Publications by authors named "Luigi Fabrizio Rodella"

77 Publications

Step-by-Step Cadaver Dissection and Surgical Technique for Compartmental Tongue and Floor of Mouth Resection.

Front Oncol 2021 23;11:613945. Epub 2021 Apr 23.

Department of Otorhinolaryngology - Head and Neck Surgery, "San Maurizio" Hospital, Bolzano, Italy.

Background: The aim of oral cancer surgery is tumor removal within clear margins of healthy tissue: the latter definition in the literature, however, may vary between 1 and 2 cm, and should be intended in the three dimensions, which further complicates its precise measurement. Moreover, the biological behavior of tongue and floor of mouth cancer can be unpredictable and often eludes the previously mentioned safe surgical margins concept due to the complexity of tongue anatomy, the intricated arrangements of its intrinsic and extrinsic muscle fibers, and the presence of rich neurovascular and lymphatic networks within it. These structures may act as specific pathways of loco-regional tumor spread, allowing the neoplasm to escape beyond its visible macroscopic boundaries. Based on this concept, in the past two decades, compartmental surgery (CS) for treatment of oral tongue and floor of mouth cancer was proposed as an alternative to more traditional transoral resections.

Methods: The authors performed three anatomical dissections on fresh-frozen cadaver heads that were injected with red and blue-stained silicon. All procedures were documented by photographs taken with a professional reflex digital camera.

Results: One of these step-by-step cadaver dissections is herein reported, detailing the pivotal points of CS with the aim to share this procedure at benefit of the youngest surgeons.

Conclusions: We herein present the CS step-by-step technique to highlight its potential in improving loco-regional control by checking all possible routes of tumor spread. Correct identification of the anatomical space between tumor and nodes (T-N tract), spatial relationships of extrinsic tongue muscles, as well as neurovascular bundles of the floor of mouth, are depicted to improve knowledge of this complex anatomical area.
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http://dx.doi.org/10.3389/fonc.2021.613945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104033PMC
April 2021

Retroesophageal right subclavian artery associated with a bicarotid trunk and an ectopic origin of vertebral arteries.

Surg Radiol Anat 2021 Apr 15. Epub 2021 Apr 15.

Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, V.le Europa 11, 25123, Brescia, Italy.

A rare branching pattern of the aortic arch in a female cadaver is reported. An aberrant right subclavian artery originated from the distal part of the aortic arch and following a retroesophageal course was recognized. Next to it, from the left to the right, the left subclavian artery and a short bicarotid trunk originating the left and the right common carotid artery were recognized. An unusual origin of the vertebral arteries was also identified. The left vertebral artery originated directly from the aortic arch, whereas the right vertebral artery originated directly from the right common carotid artery. Retroesophageal right subclavian artery associated with a bicarotid trunk and ectopic origin of vertebral arteries represents an exceptional and noteworthy case.
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http://dx.doi.org/10.1007/s00276-021-02746-1DOI Listing
April 2021

A new landmark for lingual artery identification during transoral surgery: Anatomic-radiologic study.

Head Neck 2021 May 25;43(5):1487-1498. Epub 2021 Jan 25.

Unit of Otorhinolaryngology - Head and Neck Surgery, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: A landmark for the identification of the lingual artery (LA) through a transoral perspective can provide surgeons with an easy method to prevent and manage intraoperative bleeding during transoral approach to the base of tongue (BOT).

Methods: Thirteen tongue and five head and neck specimens were dissected to identify and assess the reliability of the lingual point (LP) as a new landmark for the LA at BOT. The pathway of 42 LAs was radiologically evaluated; axial depth and vertical offset were measured for each LA.

Results: Dissection study: a description of LP is provided; the LA was easily identified in all specimens (36/36 sides) using LP as a landmark. Radiologic study: the mean depth of the LA was 4.2 mm, the mean vertical offset was 1.3 mm.

Conclusions: LP is a simple and reliable landmark for identification of the LA, potentially helping surgeons to prevent and manage intraoperative bleeding.
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http://dx.doi.org/10.1002/hed.26606DOI Listing
May 2021

Transorbital endoscopic approaches to the skull base: a systematic literature review and anatomical description.

Neurosurg Rev 2021 Jan 22. Epub 2021 Jan 22.

Section of Otorhinolaryngology - Head and Neck Surgery, Department of Neurosciences, University of Padua, Padua, Italy.

Transorbital endoscopic approaches are increasing in popularity as they provide corridors to reach various areas of the ventral skull base through the orbit. They can be used either alone or in combination with different approaches when dealing with the pathologies of the skull base. The objective of the current study is to evaluate the surgical anatomy of transorbital endoscopic approaches by cadaver dissections as well as providing objective clinical data on their actual employment and morbidity through a systematic review of the current literature. Four cadaveric specimens were dissected, and step-by-step dissection of each endoscopic transorbital approach was performed to identify the main anatomic landmarks and corridors. A systematic review with pooled analysis of the current literature from January 2000 to April 2020 was performed and the related studies were analyzed. Main anatomical landmarks are presented based on the anatomical study and systematic review of the literature. With emphasis on the specific transorbital approach used, indications, surgical technique, and complications are reviewed through the systematic review of 42 studies (19 in vivo and 23 anatomical dissections) including 193 patients. In conclusion, transorbital endoscopic approaches are promising and appear as feasible techniques for the surgical treatment of skull base lesions. Surgical anatomy of transorbital endoscopic approaches can be mastered through knowledge of a number of anatomical landmarks. Based on data available in the literature, transorbital endoscopic approaches represent an important complementary that should be included in the armamentarium of a skull base team.
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http://dx.doi.org/10.1007/s10143-020-01470-5DOI Listing
January 2021

Thymus-Pineal Gland Axis: Revisiting Its Role in Human Life and Ageing.

