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Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases

A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 32870

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Francesco Cappello

E-Mail Website
Guest Editor
Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
Interests: cell differentiation; tissue homeostasis; organ remodeling; cell stress; chaperones; heat shock proteins; chaperonopathies; exosomes
Special Issues, Collections and Topics in MDPI journals
Dr. Magdalena Gorska-Ponikowska

E-Mail Website1 Website2
Guest Editor
1. Department of Medical Chemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
2. Euro-Mediterranean Institute of Science and Technology, 90139 Palermo, Italy
3. Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, 70174 Stuttgart, Germany
Interests: cancer; neurodegenerations; nitro-oxidative stress; molecular chaperones; metabolic reprogramming
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Claudia Marino

E-Mail Website
Guest Editor
Institute of Mass Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Interests: neurodegeneration; protein homeostasis; Alzheimer’s disease; chaperones; misfolding; protein aggregation
Dr. Francesca Rappa

E-Mail Website
Guest Editor
Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy
Interests: cell differentiation; tissue homeostasis; organ remodeling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chaperones and related miRNAs are actively involved in crucial biological processes such as cell differentiation, tissue homeostasis, and organ remodeling throughout all the life span of an individual. An impairment of their function, if not counterbalanced by rescue mechanisms, can lead to the rise and/or perpetuation of human diseases by several—mostly unknown—etiopathophysiological mechanisms.

The aim of this Special Issue is to collect breakthrough papers focusing on data supporting that extracellular chaperones and their related miRNA (including either those in their soluble form or those hosted in extracellular vesicles) may represent innovative diagnostics tool in many chronic human pathologies. We will particularly consider papers that—other than presenting solid data on the aforementioned aim—also discuss original data about mechanistic roles of these molecules inside and outside cells.

Taken all together, the accepted papers will form a Special Issue that would represent a landmark in the scientific literature about this important issue that—in our opinion—is of interest for many scientists working in the fields of biomedicine, neuroscience, and advanced diagnostics.

Prof. Dr. Francesco Cappello
Dr. Magdalena Gorska-Ponikowska
Prof. Dr. Claudia Marino
Dr. Francesca Rappa
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Applied Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Molecular chaperones
  • Lipidic chaperones
  • Heat shock proteins
  • Chaperonins
  • Chpaeronopathies
  • Chaperonotherapies
  • Hsp10
  • Hsp27
  • Hsp60
  • Hsp70
  • Hsp90
  • Hsp110
  • Extracellular vesicles
  • Microvesicles
  • Exosomes
  • miRNA
  • Peripheral blood
  • Liquid biopsy
  • Carcinogenesis
  • Inflammation
  • Neurodegenerative diseases
  • Heart failure
  • Chronic obstructive pulmonary disease
  • Microbiota
  • Cell differentiation
  • Tissue homeostasis
  • Organ remodeling
  • Biomedicine
  • Neuroscience
  • Advanced diagnostics

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Published Papers (9 papers)

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Editorial

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3 pages, 191 KiB  
Editorial
Editorial for the Special Issue “Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases”
by Claudia Marino, Magdalena Gorska-Ponikowska, Francesca Rappa and Francesco Cappello
Appl. Sci. 2021, 11(12), 5517; https://doi.org/10.3390/app11125517 - 15 Jun 2021
Viewed by 1601
Abstract
Molecular chaperones are a family of proteins that are highly conserved during phylogenesis [...] Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)

