini G, Natale G, Ryskalin L, Németh ZH, Müller CE, Blandizzi C, and Colucci R
- Subjects
- Adjuvants, Immunologic toxicity, Animals, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal chemistry, Colitis chemically induced, Disease Models, Animal, Furans administration & dosage, Furans chemistry, Male, Oxazolone toxicity, Rats, Rats, Sprague-Dawley, Adenosine A2 Receptor Agonists pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Colitis pathology, Colon drug effects, Furans pharmacology
- Abstract
Adenosine represents a powerful modulating factor, which has been shown to orchestrate the scope, duration, and remission of the inflammatory response through the activation of four specific receptors, classified as A
1 , A2A , A2B , and A3 , all being widely expressed in a variety of immune cells. Several selective A2A receptor agonists have displayed anti-inflammatory effects, through the suppression of IL-12, TNF, and IFN-γ production by monocytes and lymphocytes, in the setting of chronic intestinal inflammation. However, the therapeutic application of A2A receptor agonists remains hindered by the risk of serious cardiovascular adverse effects arising from the wide systemic distribution of A2A receptors. The present study focused on evaluating the anti-inflammatory effects of the novel poorly absorbed A2A receptor agonist PSB-0777 in a rat model of oxazolone-induced colitis as well as to evaluate its cardiovascular adverse effects, paying particular attention to the onset of hypotension, one of the main adverse effects associated with the systemic pharmacological activation of A2A receptors. Colitis was associated with decreased body weight, an enhanced microscopic damage score and increased levels of colonic myeloperoxidase (MPO). PSB-0777, but not dexamethasone, improved body weight. PSB-0777 and dexamethasone ameliorated microscopic indexes of inflammation and reduced MPO levels. The beneficial effects of PSB-0777 on inflammatory parameters were prevented by the pharmacological blockade of A2A receptors. No adverse cardiovascular events were observed upon PSB-0777 administration. The novel A2A receptor agonist PSB-0777 could represent the base for the development of innovative pharmacological entities able to act in an event-specific and site-specific manner.- Published
- 2018
- Full Text
- View/download PDF
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