Publications by authors named "Francesco Cappello"

197 Publications

Extracellular heat shock proteins in cancer: From early diagnosis to new therapeutic approach.

Semin Cancer Biol 2021 Sep 23. Epub 2021 Sep 23.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), Institute of Anatomy and Histology, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy. Electronic address:

In cancer, human cells lose the ability to properly control the series of events that occur constantly during cell growth and division, including protein expression, stability, and dynamics. Heat shock proteins (Hsps) are key molecules in these events, constitutively expressed at high levels and could furthermore be induced by the response to cancer-induced stress. In tumor cells, Hsps have been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis; in some cases, they can be overexpressed and dysregulated, representing important cancer hallmarks. In the past few years, it has been demonstrated that Hsps can be released by tumor cells through several secreting pathways, including the extracellular vesicles (EVs), thus modulating the tumor microenvironment as well as long-distance intercellular communication and metastatization. In this review, we discuss the role of extracellular Hsps in cancer, with a particular interest in Hsps in EVs. We would also like to highlight the importance of fully understanding of the role of extracellular Hsps released by EVs and encourage further research in this field the use of Hsps as early cancer biomarkers and therapeutic targets.
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http://dx.doi.org/10.1016/j.semcancer.2021.09.010DOI Listing
September 2021

Molecular Chaperones and miRNAs in Epilepsy: Pathogenic Implications and Therapeutic Prospects.

Int J Mol Sci 2021 Aug 10;22(16). Epub 2021 Aug 10.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy.

Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.
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http://dx.doi.org/10.3390/ijms22168601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395327PMC
August 2021

Hsp27 and Hsp60 in human submandibular salivary gland: Quantitative patterns in healthy and cancerous tissues with potential implications for differential diagnosis and carcinogenesis.

Acta Histochem 2021 Sep 19;123(6):151771. Epub 2021 Aug 19.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, Institute of Human Anatomy and Histology, University of Palermo, Palermo, Italy. Electronic address:

Tumors of the submandibular salivary gland (SMG) are uncommon but sufficiently frequent for the physician to consider them in routine examinations and for the pathologist to be prepared to differentiate them from other tissue abnormalities. However, scarcity of specimens makes training difficult, a situation compounded by the lack of accepted universal diagnostic guidelines. Furthermore, there is little information on the chaperone system (CS) of the gland, despite the increasing evidence of its participation in carcinogenesis as a biomarker for diagnosis and patient follow up, and in the mechanisms by which the tumor cells thrive. We are investigating this aspect of various tumors, and here we describe standardized methods for assessing the tissue levels of two chaperones, Hsp27 and Hsp60, in normal SMG and its tumors. We present illustrative results obtained with immunohistochemistry (IHC) and immunofluorescence-confocal microscopy (IF-CM), which we propose as a platform onto which a data base could be built by adding new information and which would provide material for developing guidelines for tumor identification and monitoring. The initial findings are encouraging in as much as the tumors surveyed showed quantitative patterns of Hsp27 and Hsp60 that distinguished tumoral from normal tissue and certain tumors from the others, and the results from IHC were confirmed by IF-CM.
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http://dx.doi.org/10.1016/j.acthis.2021.151771DOI Listing
September 2021

Unexpected tumor reduction in metastatic colorectal cancer patients during SARS-Cov-2 infection: effect of ACE-2 expression on tumor cells or molecular mimicry phenomena? Two not mutually exclusive hypotheses.

Ther Adv Med Oncol 2021 27;13:17588359211027825. Epub 2021 Jun 27.

Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD, USA.

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http://dx.doi.org/10.1177/17588359211027825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239968PMC
June 2021

The Italian law on body donation: A position paper of the Italian College of Anatomists.