Int J Mol Sci 2020 Nov 20;21(22). Epub 2020 Nov 20.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.

For years the thymus gland (TG) and the pineal gland (PG) have been subject of increasingly in-depth studies, but only recently a link that can associate the activities of the two organs has been identified. Considering, on the one hand, the well-known immune activity of thymus and, on the other, the increasingly emerging immunological roles of circadian oscillators and the rhythmically secreted main pineal product, melatonin, many studies aimed to analyse the possible existence of an interaction between these two systems. Moreover, data confirmed that the immune system is functionally associated with the nervous and endocrine systems determining an integrated dynamic network. In addition, recent researches showed a similar, characteristic involution process both in TG and PG. Since the second half of the 20th century, evidence led to the definition of an effectively interacting thymus-pineal axis (TG-PG axis), but much has to be done. In this sense, the aim of this review is to summarize what is actually known about this topic, focusing on the impact of the TG-PG axis on human life and ageing. We would like to give more emphasis to the implications of this dynamical interaction in a possible therapeutic strategy for human health. Moreover, we focused on all the products of TG and PG in order to collect what is known about the role of peptides other than melatonin. The results available today are often unclear and not linear. These peptides have not been well studied and defined over the years. In this review we hope to awake the interest of the scientific community in them and in their future pharmacological applications.
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http://dx.doi.org/10.3390/ijms21228806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699871PMC
November 2020

Critical role of NFκB in the pathogenesis of non-alcoholic fatty liver disease: a widespread key regulator.

Curr Mol Med 2020 Oct 26. Epub 2020 Oct 26.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia. Italy.

Non-alcoholic fatty liver disease is a chronic metabolic disorder representing the most common cause of chronic liver disease in western civilization and one of the main causes of cirrhosis with a significant impact on all-cause mortality in the most advanced phases. It is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, virus infection or other specific causes of liver disease. Accumulation of fat in liver tissue occurs as a consequence of the imbalance between overconsumption of high-fat diet and increased de novo lipogenesis and decreased lipid disposal. Novel dietary and pharmacological therapies for the prevention of fatty liver disease and the progression to cirrhosis are an actual field of study but still poorly understood. In this perspective, the current review aims to summarise and clarify the transcription factor NFκB effects, which may exert among non-alcoholic fatty liver diseases and their progression. Through extensive previous research, it has become clear that several signaling pathways are involved: metabolic dysregulation (such as free fatty acids increase, adipokine alteration, insulin resistance), oxidative stress and inflammation contribute together in a "vicious circle" to the pathogenesis of non-alcoholic fatty liver diseases. Within this, NFκB signaling is a primary factor in inflammatory reactions and diseases, with important molecular connections between metabolic, oxidative, immune and inflammation systems.
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http://dx.doi.org/10.2174/1566524020666201026162343DOI Listing
October 2020

Sirtuin1 Role in the Melatonin Protective Effects Against Obesity-Related Heart Injury.

Front Physiol 2020 11;11:103. Epub 2020 Mar 11.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Obesity is a worldwide epidemic disease that induces important structural and functional changes to the heart and predisposes a patient to devastating cardiac complications. Sirtuin1 (SIRT1) has been found to have roles in regulating cardiac function, but whether it can help in cardioprotection is not clear. The aim of the present study was to determine whether melatonin, by modulating SIRT1 and in turn mitochondria signaling, may alleviate obesity-induced cardiac injuries. We investigated 10 lean control mice and 10 leptin-deficient obese mice () orally supplemented with melatonin for 8 weeks, as well as equal numbers of age-matched lean and mice that did not receive melatonin. Hearts were evaluated using multiple parameters, including biometric values, morphology, SIRT1 activity and expression of markers of mitochondria biogenesis, oxidative stress, and inflammation. We observed that mice experienced significant heart hypertrophy, infiltration by inflammatory cells, reduced SIRT1 activity, altered mitochondrial signaling and oxidative balance, and overexpression of inflammatory markers. Notably, melatonin supplementation in mice reverted these obesogenic heart alterations. Melatonin prevented heart remodeling caused by obesity through SIRT1 activation, which, together with mitochondrial pathways, reduced oxidative stress and inflammation.
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http://dx.doi.org/10.3389/fphys.2020.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078333PMC
March 2020

Melatonin's Antineoplastic Potential Against Glioblastoma.