Research

Jump to: Editorial, Review, Other

13 pages, 4369 KiB  
Article
The Triad Hsp60-miRNAs-Extracellular Vesicles in Brain Tumors: Assessing Its Components for Understanding Tumorigenesis and Monitoring Patients
by Francesca Graziano, Domenico Gerardo Iacopino, Giacomo Cammarata, Gianluca Scalia, Claudia Campanella, Antonino Giulio Giannone, Rossana Porcasi, Ada Maria Florena, Everly Conway de Macario, Alberto J.L. Macario, Giovanni Federico Nicoletti and Celeste Caruso Bavisotto
Appl. Sci. 2021, 11(6), 2867; https://doi.org/10.3390/app11062867 - 23 Mar 2021
Cited by 15 | Viewed by 2826
Abstract
Brain tumors have a poor prognosis and progress must be made for developing efficacious treatments, but for this to occur their biology and interaction with the host must be elucidated beyond current knowledge. What has been learned from other tumors may be applied [...] Read more.
Brain tumors have a poor prognosis and progress must be made for developing efficacious treatments, but for this to occur their biology and interaction with the host must be elucidated beyond current knowledge. What has been learned from other tumors may be applied to study brain tumors, for example, the role of Hsp60, miRNAs, and extracellular vesicles (EVs) in the mechanisms of cell proliferation and dissemination, and resistance to immune attack and anticancer drugs. It has been established that Hsp60 increases in cancer cells, in which it occurs not only in the mitochondria but also in the cytosol and plasma-cell membrane and it is released in EVs into the extracellular space and in circulation. There is evidence suggesting that these EVs interact with cells near and far from their original cell and that this interaction has an impact on the functions of the target cell. It is assumed that this crosstalk between cancer and host cells favors carcinogenesis in various ways. We, therefore, propose to study the triad Hsp60-related miRNAs-EVs in brain tumors and have standardized methods for the purpose. These revealed that EVs with Hsp60 and related miRNAs increase in patients’ blood in a manner that reflects disease status. The means are now available to monitor brain tumor patients by measuring the triad and to dissect its effects on target cells in vitro, and in experimental models in vivo. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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Review