Ann Anat 2021 Nov 15;238:151761. Epub 2021 Jun 15.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

In Italy, recent legislation (Law No. 10/2020) has tuned regulations concerning the donation of one's postmortem body and tissues for study, training, and scientific research purposes. This study discusses several specific issues to optimise the applicability and effectiveness of such an important, novel regulatory setting. Critical issues arise concerning the learners, the type of training and teaching activities that can be planned, the position of academic anatomy institutes, the role of family members in the donation process, the time frame of the donation process, the eligibility of partial donation, or the simultaneous donation of organs and tissues to patients awaiting transplantation. In particular, a universal time limit for donations (i.e., one year) makes it impossible to plan the long-term use of specific body parts, which could be effectively preserved for the advanced teaching and training of medical students and surgeons. The abovementioned conditions lead to the limited use of corpses, thus resulting in the inefficiency of the whole system of body donation. Overall, the donors' scope for the donation of their body could be best honoured by a more flexible and tuneable approach that can be used on a case-by-case basis. Furthermore, it is deemed necessary to closely monitor the events scheduled for corpses in public nonacademic institutions or private enterprises. This paper presents useful insights from Italian anatomists with the hope of providing inspiration for drafting the regulations. In conclusion, this paper focuses on the critical issues derived from the recently introduced Italian law on the donation and use of the body after death and provides suggestions to lawmakers for future implementations.
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http://dx.doi.org/10.1016/j.aanat.2021.151761DOI Listing
November 2021

SARS-CoV-2 in patients with cancer: possible role of mimicry of human molecules by viral proteins and the resulting anti-cancer immunity.

Cell Stress Chaperones 2021 07 11;26(4):611-616. Epub 2021 May 11.

Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Human Anatomy and Histology, University of Palermo, 90141, Palermo, Italy.

A few reports suggest that molecular mimicry can have a role in determining the more severe and deadly forms of COVID-19, inducing endothelial damage, disseminated intravascular coagulation, and multiorgan failure. Heat shock proteins/molecular chaperones can be involved in these molecular mimicry phenomena. However, tumor cells can display on their surface heat shock proteins/molecular chaperones that are mimicked by SARS-CoV-2 molecules (including the Spike protein), similarly to what happens in other bacterial or viral infections. Since molecular mimicry between SARS-CoV-2 and tumoral proteins can elicit an immune reaction in which antibodies or cytotoxic cells produced against the virus cross-react with the tumor cells, we want to prompt clinical studies to evaluate the impact of SARS-CoV-2 infection on prognosis and follow up of various forms of tumors. These topics, including a brief historical overview, are discussed in this paper.
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http://dx.doi.org/10.1007/s12192-021-01211-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112475PMC
July 2021

JNK pathway and heat shock response mediate the survival of C26 colon carcinoma bearing mice fed with the mushroom Pleurotus eryngii var. eryngii without affecting tumor growth or cachexia.

Food Funct 2021 Apr 15;12(7):3083-3095. Epub 2021 Mar 15.

Department of Biomedicine, Neurosciences and advanced Diagnostics, University of Palermo, Palermo, Italy.

In the last few years, there has been emerging interest in developing treatments against human diseases using natural bioactive content. Here, the powder of the edible mushroom Pleurotus eryngii var. eryngii was mixed with the normal diet of mice bearing C26 colon carcinoma. Interestingly, it was evidenced by a significant increase in the survival rate of C26 tumor-bearing mice accompanied by a significant increase in Hsp90 and Hsp27 protein levels in the tumors. These data were paralleled by a decrease in Hsp60 levels. The mushroom introduced in the diet induced the inhibition of the transcription of the pro-inflammatory cytokines IL-6 and IL-1 exerting an anti-inflammatory action. The effects of the mushroom were mediated by the activation of c-Jun NH-terminal kinases as a result of metabolic stress induced by the micronutrients introduced in the diet. In the tumors of C26 bearing mice fed with Pleurotus eryngii there was also a decreased expression of the mitotic regulator survivin and the anti-apoptotic factor Bcl-xL as well as an increase in the expression levels of Atg7, a protein that drives autophagy. In our hypothesis the interplay of these molecules favored the survival of the mice fed with the mushroom. These data are promising for the introduction of Pleurotus eryngii as a dietary supplement or as an adjuvant in anti-cancer therapy.
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http://dx.doi.org/10.1039/d0fo03171bDOI Listing
April 2021

Function and Fiber-Type Specific Distribution of Hsp60 and αB-Crystallin in Skeletal Muscles: Role of Physical Exercise.

Biology (Basel) 2021 Jan 21;10(2). Epub 2021 Jan 21.

Human Anatomy Section, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy.