Cells 2020 03 3;9(3). Epub 2020 Mar 3.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Glioblastoma (GBM) is one of the most intransigent and aggressive brain tumors, and its treatment is extremely challenging and ineffective. To improve patients' expectancy and quality of life, new therapeutic approaches were investigated. Melatonin is an endogenous indoleamine with an incredible variety of properties. Due to evidence demonstrating melatonin's activity against several cancer hallmarks, there is growing interest in its use for preventing and treating cancer. In this review, we report on the potential effects of melatonin, alone or in combination with anticancer drugs, against GBM. We also summarize melatonin targets and/or the intracellular pathways involved. Moreover, we describe melatonin's epigenetic activity responsible for its antineoplastic effects. To date, there are too few clinical studies (involving a small number of patients) investigating the antineoplastic effects of melatonin against GBM. Nevertheless, these studies described improvement of GBM patients' quality of life and did not show significant adverse effects. In this review, we also report on studies regarding melatonin-like molecules with the tumor-suppressive properties of melatonin together with implemented pharmacokinetics. Melatonin effects and mechanisms of action against GBM require more research attention due to the unquestionably high potential of this multitasking indoleamine in clinical practice.
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http://dx.doi.org/10.3390/cells9030599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140435PMC
March 2020

Impact of Melatonin on Skeletal Muscle and Exercise.

Cells 2020 01 24;9(2). Epub 2020 Jan 24.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut-muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of melatonin as a safe nutraceutical that limits skeletal muscle frailty and prolongs physical performance.
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http://dx.doi.org/10.3390/cells9020288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072499PMC
January 2020

Adipocyte Specific HO-1 Gene Therapy is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model.

Antioxidants (Basel) 2020 Jan 1;9(1). Epub 2020 Jan 1.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.
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http://dx.doi.org/10.3390/antiox9010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022335PMC
January 2020

Curcumin as a Therapeutic Strategy in Liver Diseases.

Nutrients 2019 Oct 17;11(10). Epub 2019 Oct 17.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.

Liver diseases are classified as acute and chronic hepatic failures. In particular, chronic pathologies are the most common diseases in the World. Chronic pathologies of liver disease are the most common diseases in the world. There are many causes that induce a progressive and irreversible degeneration of the hepatic parenchyma, but, in general, they lead to the destruction of the normal balance between reactive oxygen stress (ROS) formation and ROS degradation within the liver. The prevalence of disabling diseases, including the hepatic diseases, is increasingly widespread, and it is important to find a safe, inexpensive, accessible and effective way to face this condition. Many recent studies have focused on different natural antioxidants, which could restore the physiological hepatic environment, thereby allowing the normal functioning of this organ. Natural products have been used to discover new leads for treating several diseases; among them, it is important to emphasize curcumin, which is a polyphenol obtained from Linn, a plant naturally found throughout tropical and subtropical regions of the world.
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http://dx.doi.org/10.3390/nu11102498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835576PMC
October 2019

Unusual branch of the lingual artery supplies the infrahyoid muscles.

Anat Sci Int 2020 Jan 23;95(1):153-155. Epub 2019 Aug 23.

Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, V.le Europa 11, 25123, Brescia, Italy.

Infrahyoid muscles are usually supplied by muscular arteries, originating from the superior and inferior thyroid artery and the internal thoracic artery. In this work, we reported a unilateral anatomical variation of the branching pattern of the lingual artery, which was observed during dissection studies at the University of Brescia. We found an accessory branch arising from the root of the lingual artery that run down medially and supplied the infrahyoid muscles. A similar case has not yet been reported in literature. Considering the current use of the infrahyoid muscles as pedicled myocutaneous flap for reconstructing surgical defects in the head and neck, this vascular variation appears interesting to be reported for appropriate clinical and surgical consideration.
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http://dx.doi.org/10.1007/s12565-019-00501-6DOI Listing
January 2020

Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1α-HO-1-PGC1α-mitochondrial signaling.

Exp Cell Res 2019 07 27;380(2):180-187. Epub 2019 Apr 27.

Department of Drug Science, University of Catania, Catania, Italy. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD.

Methods: We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks.

Results: db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration.

Conclusions: EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD.
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http://dx.doi.org/10.1016/j.yexcr.2019.04.029DOI Listing
July 2019

Side-Door Temporoparietal Fascia Flap: A Novel Strategy for Anterior Skull Base Reconstruction.

World Neurosurg 2019 Jun 27;126:e360-e370. Epub 2019 Feb 27.

Unit of Otorhinolaryngology - Head and Neck Surgery, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: The armamentarium for anterior skull base (ASB) reconstruction includes a variegate spectrum of grafts, endonasal pedicled flaps, regional pedicled flaps, and free flaps, which are selected to face specific scenarios. The use of a vascularized flap in case of large ABS defects ensures an adequate blood supply. The aim of this study was to evaluate the possible role of temporoparietal fascia flap (TPFF) in ASB reconstruction.

Methods: Eight fresh-frozen head specimens were dissected to evaluate the adequacy of TPFF and pericranial flap (PF) for the reconstruction of ASB defects. The percentage of coverage of the ASB was calculated for TPFF and PF. An anatomic-radiologic analysis was performed to provide useful practical information for flap harvesting and positioning.

Results: The TPFF was easily transposed to the ABS defect through an epidural corridor; the edges of the TPFF were successfully placed in the intradural space, in the epidural space, or on the extracranial surface of the ABS defect. The PF was particularly adequate for median defects, and the TPFF was shown to be useful also in cases with paramedian-supraorbital extension. The median percentage of coverage of the ASB was significantly higher for TPFF (85.1%) than PF (65.7%) (P = 0.018).

