Early post-surgical rehabilitation and functional outcomes of a traumatic ulnar nerve injury: a pediatric case report.

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.

Pain-Relieving Effects of Shockwave Therapy for Ledderhose Disease: An Ultrasound-Based Study of an Unusual Bilateral Case.

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/mm2. 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.

Do the fasciae of the soleus have a role in plantar fasciitis?

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.

Treatment of delayed union of the forearm with extracorporeal shockwave therapy: a case report and literature review.

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.

Use of Saccharomyces boulardii CNCM I-745 as therapeutic strategy for prevention of nonsteroidal anti-inflammatory drug-induced intestinal injury.

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-1ß, 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.

Effects of a 24-Week Exercise Program on Functional Fitness, Oxidative Stress, and Salivary Cortisol Levels in Elderly Subjects.

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.

Molecular Mechanisms Underlying the Pain-Relieving Effects of Extracorporeal Shock Wave Therapy: A Focus on Fascia Nociceptors.

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.

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity.

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 ß- 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.

Spreading of Alpha Synuclein from Glioblastoma Cells towards Astrocytes Correlates with Stem-like Properties.

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.

Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis.

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-1ß 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-1ß 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.

Inhibition of Autophagy In Vivo Extends Methamphetamine Toxicity to Mesencephalic Cell Bodies.

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.

Lactoferrin Protects against Methamphetamine Toxicity by Modulating Autophagy and Mitochondrial Status.

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 ßIII-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.

The Autophagy-Related Organelle Autophagoproteasome Is Suppressed within Ischemic Penumbra.

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.

The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson's Disease.

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.

Stoichiometric Analysis of Shifting in Subcellular Compartmentalization of HSP70 within Ischemic Penumbra.

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.

Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy.

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.

Neuroprotective Effects of Curcumin in Methamphetamine-Induced Toxicity.

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.

The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer.

Cellular prion protein (PrPC) 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.