Skeletal muscle is a plastic and complex tissue, rich in proteins that are subject to continuous rearrangements. Skeletal muscle homeostasis can be affected by different types of stresses, including physical activity, a physiological stressor able to stimulate a robust increase in different heat shock proteins (HSPs). The modulation of these proteins appears to be fundamental in facilitating the cellular remodeling processes related to the phenomenon of training adaptations such as hypertrophy, increased oxidative capacity, and mitochondrial activity. Among the HSPs, a special attention needs to be devoted to Hsp60 and αB-crystallin (CRYAB), proteins constitutively expressed in the skeletal muscle, where their specific features could be highly relevant in understanding the impact of different volumes of training regimes on myofiber types and in explaining the complex picture of exercise-induced mechanical strain and damaging conditions on fiber population. This knowledge could lead to a better personalization of training protocols with an optimal non-harmful workload in populations of individuals with different needs and healthy status. Here, we introduce for the first time to the reader these peculiar HSPs from the perspective of exercise response, highlighting the control of their expression, biological function, and specific distribution within skeletal muscle fiber-types.
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http://dx.doi.org/10.3390/biology10020077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911561PMC
January 2021

Plausible Role of Estrogens in Pathogenesis, Progression and Therapy of Lung Cancer.

Int J Environ Res Public Health 2021 01 14;18(2). Epub 2021 Jan 14.

Department of Medical Chemistry, Medical University of Gdansk, 80-211 Gdansk, Poland.

Malignant neoplasms are among the most common diseases and are responsible for the majority of deaths in the developed world. In contrast to men, available data show a clear upward trend in the incidence of lung cancer in women, making it almost as prevalent as breast cancer. Women might be more susceptible to the carcinogenic effect of tobacco smoke than men. Furthermore, available data indicate a much more frequent mutation of the tumor suppressor gene- in non-small cell lung cancer (NSCLC) female patients compared to males. Another important factor, however, might lie in the female sex hormones, whose mitogenic or carcinogenic effect is well known. Epidemiologic data show a correlation between hormone replacement therapy (HRT) or oral contraceptives (OCs), and increased mortality rates due to the increased incidence of malignant tumors, including lung cancer. Interestingly, two types of estrogen receptors have been detected in lung cancer cells: ERα and ERβ. The presence of ERα has been detected in tissues and non-small-cell lung carcinoma (NSCLC) cell lines. In contrast, overexpression of ERβ is a prognostic marker in NSCLC. Herein, we summarize the current knowledge on the role of estrogens in the etiopathogenesis of lung cancer, as well as biological, hormonal and genetic sex-related differences in this neoplasm.
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http://dx.doi.org/10.3390/ijerph18020648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828659PMC
January 2021

Sex-based differences after a single bout of exercise on PGC1α isoforms in skeletal muscle: A pilot study.

FASEB J 2021 02;35(2):e21328

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Palermo, Italy.

To date, there are limited and incomplete data on possible sex-based differences in fiber-types of skeletal muscle and their response to physical exercise. Adult healthy male and female mice completed a single bout of endurance exercise to examine the sex-based differences of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), heat shock protein 60 (Hsp60), interleukin 6 (IL-6) expression, as well as the Myosin Heavy Chain (MHC) fiber-type distribution in soleus and extensor digitorum longus (EDL) muscles. Our results showed for the first time that in male soleus, a muscle rich of type IIa fibers, endurance exercise activates specifically genes involved in mitochondrial biogenesis such as PGC1 α1 isoform, Hsp60 and IL-6, whereas the expression of PGC1 α2 and α3 was significantly upregulated in EDL muscle, a fast-twitch skeletal muscle, independently from the gender. Moreover, we found that the acute response of different PGC1α isoforms was muscle and gender dependent. These findings add a new piece to the huge puzzle of muscle response to physical exercise. Given the importance of these genes in the physiological response of the muscle to exercise, we strongly believe that our data could support future research studies to personalize a specific and sex-based exercise training protocol.
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http://dx.doi.org/10.1096/fj.202002173RDOI Listing
February 2021

The Role of Molecular Chaperones in Virus Infection and Implications for Understanding and Treating COVID-19.

J Clin Med 2020 Oct 30;9(11). Epub 2020 Oct 30.

Department of Biomedicine, Neuroscience and Advances Diagnosis (BIND), Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy.