Conclusions: The supraorbital epidural corridor is a possible novel pathway for transposition of the TPFF for ASB reconstruction. Side-door TPFF was shown to be an ideal choice for large ASB defect with lateral supraorbital extension and could be useful in the scenario of salvage reconstruction for recurrent ABS cerebrospinal fluid leak.
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http://dx.doi.org/10.1016/j.wneu.2019.02.056DOI Listing
June 2019

Platelet-Rich Plasma in Treatment of Temporomandibular Joint Dysfunctions: Narrative Review.

Int J Mol Sci 2019 Jan 11;20(2). Epub 2019 Jan 11.

Department of Surgery, Dentistry, Paediatric and Gynaecology, University of Verona. Policlinico G. B. Rossi. Piazzale L. Scuro n.10, 37134 Verona, Italy.

Background: The aims of this narrative review were to examine up-to-date literature in order to evaluate the effectiveness of arthrocentesis or injections with platelet-rich plasma in temporomandibular affections and to compare them to arthrocentesis alone or with hyaluronic acid (HA) or to hyaluronic acid injections.

Methods: The search of international literature was made on the PMC, PubMed and Cochrane databases, including all full-length text of studies on humans focused on osteoarthritis and disc displacements and their treatment with platelet-rich plasma arthrocentesis or injections. All design studies were included in the review and they were examined for three different outcomes: pain, joint sound and mandibular motion. English papers were only selected.

Results: Even though the low number of studies in this field, arthrocentesis with platelet-rich plasma and platelet-rich plasma injections in temporomandibular disorders' management were found to be effective in reducing pain and joint sound as well as in improving mandibular motion in a maximum follow-up of 24 months.

Conclusion: Comparison to arthrocentesis alone or to HA use in arthrocentesis or by injections provided encouraging results in terms of the effectiveness of platelet-rich plasma use.
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http://dx.doi.org/10.3390/ijms20020277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358929PMC
January 2019

Surgical anatomy of the parapharyngeal space: Multiperspective, quantification-based study.

Head Neck 2019 03 28;41(3):642-656. Epub 2018 Dec 28.

Unit of Otorhinolaryngology-Head and Neck Surgery, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: Several surgical approaches to the parapharyngeal space (PPS) have been proposed. An objective description of advantages and limitations of the surgical routes is lacking.

Methods: Ten cadaver heads were dissected using the transnasal (medial, lateral), sublabial, transoral (transpharyngeal, transvestibular, transmandibular), transcervical (transcervical, transparotid, transmandibular, transmastoid), and type C and D infratemporal approaches. Neurovascular and musculoskeletal structures encountered were analyzed. A navigation-based quantification of working volume and exposure of PPS compartments was accomplished.

Results: Transnasal approaches exposed the upper PPS, though with limited working volume. Transoral approaches exposed the middle PPS, minimizing neurovascular structures crossed. Only transcervical and skull base approaches exposed the entire PPS, crossing several neurovascular structures.

Conclusion: A tentative systematization of the surgical approach(es) to PPS in relation to different targets is provided: unicompartmental resection can be performed with a single, conservative access, whereas multicompartmental dissections frequently require a wider or multiportal approach.
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http://dx.doi.org/10.1002/hed.25378DOI Listing
March 2019

Correlation between human nervous system development and acquisition of fetal skills: An overview.

Brain Dev 2019 Mar 31;41(3):225-233. Epub 2018 Oct 31.

Department of Clinical and Experimental Sciences, Division of Neurosciences, Unit of General Psychology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy; Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs - (ARTO)", University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Understanding the association between fetal nervous system structure and functioning should be an important goal in neurodevelopmental sciences, especially when considering the emerging knowledge regarding the importance of prenatal onset. Intrauterine development of the human central nervous system consists of specific processes: neurogenesis, neuronal migration, synaptogenesis, and myelination. However, as extensively shown by the neurobehavioral studies in the last century, the development of the central nervous system involves both structure and functioning. It is now recognised that the developing motor and sensory systems are able to function long before they have completed their neural maturation and that the intrauterine experience contributes to neurobehavioral development. This review analyzes the recent literature, looking at the association between the human nervous system maturation and fetal behavior. This article will follow the development and skill acquisition of the anatomical nervous system across the three trimesters of the gestation period.
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http://dx.doi.org/10.1016/j.braindev.2018.10.009DOI Listing
March 2019

Promising Antineoplastic Actions of Melatonin.

