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1.
Biomed Pharmacother ; 173: 116380, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38447450

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.


Subject(s)
Amyotrophic Lateral Sclerosis , Benzamides , Nanoparticles , Neurodegenerative Diseases , Mice , Animals , Superoxide Dismutase-1/metabolism , Reactive Oxygen Species/metabolism , Amyotrophic Lateral Sclerosis/drug therapy , Neurodegenerative Diseases/pathology , Myoblasts/metabolism , Atrophy/pathology , Mice, Transgenic , Disease Models, Animal , Superoxide Dismutase/metabolism
2.
Mamm Genome ; 35(2): 122-134, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38523187

ABSTRACT

Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets.


Subject(s)
Collagen Type VI , Disease Models, Animal , Mutation , Pruritus , Animals , Mice , Pruritus/genetics , Pruritus/pathology , Female , Male , Collagen Type VI/genetics , Collagen Type VI/metabolism , Skin/pathology , Skin/metabolism , Chronic Disease , Humans , CRISPR-Cas Systems
3.
Ann Clin Transl Neurol ; 11(5): 1122-1134, 2024 May.
Article in English | MEDLINE | ID: mdl-38389222

ABSTRACT

OBJECTIVE: In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. METHODS: In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. RESULTS: Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). INTERPRETATION: Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , Loneliness , Quality of Life , Humans , Amyotrophic Lateral Sclerosis/physiopathology , Amyotrophic Lateral Sclerosis/psychology , Amyotrophic Lateral Sclerosis/diagnostic imaging , Male , Loneliness/psychology , Female , Aged , Middle Aged , Magnetic Resonance Imaging , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/diagnostic imaging , Depression/physiopathology
7.
Clin Exp Rheumatol ; 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-38019150

ABSTRACT

OBJECTIVES: Adapted physical activity (APA) has been recommended for fibromyalgia (FM) treatment as an essential component of a biopsychosocial therapeutic approach for patients. Previous studies report that aerobic and resistance training are the most effective programs in improving the quality of life and psycho-physical well-being. Patients with FM are frequently affected by an impairment of small fibers innervation, which is evident in the proximal somatic districts. Therefore, this pilot randomised controlled not pharmacological trial aimed to investigate if a 12-week home-based multicomponent (aerobic and resistance training and mobility) physical activity (PA) intervention was effective in improving pain perception, FM-related disability, and IntraEpidermal Nerve Fibers Density (IENFD) in adult FM patients. METHODS: Thirty-four female subjects with a fibromyalgia diagnosis (51.5±11.88 years) were randomly assigned to an experimental group (n=17) that received a supervised home-based multicomponent PA intervention twice a week and a control group (n=17) that received a generic program of aerobic exercise. Skin biopsy was performed before the physical program and after 18 months with constant execution of the supervised PA intervention or generic aerobic exercise. Both groups assumed pharmacological treatment with duloxetine and/or pregabalin. RESULTS: We found that the group performing physical activity in a supervised and regular way showed a significant improvement in the Fibromyalgia-linked invalidity questionnaire (FIQ) as well as epidermal fibers density at proximal and distal sites. CONCLUSIONS: Physical activity could improve FM outcomes, with a possible beneficial impact on peripheral factors contributing to pain-related disability.

8.
BMC Cardiovasc Disord ; 23(1): 507, 2023 10 12.
Article in English | MEDLINE | ID: mdl-37828445

ABSTRACT

BACKGROUND: Per-procedural severe mitral regurgitation is a rare complication in concomitant surgical ventricular restoration and postinfarction ventricular septal rupture repair. It is challenging to discover the underlying etiology and adopt an appropriate strategy, in particular, in a high-risk patient. CASE PRESENTATION: Semi-emergent surgical ventricular restoration combined with ventricular septal rupture closure and coronary artery bypassing was performed in a 67-year-old male patient. Severe mitral regurgitation was detected after the weaning of cardiopulmonary bypass. Two key questions arose in the management of this condition: did the regurgitation exist previously and was dissimulated by significant left-to-right shunt, or it occurred secondarily to the Dor procedure? Which was the better management strategy, chordal-sparing mitral valve replacement or mitral plasty? We believed that severe mitral regurgitation was under-estimated pre-operatively and we performed an downsizing annuloplasty to treat mitral regurgitation. The outcomes were promising and the patient did well in follow-up. CONCLUSIONS: Our case brought out an open discussion on the etiology and therapeutic strategies of this complicated condition.