The COVID-19 pandemic made imperative the search for means to end it, which requires a knowledge of the mechanisms underpinning the multiplication and spread of its cause, the coronavirus SARS-CoV-2. Many viruses use members of the hosts' chaperoning system to infect the target cells, replicate, and spread, and here we present illustrative examples. Unfortunately, the role of chaperones in the SARS-CoV-2 cycle is still poorly understood. In this review, we examine the interactions of various coronaviruses during their infectious cycle with chaperones in search of information useful for future research on SARS-CoV-2. We also call attention to the possible role of molecular mimicry in the development of autoimmunity and its widespread pathogenic impact in COVID-19 patients. Viral proteins share highly antigenic epitopes with human chaperones, eliciting anti-viral antibodies that crossreact with the chaperones. Both, the critical functions of chaperones in the infectious cycle of viruses and the possible role of these molecules in COVID-19 autoimmune phenomena, make clear that molecular chaperones are promising candidates for the development of antiviral strategies. These could consist of inhibiting-blocking those chaperones that are necessary for the infectious viral cycle, or those that act as autoantigens in the autoimmune reactions causing generalized destructive effects on human tissues.
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http://dx.doi.org/10.3390/jcm9113518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693988PMC
October 2020

A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy.

Int J Mol Sci 2020 Oct 15;21(20). Epub 2020 Oct 15.

Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy.

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, ) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, ). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous c.670C>G p.(Leu224Val) variant in the gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient's clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease.
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http://dx.doi.org/10.3390/ijms21207631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589105PMC
October 2020

Missense Mutations of Human Hsp60: A Computational Analysis to Unveil Their Pathological Significance.

Front Genet 2020 18;11:969. Epub 2020 Aug 18.

Department of Biomedicine, Neuroscience and Advanced Diagnosis, Section of Human Anatomy, University of Palermo, Palermo, Italy.

Two chaperonopathies have been linked to mutations in the human (; ) gene, but other existing variants might cause diseases, even if there is no comprehensive information about this possibility. To fill this vacuum, which might be at the basis of misdiagnoses or simply ignorance of chaperonopathies in patients who would benefit by proper identification of their ailments, we searched the sequenced human genomes available in public databases to determine the range of missense mutations in the single gene. A total of 224 missense mutations were identified, including those already characterized. Detailed examination of these mutations was carried out to assess their possible impact on protein structure-function, considering: (a) the properties of individual amino acids; (b) the known functions of the amino acids in the human Hsp60 and/or in the highly similar bacterial ortholog GroEL; (c) the location of the mutant amino acids in the monomers and oligomers; and (d) structure-function relationships inferred from crystal structures. And we also applied a bioinformatics tool for predicting the impact of mutations on proteins. A portion of these genetic variants could have a deleterious impact on protein structure-function, but have not yet been associated with any pathology. Are these variants causing disease with mild clinical manifestations and are, therefore, being overlooked? Or are they causing overt disease, which is misdiagnosed? Our data indicate that more chaperonopathies might occur than is currently acknowledged and that awareness of chaperonopathies among medical personnel will increase their detection and improve patient management.
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http://dx.doi.org/10.3389/fgene.2020.00969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461820PMC
August 2020

Bacterial and viral infections and related inflammatory responses in chronic obstructive pulmonary disease.

Ann Med 2021 12;53(1):135-150

Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri, IRCCS, Veruno, Italy.

In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline. KEY MESSAGE Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients. The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung. The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.
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http://dx.doi.org/10.1080/07853890.2020.1831050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877965PMC
December 2021

Lipid chaperones and associated diseases: a group of chaperonopathies defining a new nosological entity with implications for medical research and practice.

Cell Stress Chaperones 2020 11 27;25(6):805-820. Epub 2020 Aug 27.

Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Biochemistry, University of Palermo, 90127, Palermo, Italy.

Fatty acid-binding proteins (FABPs) are lipid chaperones assisting in the trafficking of long-chain fatty acids with functions in various cell compartments, including oxidation, signaling, gene-transcription regulation, and storage. The various known FABP isoforms display distinctive tissue distribution, but some are active in more than one tissue. Quantitative and/or qualitative changes of FABPs are associated with pathological conditions. Increased circulating levels of FABPs are biomarkers of disorders such as obesity, insulin resistance, cardiovascular disease, and cancer. Deregulated expression and malfunction of FABPs can result from genetic alterations or posttranslational modifications and can be pathogenic. We have assembled the disorders with abnormal FABPs as chaperonopathies in a distinct nosological entity. This entity is similar but separate from that encompassing the chaperonopathies pertaining to protein chaperones. In this review, we discuss the role of FABPs in the pathogenesis of metabolic syndrome, cancer, and neurological diseases. We highlight the opportunities for improving diagnosis and treatment that open by encompassing all these pathological conditions within of a coherent nosological group, focusing on abnormal lipid chaperones as biomarkers of disease and etiological-pathogenic factors.
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http://dx.doi.org/10.1007/s12192-020-01153-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591661PMC
November 2020

Extracorporeal Shock Waves Increase Markers of Cellular Proliferation in Bronchial Epithelium and in Primary Bronchial Fibroblasts of COPD Patients.