Front Pharmacol 2018 16;9:1086. Epub 2018 Oct 16.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Melatonin is an endogenous indoleamine with an incredible variety of properties and activities. In recent years, an increasing number of studies have investigated this indoleamine's interaction with cancerous cells. In particular, it seems that melatonin not only has the ability to improve the efficacy of many drugs used in chemotherapy but also has a direct inhibitory action on neoplastic cells. Many publications underlined the ability of melatonin to suppress the proliferation of various cancer cells or to modulate the expression of membrane receptors on these cells, thereby reducing tumor aggressiveness to metastasize. In addition, while melatonin has antiapoptotic actions in normal cells, in many cancer cells it has proapoptotic effects; these dichotomous actions have gained the interest of researchers. The increasing focus on melatonin in the field of oncology and the growing number of studies on this topic require a deep understanding of what we already know about the antineoplastic actions of melatonin. This information would be of value for potential use of melatonin against neoplastic diseases.
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http://dx.doi.org/10.3389/fphar.2018.01086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198052PMC
October 2018

Taurine Supplementation Alleviates Puromycin Aminonucleoside Damage by Modulating Endoplasmic Reticulum Stress and Mitochondrial-Related Apoptosis in Rat Kidney.

Nutrients 2018 May 29;10(6). Epub 2018 May 29.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Taurine (TAU) is a sulfur-containing beta amino acid that is not involved in protein composition and anabolism, conditionally essential in mammals provided through diet. Growing evidence supports a protective role of TAU supply in osmoregulation, calcium flux, and reduction of inflammation and oxidant damage in renal diseases like diabetes. Endoplasmic reticulum (ER) stress, due to abnormal proteostasis, is a contributor to nephrotic syndrome and related renal damage. Here, we investigated the effect of dietary TAU (1.5% in drinking water for 15 days) in an established rat model that mimics human minimal change nephrosis, consisting of a single puromycin aminonucleoside (PAN) injection (intraperitoneally 15 mg/100 g body weight), with sacrifice after eight days. TAU limited proteinuria and podocytes foot processes effacement, and balanced slit diaphragm nephrin and glomerular claudin 1 expressions. In cortical proximal tubules, TAU improved lysosomal density, ER perimeter, restored proper ER-mitochondria tethering and mitochondrial cristae, and decreased inflammation. Remarkably, TAU downregulated glomerular ER stress markers (GRP78, GRP94), pro-apoptotic C/EBP homologous protein, activated caspase 3, tubular caspase1, and mitochondrial chaperone GRP75, but maintained anti-apoptotic HSP25. In conclusion, TAU, by targeting upstream ER stress separate from mitochondria dysfunctions at crucial renal sites, might be a promising dietary supplement in the treatment of the drug-resistant nephrotic syndrome.
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http://dx.doi.org/10.3390/nu10060689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024760PMC
May 2018

Growth Factors Release From Concentrated Growth Factors: Effect of β-Tricalcium Phosphate Addition.

J Craniofac Surg 2018 Nov;29(8):2291-2295

Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Brescia, Italy.

Background: Platelet concentrates represent a new approach to improve tissue regeneration and can be used alone or together with autogenous bone, recombinant human growth factors, and/or other biomaterials, to enhance tissue regeneration. Among platelet concentrates, concentrated growth factors (CGFs) exhibit an interesting clinical and biotechnological application potential.

Objective: The aim of this study was to evaluate the in vitro release of 4 growth factors (bone morphogenetic proteins [BMP] -2, BMP-7, transforming growth factor [TGF] -β1, and insulin-like growth factor [IGF] -1) by the enzyme-linked immunosorbent assay (ELISA) technique, in CGFs mixed or not with β-tricalcium phosphate (β-TCP), using or not the Round-up device, at different times.

Methods: CGFs were obtained from healthy volunteers, mixed or not with β-TCP, using or not the Round-up device. The release of 4 growth factors from these CGFs was then measured at 5 hours, 1, 3, 6, and 8 days, using the ELISA assay.

Results: Comparison of the results obtained with those achieved for CGFs alone showed that BMP2 and BMP-7 release, significantly increased in CGFs mixed with Round-up and β-TCP, TGF-β1 release was similar to CGFs alone, whereas IG-1 release was lower compared with CGFs alone.

Conclusion: The present data suggest that β-TCP addition to CGF could enhance and improve tissue regeneration, especially bone regeneration, increasing the release of some growth factors that play an important role in osteogenesis.
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http://dx.doi.org/10.1097/SCS.0000000000004607DOI Listing
November 2018

Anatomical Cadaver Study of Endolaryngeal Vascularization: Focus on the Glottis, Supraglottis, and Subglottis From the Transoral Microsurgical Point of View.

Front Oncol 2018 30;8:138. Epub 2018 Apr 30.

Department of Otorhinolaryngology - Head and Neck Surgery, Fondazione IRCCS, National Cancer Institute of Milan, University of Milan, Milan, Italy.

Introduction: Carbon dioxide laser coagulation during transoral laser microsurgery (TLM) for laryngeal cancer allows control of bleeding from vessels smaller than 0.5 mm. Therefore, larger arteries and veins must be carefully managed by clipping and/or monopolar cautery. The aim of this paper is to detail endolaryngeal vascular anatomy and identify areas of possible bleeding during TLM.

Methods: We performed an anatomical study on a series of 11 fresh-frozen human cadavers. After injection of a bicomponent red silicone into the innominate, left common carotid, and left subclavian arteries, 22 hemilarynges were dissected, the course of the supraglottic, glottic, and subglottic vessels were traced after microdissection of the intervening structures, and their size measured at specific landmark points where such vessels are more frequently encountered during TLM.