Subject(s)
Mitral Valve Insufficiency , Ventricular Septal Rupture , Male , Humans , Aged , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/etiology , Mitral Valve Insufficiency/surgery , Ventricular Septal Rupture/diagnostic imaging , Ventricular Septal Rupture/etiology , Ventricular Septal Rupture/surgery , Mitral Valve/diagnostic imaging , Mitral Valve/surgery , Coronary Artery Bypass/adverse effects , Heart Ventricles , Treatment Outcome
9.
Mol Ther Methods Clin Dev ; 31: 101116, 2023 Dec 14.
Article in English | MEDLINE | ID: mdl-37808256

ABSTRACT

Archived specimens, taken by standardized procedures in clinical practice, represent a valuable resource in translational medicine. Their use in retrospective molecular-based studies could provide disease and therapy predictors. Microfluidic array is a user-friendly and cost-effective method allowing profiling of hundreds of microRNAs (miRNAs) from a low amount of RNA. However, even though tissue miRNAs may include potentially robust biomarkers, non-uniformed post-analytical pipelines could hinder translation into clinics. In this study, epidermal RNA from archival skin biopsy specimens was isolated from patients with peripheral neuropathy and healthy individuals. Unbiased miRNA profiling was performed using RT-qPCR-based microfluidic array. We demonstrated that RNA obtained from archival tissue is appropriate for miRNA profiling, providing evidence that different practices in threshold selection could significantly influence the final results. We showed the utility of software-based quality control for amplification curves. We revealed that selection of the most stable reference and the calculation of geometric mean are suitable when utilizing microfluidic arrays without known references. By applying appropriate post-analytical settings, we obtained miRNA profile of human epidermis associated with biological processes and a list of suitable references. Our results, which outline technical and post-analytical considerations, support the broad use of archived specimens for miRNA analysis to unravel disease-specific molecular signatures.

10.
J Clin Med ; 12(20)2023 Oct 18.
Article in English | MEDLINE | ID: mdl-37892739

ABSTRACT

The COVID-19 pandemic has deeply affected the activity and patient flows of Emergency Departments (EDs), and concern for the worsening outcome of cardiovascular emergencies has been raised. However, the impact of COVID-19 on all subtypes of acute aortic syndromes (AASs) has not been evaluated so far. Cases of AASs managed in the ED of three hub hospitals in a large area of Northern Italy were retrospectively analyzed, comparing those registered during the pandemic (March 2020 to May 2021) with corresponding pre-COVID-19 periods. A total of 124 patients with AAS were managed during the COVID-19 period vs. 118 pre-COVID-19 (p = 0.70), despite a -34.6% change in ED visits. Posterior chest pain at presentation was the only clinical variable with a different prevalence (46.0% vs. 32.2%, p = 0.03). Surgery and endovascular treatment rates were unchanged. Time intervals influenced by patient transfer to the hub center were longer during the COVID-19 period and longest during high viral circulation periods. Ninety-day mortality was unchanged, with a higher mortality trend during the pandemic surges. In conclusion, ED presentation and care of AASs were marginally affected by COVID-19, but efforts are needed to preserve efficient patient transfer to specialized centers and prevent mortality, especially during pandemic peaks.

12.
Med Trop Sante Int ; 3(2)2023 06 30.
Article in French | MEDLINE | ID: mdl-37525680

ABSTRACT

Muscoid larvae were observed on self-medicated dressing material loaded with purulent material taken from a 91-year-old hospital patient. These larvae were identified as Lucilia sericata. However, no larvae were found in the patient's tissues. The observation of larvae on dressings should not automatically lead to a diagnosis of cutaneous myiasis.