Can Respir J 2020 8;2020:1524716. Epub 2020 Aug 8.

Dipartimento di Scienze Mediche, Università di Torino, Turin, Italy.

Chronic obstructive pulmonary disease (COPD) is due to structural changes and narrowing of small airways and parenchymal destruction (loss of the alveolar attachment as a result of pulmonary emphysema), which all lead to airflow limitation. Extracorporeal shock waves (ESW) increase cell proliferation and differentiation of connective tissue fibroblasts. To date no studies are available on ESW treatment of human bronchial fibroblasts and epithelial cells from COPD and control subjects. We obtained primary bronchial fibroblasts from bronchial biopsies of 3 patients with mild/moderate COPD and 3 control smokers with normal lung function. 16HBE cells were also studied. Cells were treated with a piezoelectric shock wave generator at low energy (0.3 mJ/mm, 500 pulses). After treatment, viability was evaluated and cells were recultured and followed up for 4, 24, 48, and 72 h. Cell growth (WST-1 test) was assessed, and proliferation markers were analyzed by qRT-PCR in cell lysates and by ELISA tests in cell supernatants and cell lysates. After ESW treatment, we observed a significant increase of cell proliferation in all cell types. C-Kit (CD117) mRNA was significantly increased in 16HBE cells at 4 h. Protein levels were significantly increased for c-Kit (CD117) at 4 h in 16HBE ( < 0.0001) and at 24 h in COPD-fibroblasts ( = 0.037); for PCNA at 4 h in 16HBE ( = 0.046); for Thy1 (CD90) at 24 and 72 h in CS-fibroblasts ( = 0.031 and  = 0.041); for TGF1 at 72 h in CS-fibroblasts ( = 0.038); for procollagen-1 at 4 h in COPD-fibroblasts ( = 0.020); and for NF-B-p65 at 4 and 24 h in 16HBE ( = 0.015 and  = 0.0002). In the peripheral lung tissue of a representative COPD patient, alveolar type II epithelial cells (TTF-1+) coexpressing c-Kit (CD117) and PCNA were occasionally observed. These data show an increase of cell proliferation induced by a low dosage of extracorporeal shock waves in 16HBE cells and primary bronchial fibroblasts of COPD and control smoking subjects.
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http://dx.doi.org/10.1155/2020/1524716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429777PMC
September 2021

The Post-Lockdown Era: What Is Next in Italy?

Front Pharmacol 2020 15;11:1074. Epub 2020 Jul 15.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy.

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http://dx.doi.org/10.3389/fphar.2020.01074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373777PMC
July 2020

Human molecular chaperones share with SARS-CoV-2 antigenic epitopes potentially capable of eliciting autoimmunity against endothelial cells: possible role of molecular mimicry in COVID-19.

Cell Stress Chaperones 2020 09 4;25(5):737-741. Epub 2020 Aug 4.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Palermo, Italy.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), the cause of COVID-19 disease, has the potential to elicit autoimmunity because mimicry of human molecular chaperones by viral proteins. We compared viral proteins with human molecular chaperones, many of which are heat shock proteins, to determine if they share amino acid-sequence segments with immunogenic-antigenic potential, which can elicit cross-reactive antibodies and effector immune cells with the capacity to damage-destroy human cells by a mechanism of autoimmunity. We identified the chaperones that can putatively participate in molecular mimicry phenomena after SARS-CoV-2 infection, focusing on those for which endothelial cell plasma-cell membrane localization has already been demonstrated. We also postulate that post-translational modifications, induced by physical (shear) and chemical (metabolic) stress caused respectively by the risk factors hypertension and diabetes, might have a role in determining plasma-cell membrane localization and, in turn, autoimmune-induced endothelial damage.
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http://dx.doi.org/10.1007/s12192-020-01148-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402394PMC
September 2020

Extracellular Vesicles-Based Drug Delivery Systems: A New Challenge and the Exemplum of Malignant Pleural Mesothelioma.