Results: Three vessels arising from the superior laryngeal artery were identified after its entry point at the level of the thyro-hyoid membrane: (1) the epiglottic artery (EA), documented in 100% of cases, a common trunk dividing into two main vessels (2) the postero-inferior artery (PIA), present in 100% of the specimens, running downward and dividing in a posterior (pPIA), and anterior (aPIA) branches (3) the antero-inferior artery (AIA), present in 95% of our specimens, running downward to the anterior commissure (AC). Two transverse anastomotic networks (TANs) connected the AIA and PIA, both parallel to the vocal muscle, one lateral (present in 100% of cases), and another medial (91% of specimens). Finally, a fourth vessel supplying the glottic plane was found to be the endolaryngeal paracommissural branch of the crico-thyroid artery (PCA), arising from the inferior laryngeal artery and emerging just below the AC, through the crico-thyroid membrane (reported in 100% of the specimens). This vessel anastomosed in 91% of cases with the AIA, through one or both of the TANs.

Conclusion: The course of the endolaryngeal arteries, their relationships with adjacent structures, and size at specific landmark points have been herein described in order to provide surgeons with a map to guide them during the steep learning curve of transoral surgery of the larynx, with special emphasis given to TLM.
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http://dx.doi.org/10.3389/fonc.2018.00138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937054PMC
April 2018

Melatonin Modulation of Sirtuin-1 Attenuates Liver Injury in a Hypercholesterolemic Mouse Model.

Biomed Res Int 2018 4;2018:7968452. Epub 2018 Feb 4.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Hypercholesterolemia increases and exacerbates stress signals leading also to liver damage (LD) and failure. Sirtuin1 (SIRT1) is involved in lifespan extension and it plays an essential role in hepatic lipid metabolism. However, its involvement in liver hypercholesterolemic damage is not yet completely defined. This study evaluated the role of SIRT1 in the hypercholesterolemic-related LD and, then, investigated how oral supplementation of melatonin, pleiotropic indoleamine, may be protective. Control mice and apolipoprotein E-deficient mice (ApoE) of 6 and 15 weeks of age were treated or not treated with melatonin at the dose of 10 mg/kg/day for 9 weeks. In this study, we evaluated serum biochemical markers, liver SIRT1 expression, and oxidative stress markers. We observed that hypercholesterolemia increased significantly serum cholesterol and triglycerides, reduced significantly liver SIRT1, and, in turn, induced hepatic oxidative stress in untreated ApoE mice with respect to control mice. Interestingly, melatonin treatment improved serum biochemical markers and hepatic morphological impairment and inhibited oxidative stress through its antioxidant properties and also by SIRT1 upregulation. In summary, melatonin oral supplementation may represent a new protective approach to block hypercholesterolemic liver alterations involving also a SIRT1-dependent mechanism.
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http://dx.doi.org/10.1155/2018/7968452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817311PMC
August 2018

Transnasal Endoscopic and Lateral Approaches to the Clivus: A Quantitative Anatomic Study.

World Neurosurg 2018 May 28;113:e659-e671. Epub 2018 Feb 28.

Department of Neurosurgery, Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: Transnasal endoscopic approaches to the clivus have been established recently. Comparative analyses with classic lateral approaches are limited. In this study, we compared transnasal endoscopic and lateral approaches to the clivus, quantifying the exposure and working volume of each approach in the anatomy laboratory.

Methods: High-resolution computed tomography scans were performed on 5 injected specimens (10 sides). In each specimen, transnasal endoscopic approaches (i.e., paraseptal, transrostral, extended transrostral, transethmoidal, and extended transclival without and with intradural hypophysiopexy) and lateral approaches (i.e., retrosigmoid, far-lateral, presigmoid retrolabyrinthine and translabyrinthine) to the clivus were performed. An optic neuronavigation system and dedicated software (ApproachViewer; Guided Therapeutics Program, University Health Network, Toronto, Ontario, Canada) were used to quantify the working volume and exposed clival area of each approach. Statistical evaluation was performed with the Kruskal-Wallis test and Steel-Dwass-Critchlow-Fligner post hoc test.

Results: Endoscopic transnasal transclival approaches showed higher working volume and larger clival exposure compared with lateral approaches. Incremental volumetric values were evident for transnasal approaches; presigmoid approaches provided less working volume than retrosigmoid approaches. A transnasal transclival approach with hypophysiopexy provided significant exposure of the upper clivus (84.4%). The transrostral approach was the first transnasal approach providing satisfactory access to the midclivus (66%); retrosigmoid and far-lateral approaches provided exposure of approximately one half of the midclivus. The lower clivus was optimally exposed with endoscopic transclival approaches (83%), whereas access to this region was limited with lateral approaches.

Conclusions: This quantitative anatomic study shows that endoscopic transnasal approaches to the clivus provide a larger working volume and wider exposure of the clivus compared with lateral approaches.
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http://dx.doi.org/10.1016/j.wneu.2018.02.118DOI Listing
May 2018

In vitro treatment with concentrated growth factors (CGF) and sodium orthosilicate positively affects cell renewal in three different human cell lines.

Cell Biol Int 2018 Mar 20;42(3):353-364. Epub 2017 Nov 20.

Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, V.le Europa 11, Brescia, 25123, Italy.