Subject(s)
Diptera , Myiasis , Animals , Humans , Aged, 80 and over , Myiasis/diagnosis , Larva , Bandages , Blindness
13.
Nat Commun ; 14(1): 4970, 2023 08 17.
Article in English | MEDLINE | ID: mdl-37591957

ABSTRACT

In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Interleukin-18 , Quality of Life , Ribosomal Proteins , Autophagy
14.
EClinicalMedicine ; 59: 101971, 2023 May.
Article in English | MEDLINE | ID: mdl-37152360

ABSTRACT

Background: No pharmacological treatments are specifically indicated for painful small fibre neuropathy (SFN). CONVEY, a phase 2 enriched-enrolment study, evaluated the efficacy and safety of vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN. Methods: CONVEY was a phase 2, multicentre, placebo-controlled, double-blind (DB), enriched-enrolment, randomised withdrawal study. The study was conducted at 68 sites in 13 countries (Europe and Canada) between May 17, 2018, and April 12, 2021. Following a 4-week open-label period in which 265 adults with painful SFN (a mixture of large and small fibre neuropathy was not exclusionary) received oral vixotrigine 350 mg twice daily (BID), 123 participants (with a ≥30% reduction from baseline in average daily pain [ADP] score during the open-label period) were randomised 1:1:1 to receive 200 mg BID, 350 mg BID or placebo for a 12-week double-blind (DB) period. Primary endpoint was change from baseline in ADP at DB Week 12. Secondary endpoints included the proportion of participants with a ≥30% reduction from baseline in ADP and the proportion of Patient Global Impression of Pain (PGIC) responders at DB Week 12. Treatment-emergent adverse events (AEs) were monitored. Statistical significance was set at 0.10 (2-sided). The trial was registered on ClinicalTrials.gov (NCT03339336) and on ClinicalTrialsregister.eu (2017-000991-27). Findings: A statistically significant difference from placebo in least squares mean reduction in ADP score from baseline to DB Week 12 was observed with vixotrigine 200 mg BID (-0.85; SE, 0.43; 95% CI, -1.71 to 0.00; p = 0.050) but not 350 mg BID (-0.17; SE, 0.43; 95% CI, -1.01 to 0.68; p = 0.70). Numerically, but not statistically significantly, more participants who received vixotrigine vs placebo experienced a ≥30% ADP reduction from baseline (68.3-72.5% vs 52.5%), and only the 350 mg BID group had significantly more PGIC responders vs placebo (48.8% vs 30.0%; odds ratio = 2.60; 95% CI, 0.97-6.99; p = 0.058) at DB Week 12. AEs were mostly mild to moderate in the vixotrigine groups. The most common AEs (≥5% of vixotrigine-treated participants) in the DB 200 mg BID and 350 mg BID vixotrigine groups were falls, nasopharyngitis, muscle spasm, and urinary tract infection. Interpretation: In our study, vixotrigine 200 mg BID, but not 350 mg BID, met the primary endpoint; more vixotrigine-treated participants experienced a ≥30% reduction from baseline in ADP at DB Week 12. Vixotrigine (at both dosages) was well tolerated in participants with SFN. Funding: Biogen, Inc.

15.
Int J Mol Sci ; 24(9)2023 May 05.
Article in English | MEDLINE | ID: mdl-37175987

ABSTRACT

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.


Subject(s)
Diabetes Mellitus , Diabetic Neuropathies , Neuralgia , Small Fiber Neuropathy , Humans , Neuralgia/pathology , Diabetic Neuropathies/pathology , Sodium Channels , NAV1.7 Voltage-Gated Sodium Channel/genetics
16.
J Neurol Neurosurg Psychiatry ; 94(8): 614-621, 2023 08.
Article in English | MEDLINE | ID: mdl-37015771