Int J Mol Sci 2020 Jul 30;21(15). Epub 2020 Jul 30.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy.

Research for the most selective drug delivery to tumors represents a fascinating key target in science. Alongside the artificial delivery systems identified in the last decades (e.g., liposomes), a family of natural extracellular vesicles (EVs) has gained increasing focus for their potential use in delivering anticancer compounds. EVs are released by all cell types to mediate cell-to-cell communication both at the paracrine and the systemic levels, suggesting a role for them as an ideal nano-delivery system. Malignant pleural mesothelioma (MPM) stands out among currently untreatable tumors, also due to the difficulties in achieving an early diagnosis. Thus, early diagnosis and treatment of MPM are both unmet clinical needs. This review looks at indirect and direct evidence that EVs may represent both a new tool for allowing an early diagnosis of MPM and a potential new delivery system for more efficient therapeutic strategies. Since MPM is a relatively rare malignant tumor and preclinical MPM models developed to date are very few and not reliable, this review will report data obtained in other tumor types, suggesting the potential use of EVs in mesothelioma patients as well.
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http://dx.doi.org/10.3390/ijms21155432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432055PMC
July 2020

The eSports conundrum: is the sports sciences community ready to face them? A perspective.

J Sports Med Phys Fitness 2020 Dec 1;60(12):1591-1602. Epub 2020 Jul 1.

Department of Biomedicine, Neuroscience and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy.

The reality of eSports is something much more complex than individual users playing video games. There are several characteristics that eSports have in common with traditional sports: from the spirit of competition to the structural composition of the teams, including the increase in performance with training and practice, up to the injuries and physical and psychological stress of the athlete. The number of scientific papers interested in this reality is still relatively low, although in recent years there has been a significant increase in this regard. Probably the lack of knowledge of the world of eSports by inexperts can represent an initial obstacle in the approach to this environment. Therefore, an all-round analysis of the eSports industry is fundamental: including the figures that characterize them, the different eSports disciplines, the possible physical and mental consequences for athletes. Emphasizing the similarities between electronic and non-electronic sports is essential in order to make people, and the scientific community in particular, understand how they should be considered equal to the "traditional" vision of sports especially in the need for professional medical support. The number of professional and amateur eSports players increase every day as well as the birth of professional organizations and national teams while medical monitoring seems to have fallen behind. In the near future, we hope that the scientific community and in particular the medical disciplines will be able to closely support the world of eSports to guarantee the correct assistance to all professional and non-professional athletes. An increase in the number of scientific work and specific studies will certainly bring benefits in countering physical attrition, reducing the risk of injury, in psychological support to athletes and in the fight against doping reality.
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http://dx.doi.org/10.23736/S0022-4707.20.10892-2DOI Listing
December 2020

Does SARS-CoV-2 Trigger Stress-InducedAutoimmunity by Molecular Mimicry? A Hypothesis.

J Clin Med 2020 Jun 29;9(7). Epub 2020 Jun 29.

Euro-Mediterranean Institute of Science and Technology (IEMEST), 90141 Palermo, Italy.

Viruses can generate molecular mimicry phenomena within their hosts. Why shouldsevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not be considered one of these?Information in this short review suggests that it might be so and, thus, encourages research aimingat testing this possibility. We propose, as a working hypothesis, that the virus induces antibodiesand that some of them crossreact with host's antigens, thus eliciting autoimmune phenomena withdevasting consequences in various tissues and organs. If confirmed, by in vitro and in vivo tests,this could drive researchers to find effective treatments against the virus.
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http://dx.doi.org/10.3390/jcm9072038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408943PMC
June 2020

Hsp60 Post-translational Modifications: Functional and Pathological Consequences.

Front Mol Biosci 2020 4;7:95. Epub 2020 Jun 4.

Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy.