The aim of this study was to investigate the in vitro effect of Silicon, in the soluble form of sodium orthosilicate, combined and not with the concentrated growth factors (CGF), a platelet-rich preparation, on three different human cell lines of fibroblasts (NHDF), endothelial cells (HUVEC), and osteoblasts (HOBs). Each cell type was treated with sodium orthosilicate at the final concentration of 0.5 mM and 1 mM, CGF, and sodium orthosilicate combined with CGF, for 72 h. At the end of the experimental period, the in vitro effect on cell growth, proliferation, and metabolic activity was evaluated by performing a simple cell count, using an automated cell counter and by evaluating the expression of the intracellular proliferation marker Ki-67, using Fluorescence-activated cell sorting (FACS) analysis. Moreover, the expression of other cell markers and active molecules, such as Collagen type I, Osteopontin, Vascular Endothelial Growth Factor, and endothelial Nitric Oxide Synthase, was evaluated, through immunohistochemistry. Results obtained showed that the combined use of CGF and sodium orthosilicate stimulates cell growth, proliferation, and metabolic activity, suggesting that this treatment could be effective in tissue regeneration.
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http://dx.doi.org/10.1002/cbin.10908DOI Listing
March 2018

Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation.

Int J Endocrinol 2017 1;2017:1835195. Epub 2017 Oct 1.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Inflammation may be defined as the innate response to harmful stimuli such as pathogens, injury, and metabolic stress; its ultimate function is to restore the physiological homeostatic state. The exact aetiology leading to the development of inflammation is not known, but a combination of genetic, epigenetic, and environmental factors seems to play an important role in the pathogenesis of many inflammation-related clinical conditions. Recent studies suggest that the pathogenesis of different inflammatory diseases also involves the inflammasomes, intracellular multiprotein complexes that mediate activation of inflammatory caspases thereby inducing the secretion of proinflammatory cytokines. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule with fundamental clinical applications. It is involved in mood modulation, sexual behavior, vasomotor control, and immunomodulation and influences energy metabolism; moreover, it acts as an oncostatic and antiaging molecule. Melatonin is an important antioxidant and also a widespread anti-inflammatory molecule, modulating both pro- and anti-inflammatory cytokines in different pathophysiological conditions. This review, first, gives an overview concerning the growing importance of melatonin in the inflammatory-mediated pathological conditions and, then, focuses on its roles and its protective effects against the activation of the inflammasomes and, in particular, of the NLRP3 inflammasome.
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http://dx.doi.org/10.1155/2017/1835195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643098PMC
October 2017

Oral supplementation of melatonin protects against lupus nephritis renal injury in a pristane-induced lupus mouse model.

Life Sci 2018 Jan 31;193:242-251. Epub 2017 Oct 31.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy; Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs- (ARTO)", University of Brescia, Italy. Electronic address:

Aims: Since lupus nephritis (LN) etiopathogenesis is not fully understood, herein we investigated the morphological basis of LN in mice induced with pristane.

Main Methods: To evaluate the melatonin effects in these animals, we studied the renal cytoarchitecture by means of morphological analyses, immunofluorescence expression of specific markers related to fibrosis, oxidative stress, inflammation and apoptosis.

Key Findings: We observed that pristane-LN mice have serious alterations in the kidney cytoarchitecture, i.e. tubular degeneration, glomerular hypercellularity, matrix mesangial expansion and interstitial inflammation. The pristane-induced LN mice treated with melatonin exhibited a well preserved cytoarchitecture.

Significance: Our results document that LN etiopathogenesis is related to both tubular damage and glomerular lesions. We suggest that it is essential to take in consideration both these lesions for LN diagnosis and classification. Clearly, we show that the use of melatonin may be a possible therapeutic strategy for improvement the renal injury in this disorder.
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http://dx.doi.org/10.1016/j.lfs.2017.10.038DOI Listing
January 2018

Sodium-DNA for Bone Tissue Regeneration: An Experimental Study in Rat Calvaria.

Biomed Res Int 2017 10;2017:7320953. Epub 2017 Sep 10.

Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Surgical techniques in dental and maxillofacial surgery request fast bone tissue regeneration, so there is a significant need to improve therapy for bone regeneration. Several studies have recently underlined the importance of nucleotides and nucleosides to increase cell proliferation and activity; in particular, the ability of polydeoxyribonucleotide (PDRN) to induce growth and activity of human osteoblasts was demonstrated. Sodium-DNA is the deoxyribonucleic acid (DNA) extracted from the gonadic tissue of male sturgeon and then purified, depolymerized, and neutralized with sodium hydroxide. To date, there are no evidences about the use of Sodium-DNA for bone tissue regeneration. Consequently, our question is about the efficacy of Sodium-DNA in bone healing. For testing the role of Sodium-DNA in bone healing we used a rat calvarial defect model. Sodium-DNA at different concentrations used alone or in association with Fibrin and/or Bio-Oss was used for healing treatments and the bone healing process was evaluated by histomorphometric and immunohistochemical analyses. Our results suggested a positive effect of Sodium-DNA in bone regeneration, providing a useful protocol and a model for the future clinical evaluation of its osteogenic properties.
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http://dx.doi.org/10.1155/2017/7320953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610838PMC
June 2018

Modular Classification of Endoscopic Endonasal Transsphenoidal Approaches to Sellar Region: Anatomic Quantitative Study.