ABSTRACT

BACKGROUND: To assess the ability of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) clinical criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to include within their classification the whole spectrum of clinical heterogeneity of the disease and to define the clinical characteristics of the unclassifiable clinical forms. METHODS: The 2021 EAN/PNS clinical criteria for CIDP were applied to 329 patients fulfilling the electrodiagnostic (and in some cases also the supportive) criteria for the diagnosis of CIDP. Clinical characteristics were reviewed for each patient not strictly fulfilling the clinical criteria ('unclassifiable'). RESULTS: At study inclusion, 124 (37.5%) patients had an unclassifiable clinical presentation, including 110 (89%) with a typical CIDP-like clinical phenotype in whom some segments of the four limbs were unaffected by weakness ('incomplete typical CIDP'), 10 (8%) with a mild distal, symmetric, sensory or sensorimotor polyneuropathy confined to the lower limbs with cranial nerve involvement ('cranial nerve predominant CIDP') and 4 (1%) with a symmetric sensorimotor polyneuropathy limited to the proximal and distal areas of the lower limbs ('paraparetic CIDP'). Eighty-one (65%) patients maintained an unclassifiable presentation during the entire disease follow-up while 13 patients progressed to typical CIDP. Patients with the unclassifiable clinical forms compared with patients with typical CIDP had a milder form of CIDP, while there was no difference in the distribution patterns of demyelination. CONCLUSIONS: A proportion of patients with CIDP do not strictly fulfil the 2021 EAN/PNS clinical criteria for diagnosis. These unclassifiable clinical phenotypes may pose diagnostic challenges and thus deserve more attention in clinical practice and research.


Subject(s)
Polyneuropathies , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Peripheral Nerves , Cranial Nerves , Phenotype , Neural Conduction/physiology
18.
Acute Med ; 22(1): 47-49, 2023.
Article in English | MEDLINE | ID: mdl-37039056

ABSTRACT

We report the case of a 54 year old man referred to the Emergency Department for rapid onset of an itchy rash and oppressive epigastric pain after assumption of amoxicillin/clavulanate. Electrocardiogram aand laboratory findings were consistent with acute coronaty syndrome. After coronary angiography, diagnosis of type II Kounis syndrome was made.


Subject(s)
Acute Coronary Syndrome , Male , Humans , Middle Aged , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/diagnostic imaging , Amoxicillin-Potassium Clavulanate Combination/adverse effects , Coronary Angiography , Electrocardiography , Emergency Service, Hospital
19.
Int J Mol Sci ; 24(5)2023 Feb 27.
Article in English | MEDLINE | ID: mdl-36902041

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive, irreversible loss of upper and lower motor neurons (UMNs, LMNs). MN axonal dysfunctions are emerging as relevant pathogenic events since the early ALS stages. However, the exact molecular mechanisms leading to MN axon degeneration in ALS still need to be clarified. MicroRNA (miRNA) dysregulation plays a critical role in the pathogenesis of neuromuscular diseases. These molecules represent promising biomarkers for these conditions since their expression in body fluids consistently reflects distinct pathophysiological states. Mir-146a has been reported to modulate the expression of the NFL gene, encoding the light chain of the neurofilament (NFL) protein, a recognized biomarker for ALS. Here, we analyzed miR-146a and Nfl expression in the sciatic nerve of G93A-SOD1 ALS mice during disease progression. The miRNA was also analyzed in the serum of affected mice and human patients, the last stratified relying on the predominant UMN or LMN clinical signs. We revealed a significant miR-146a increase and Nfl expression decrease in G93A-SOD1 peripheral nerve. In the serum of both ALS mice and human patients, the miRNA levels were reduced, discriminating UMN-predominant patients from the LMN ones. Our findings suggest a miR-146a contribution to peripheral axon impairment and its potential role as a diagnostic and prognostic biomarker for ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , MicroRNAs , Nerve Degeneration , Animals , Humans , Mice , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Biomarkers/blood , Biomarkers/metabolism , Disease Models, Animal , Mice, Transgenic , MicroRNAs/blood , MicroRNAs/genetics , MicroRNAs/metabolism , Nerve Degeneration/diagnosis , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Peripheral Nerves/pathology , Superoxide Dismutase-1/genetics , Axons/pathology , Neurofilament Proteins , Early Diagnosis , Disease Progression
20.
Brain ; 146(7): 3049-3062, 2023 07 03.
Article in English | MEDLINE | ID: mdl-36730021

ABSTRACT

Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalized medicine in patients with neuropathic pain.


Subject(s)
MicroRNAs , Neuralgia , Humans , RNA, Messenger , Neuralgia/genetics , Neuralgia/metabolism , Epidermis/metabolism , MicroRNAs/genetics , Epidermal Cells/metabolism , NAV1.7 Voltage-Gated Sodium Channel/genetics , NAV1.7 Voltage-Gated Sodium Channel/metabolism
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