Hsp60 is a chaperone belonging to the Chaperonins of Group I and typically functions inside mitochondria in which, together with the co-chaperonin Hsp10, maintains protein homeostasis. In addition to this canonical role, Hsp60 plays many others beyond the mitochondria, for instance in the cytosol, plasma-cell membrane, extracellular space, and body fluids. These non-canonical functions include participation in inflammation, autoimmunity, carcinogenesis, cell replication, and other cellular events in health and disease. Thus, Hsp60 is a multifaceted molecule with a wide range of cellular and tissue locations and functions, which is noteworthy because there is only one gene. The question is by what mechanism this protein can become multifaceted. Likely, one factor contributing to this diversity is post-translational modification (PTM). The amino acid sequence of Hsp60 contains many potential phosphorylation sites, and other PTMs are possible such as O-GlcNAcylation, nitration, acetylation, S-nitrosylation, citrullination, oxidation, and ubiquitination. The effect of some of these PTMs on Hsp60 functions have been examined, for instance phosphorylation has been implicated in sperm capacitation, docking of H2B and microtubule-associated proteins, mitochondrial dysfunction, tumor invasiveness, and delay or facilitation of apoptosis. Nitration was found to affect the stability of the mitochondrial permeability transition pore, to inhibit folding ability, and to perturb insulin secretion. Hyperacetylation was associated with mitochondrial failure; S-nitrosylation has an impact on mitochondrial stability and endothelial integrity; citrullination can be pro-apoptotic; oxidation has a role in the response to cellular injury and in cell migration; and ubiquitination regulates interaction with the ubiquitin-proteasome system. Future research ought to determine which PTM causes which variations in the Hsp60 molecular properties and functions, and which of them are pathogenic, causing chaperonopathies. This is an important topic considering the number of acquired Hsp60 chaperonopathies already cataloged, many of which are serious diseases without efficacious treatment.
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http://dx.doi.org/10.3389/fmolb.2020.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289027PMC
June 2020

The posterior talocalcaneal ligament: an MRI evaluation.

Surg Radiol Anat 2020 Oct 23;42(10):1167-1174. Epub 2020 Jun 23.

Postgraduate University School of Sports Medicine, University Hospital of Palermo, Palermo, Italy.

Purpose: A wide inter-individual variability in terms of size, orientation and insertion is observed regarding ankle ligaments. The aim of this study is to identify and describe the anatomical features of the posterior talocalcaneal ligament (PTCL) observed through the use of magnetic resonance imaging (MRI) of the ankle.

Methods: The study was retrospectively carried out on 893 ankle MRI's exams. The exams have all been performed using a 1.5-T (T) MRI. The same scanning protocols and scan planes were carried out in all the exams. The first evaluated parameter was the recognition of the PTCL. Subsequently, in all those cases where the ligament was present, its features such as insertion sites, length, and thickness were evaluated.

Results: The PTCL identification was possible in 77 exams (8.6% of the total number). Among these, we were able to identify some variants regarding insertion sites, length, and thickness. The PTCL could be further classified into four categories based on the most common characteristics observed.

Conclusions: Our study has identified different characteristics of the PTCL that allow us to further understand the characteristics of the ligament itself. In conclusion, the need for further studies focused on the biomechanical role of the PTCL in the ankle joint appears mandatory.
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http://dx.doi.org/10.1007/s00276-020-02506-7DOI Listing
October 2020

Molecular mimicry may explain multi-organ damage in COVID-19.

Autoimmun Rev 2020 08 11;19(8):102591. Epub 2020 Jun 11.

University of Palermo, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), Palermo, Italy; Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2020.102591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289093PMC
August 2020

Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID-19?

Br J Haematol 2020 07 8;190(2):e92-e93. Epub 2020 Jun 8.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Palermo, Italy.

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http://dx.doi.org/10.1111/bjh.16883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283741PMC
July 2020

Myocardial bridge pathology and preventable accidents during physical activity of healthy subjects: A case report and a literature review.

Med Leg J 2020 Dec 21;88(4):209-214. Epub 2020 May 21.

Department Pro.Mi.Se, Legal Medicine, School of Medicine, University of Palermo, Palermo, Italy.

Myocardial bridging is a congenital coronary pathology described as a segment of coronary artery which courses through the myocardial wall under the muscle bridge. Although the prognosis of myocardial bridging is benign, sports medicine recognises myocardial bridging as a leading cause of sudden death among young basketball, football and soccer players. The authors report a case of a 42-year-old man who collapsed while playing football. He died notwithstanding prompt medical assistance and cardiopulmonary resuscitation. At autopsy, gross examination of the heart revealed the intramural course of the left anterior descending coronary artery to be 2 cm from its coronary ostial origin. Histological examination of ventricular septal and left myocardium showed early signs of ischaemic injury without disease of small coronary vessels and hypertrophic cardiomyopathy. The cause of the death was due to malignant ventricular arrhythmia during intense physical activity.
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http://dx.doi.org/10.1177/0025817220923638DOI Listing
December 2020

COVID-19 and molecular mimicry: The Columbus' egg?