World Neurosurg 2018 Jan 6;109:e281-e291. Epub 2017 Oct 6.

Unit of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.

Background: Endoscopic visualization does not necessarily correspond to an adequate working space. The need for balancing invasiveness and adequacy of sellar tumor exposure has recently led to the description of multiple endoscopic endonasal transsphenoidal approaches. Comparative anatomic data on these variants are lacking.

Object: We sought to quantitatively compare endoscopic endonasal transsphenoidal approaches to the sella and parasellar region, using the concept of "surgical pyramid."

Methods: Four endoscopic transsphenoidal approaches were performed in 10 injected specimens: 1) hemisphenoidotomy; 2) transrostral; 3) extended transrostral (with superior turbinectomy); and 4) extended transrostral with posterior ethmoidectomy. ApproachViewer software (part of GTx-Eyes II, University Health Network, Toronto, Canada) with a dedicated navigation system was used to quantify the surgical pyramid volume, as well as exposure of sellar and parasellar areas. Statistical analyses were performed with Friedman's tests and Nemenyi's procedure.

Results: Hemisphenoidotomy provided limited exposure of the sellar area and a small working volume. A transrostral approach was necessary to expose the entire sella. Exposure of lateral parasellar areas required superior turbinectomy or posterior ethmoidectomy. The differences between each of the modules was statistically significant.

Conclusion: The present study validates, from an anatomic point of view, a modular classification of endoscopic endonasal transsphenoidal approaches to the sellar region.
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http://dx.doi.org/10.1016/j.wneu.2017.09.165DOI Listing
January 2018

Anterior superior alveolar nerve injury after extended endoscopic medial maxillectomy: a preclinical study to predict neurological morbidity.

Int Forum Allergy Rhinol 2017 10 14;7(10):1014-1021. Epub 2017 Aug 14.

Unit of Otorhinolaryngology-Head and Neck Surgery, Department of Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: Endoscopic medial maxillectomies (EMMs) are used to optimize exposure of the maxillary sinus and retromaxillary areas. Although in type D EMM (Sturmann-Canfield procedure) the anterior superior alveolar nerve (ASAN) is always at risk of injury, only 29% of patients complained of alveolar process and dental anesthesia. The purpose of this anatomical study is to assess the neural anastomotic network of the ASAN (ASAN-NAN) and describe different extensions of type D EMMs in a preclinical setting.

Methods: The ASAN and its medial anastomotic branches (MABs) and lateral anastomotic branches (LABs) were evaluated by cone-beam computerized tomography (CBCT). Five different extensions of type D (D1 to D5) EMMs were identified and nerves at risk of injury in each type were assessed by CBCT. Moreover, quantification of surgical corridors was performed on cadaver heads with a neuronavigation system.

Results: Fifty-seven CBCT scans were analyzed. The ASAN would be spared in 16.3% of cases with a type D1 EMM, while it would be injured in the majority of type D2 to D5 resections. At least 1 nerve of the ASAN-NAN was spared in 96.6%, 93%, 74.6%, 0%, and 65.8% of type D1 to D5 EMMs, respectively. Two cadaver heads were dissected and the incremental volume and number of maxillary subsites exposed was assessed in type D1 to D5 EMMs.

Conclusion: ASAN function impairment is probably compensated by LABs and MABs. If this hypothesis will be validated in a prospective study on patients, preoperative CBCT evaluation could predict neurological morbidity after type D EMM, and allow tailoring the procedure to minimize impairment of the ASAN-NAN.
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http://dx.doi.org/10.1002/alr.22001DOI Listing
October 2017

Oral Supplementation of Melatonin Protects against Fibromyalgia-Related Skeletal Muscle Alterations in Reserpine-Induced Myalgia Rats.

Int J Mol Sci 2017 Jun 29;18(7). Epub 2017 Jun 29.

Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain and an extensive array of other symptoms including disordered sleep, fatigue, depression and anxiety. Important factors involved in the pathogenic process of fibromyalgia are inflammation and oxidative stress, suggesting that ant-inflammatory and/or antioxidant supplementation might be effective in the management and modulation of this syndrome. Recent evidence suggests that melatonin may be suitable for this purpose due to its well known ant-inflammatory, antioxidant and analgesic effects. Thus, in the current study, the effects of the oral supplementation of melatonin against fibromyalgia-related skeletal muscle alterations were evaluated. In detail, 90 Sprague Dawley rats were randomly treated with reserpine, to reproduce the pathogenic process of fibromyalgia and thereafter they received melatonin. The animals treated with reserpine showed moderate alterations at hind limb skeletal muscles level and had difficulty in moving, together with significant morphological and ultrastructural alterations and expression of inflammatory and oxidative stress markers in the gastrocnemius muscle. Interestingly, melatonin, dose and/or time dependently, reduced the difficulties in spontaneous motor activity and the musculoskeletal morphostructural, inflammatory, and oxidative stress alterations. This study suggests that melatonin in vivo may be an effective tool in the management of fibromyalgia-related musculoskeletal morphofunctional damage.
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http://dx.doi.org/10.3390/ijms18071389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535882PMC
June 2017