J Clin Neurosci 2020 07 6;77:246. Epub 2020 May 6.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Human Anatomy and Histology, University of Palermo, via del Vespro 129, 90141 Palermo, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jocn.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200327PMC
July 2020

COVID-19 Deaths: Are We Sure It Is Pneumonia? Please, Autopsy, Autopsy, Autopsy!

J Clin Med 2020 Apr 26;9(5). Epub 2020 Apr 26.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90100 Palermo, Italy.

The current outbreak of COVID-19 severe respiratory disease, which started in Wuhan, China, is an ongoing challenge, and a major threat to public health that requires surveillance, prompt diagnosis, and research efforts to understand this emergent pathogen and to develop an effective response. Due to the scientific community's efforts, there is an increasing body of published studies describing the virus' biology, its transmission and diagnosis, its clinical features, its radiological findings, and the development of candidate therapeutics and vaccines. Despite the decline in postmortem examination rate, autopsy remains the gold standard to determine why and how death happens. Defining the pathophysiology of death is not only limited to forensic considerations; it may also provide useful clinical and epidemiologic insights. Selective approaches to postmortem diagnosis, such as limited postmortem sampling over full autopsy, can also be useful in the control of disease outbreaks and provide valuable knowledge for managing appropriate control measures. In this scenario, we strongly recommend performing full autopsies on patients who died with suspected or confirmed COVID-19 infection, particularly in the presence of several comorbidities. Only by working with a complete set of histological samples obtained through autopsy can one ascertain the exact cause(s) of death, optimize clinical management, and assist clinicians in pointing out a timely and effective treatment to reduce mortality. Death can teach us not only about the disease, it might also help with its prevention and, above all, treatment.
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http://dx.doi.org/10.3390/jcm9051259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287760PMC
April 2020

Is COVID-19 a proteiform disease inducing also molecular mimicry phenomena?

Cell Stress Chaperones 2020 05 20;25(3):381-382. Epub 2020 Apr 20.

University of Palermo, Palermo, Italy.

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http://dx.doi.org/10.1007/s12192-020-01112-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167495PMC
May 2020

Molecular chaperones in tumors of salivary glands.

J Mol Histol 2020 Apr 16;51(2):109-115. Epub 2020 Apr 16.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, Institute of Human Anatomy and Histology, University of Palermo, Palermo, Italy.

The salivary glands are key components of the mouth and play a central role in its physiology. Their importance may be appreciated considering their number, occurrence in pairs, and distribution in the mouth: two parotids, two submandibular, two sublingual, and many other small ones scattered throughout the mouth. They produce saliva, without which ingestion of non-liquid nutrients and speech would be practically impossible. Nevertheless, the physiology and pathology of salivary glands are poorly understood. For instance, tumors of salivary glands occur, and their incidence is on the rise, but their etiology and pathogenesis are virtually unknown, although some risk factors have been identified. Likewise, the role of the chaperoning system in the development, normal functioning, and pathology, including carcinogenesis, remains to be determined. This scarcity of basic knowledge impedes progress in diagnosis, disease monitoring, and therapeutics of salivary gland tumors. We are currently involved in examining the chaperoning system of human salivary glands and we performed a search of the literature to determine what has been reported relating to oncology. We found data pertaining to six components of the chaperone system, namely HSP27, HSP60, HSP70, HSP84, HSP86, and GRP78, and to another HSP, the heme-oxygenase H-O1, also named HSP32, which does not belong in the chaperoning system but seemed to have potential as a biomarker for diagnostic purposes as much as the HSP/chaperones mentioned above. The reported quantitative variations of the six chaperones were distinctive enough to distinguish malignant from benign tumors, suggesting that these molecules hold potential as biomarkers useful in differential diagnosis. Also, the quantitative variations described accompanying tumor development, as observed in cancers of other organs, encourages research to elucidate whether chaperones play a role in the initiation and/or progression of salivary gland tumors.
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http://dx.doi.org/10.1007/s10735-020-09871-yDOI Listing
April 2020
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