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18 pages, 1377 KiB  
Review
The Challenging Riddle about the Janus-Type Role of Hsp60 and Related Extracellular Vesicles and miRNAs in Carcinogenesis and the Promises of Its Solution
by Sabrina David, Alessandra Maria Vitale, Alberto Fucarino, Federica Scalia, Giuseppe Vergilio, Everly Conway de Macario, Alberto J. L. Macario, Celeste Caruso Bavisotto and Alessandro Pitruzzella
Appl. Sci. 2021, 11(3), 1175; https://doi.org/10.3390/app11031175 - 27 Jan 2021
Cited by 7 | Viewed by 3300
Abstract
Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 [...] Read more.
Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 also occurs in other locations, intracellularly and extracellularly, including cytosol, plasma-cell membrane, and extracellular vesicles (EVs). Consequently, non-canonical functions and interacting partners of Hsp60 have been identified and it has been realized that it is a hub molecule in diverse networks and pathways and that it is implicated, directly or indirectly, in the development of various pathological conditions, the Hsp60 chaperonopathies. In this review, we will focus on the multi-faceted role of this chaperonin in human cancers, showing the contribution of intra- and extracellular Hsp60 in cancer development and progression, as well as the impact of miRNA-mediated regulation of Hsp60 in carcinogenesis. There are still various aspects of this intricate biological scenario that are poorly understood but ongoing research is steadily providing new insights and we will direct attention to them. For instance, we will highlight the possible applications of the Hsp60 involvement in carcinogenesis not only in diagnosis, but also in the development of specific anti-cancer therapies centered on the use of the chaperonin as therapeutic target or agent and depending on its role, pro- or anti-tumor. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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22 pages, 1238 KiB  
Review
The Neurochaperonopathies: Anomalies of the Chaperone System with Pathogenic Effects in Neurodegenerative and Neuromuscular Disorders
by Federica Scalia, Alessandra Maria Vitale, Radha Santonocito, Everly Conway de Macario, Alberto J. L. Macario and Francesco Cappello
Appl. Sci. 2021, 11(3), 898; https://doi.org/10.3390/app11030898 - 20 Jan 2021
Cited by 11 | Viewed by 4107
Abstract
The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively [...] Read more.
The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively abnormal molecular chaperones. Since the CS is ubiquitous, chaperonopathies are systemic, affecting various tissues and organs, playing an etiologic-pathogenic role in diverse conditions. In this review, we focus on chaperonopathies involved in the pathogenic mechanisms of diseases of the central and peripheral nervous systems: the neurochaperonopathies (NCPs). Genetic NCPs are linked to pathogenic variants of chaperone genes encoding, for example, the small Hsp, Hsp10, Hsp40, Hsp60, and CCT-BBS (chaperonin-containing TCP-1- Bardet–Biedl syndrome) chaperones. Instead, the acquired NCPs are associated with malfunctional chaperones, such as Hsp70, Hsp90, and VCP/p97 with aberrant post-translational modifications. Awareness of the chaperonopathies as the underlying primary or secondary causes of disease will improve diagnosis and patient management and open the possibility of investigating and developing chaperonotherapy, namely treatment with the abnormal chaperone as the main target. Positive chaperonotherapy would apply in chaperonopathies by defect, i.e., chaperone insufficiency, and consist of chaperone replacement or boosting, whereas negative chaperonotherapy would be pertinent when a chaperone actively participates in the initiation and progression of the disease and must be blocked and eliminated. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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13 pages, 629 KiB  
Review
Functions and Therapeutic Potential of Extracellular Hsp60, Hsp70, and Hsp90 in Neuroinflammatory Disorders
by Giusi Alberti, Letizia Paladino, Alessandra Maria Vitale, Celeste Caruso Bavisotto, Everly Conway de Macario, Claudia Campanella, Alberto J. L. Macario and Antonella Marino Gammazza
Appl. Sci. 2021, 11(2), 736; https://doi.org/10.3390/app11020736 - 14 Jan 2021
Cited by 19 | Viewed by 4612
Abstract
Neuroinflammation is implicated in central nervous system (CNS) diseases, but the molecular mechanisms involved are poorly understood. Progress may be accelerated by developing a comprehensive view of the pathogenesis of CNS disorders, including the immune and the chaperone systems (IS and CS). The [...] Read more.
Neuroinflammation is implicated in central nervous system (CNS) diseases, but the molecular mechanisms involved are poorly understood. Progress may be accelerated by developing a comprehensive view of the pathogenesis of CNS disorders, including the immune and the chaperone systems (IS and CS). The latter consists of the molecular chaperones; cochaperones; and chaperone cofactors, interactors, and receptors of an organism and its main collaborators in maintaining protein homeostasis (canonical function) are the ubiquitin–proteasome system and chaperone-mediated autophagy. The CS has also noncanonical functions, for instance, modulation of the IS with induction of proinflammatory cytokines. This deserves investigation because it may be at the core of neuroinflammation, and elucidation of its mechanism will open roads toward developing efficacious treatments centered on molecular chaperones (i.e., chaperonotherapy). Here, we discuss information available on the role of three members of the CS—heat shock protein (Hsp)60, Hsp70, and Hsp90—in IS modulation and neuroinflammation. These three chaperones occur intra- and extracellularly, with the latter being the most likely involved in neuroinflammation because they can interact with the IS. We discuss some of the interactions, their consequences, and the molecules involved but many aspects are still incompletely elucidated, and we hope that this review will encourage research based on the data presented to pave the way for the development of chaperonotherapy. This may consist of blocking a chaperone that promotes destructive neuroinflammation or replacing or boosting a defective chaperone with cytoprotective activity against neurodegeneration. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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26 pages, 687 KiB  
Review
Brain Tumor-Derived Extracellular Vesicles as Carriers of Disease Markers: Molecular Chaperones and MicroRNAs
by Alessandra Maria Vitale, Radha Santonocito, Giuseppe Vergilio, Antonella Marino Gammazza, Claudia Campanella, Everly Conway de Macario, Fabio Bucchieri, Alberto J. L. Macario and Celeste Caruso Bavisotto
Appl. Sci. 2020, 10(19), 6961; https://doi.org/10.3390/app10196961 - 5 Oct 2020
Cited by 5 | Viewed by 4074
Abstract
Primary and metastatic brain tumors are usually serious conditions with poor prognosis, which reveal the urgent need of developing rapid diagnostic tools and efficacious treatments. To achieve these objectives, progress must be made in the understanding of brain tumor biology, for example, how [...] Read more.
Primary and metastatic brain tumors are usually serious conditions with poor prognosis, which reveal the urgent need of developing rapid diagnostic tools and efficacious treatments. To achieve these objectives, progress must be made in the understanding of brain tumor biology, for example, how they resist natural defenses and therapeutic intervention. One resistance mechanism involves extracellular vesicles that are released by tumors to meet target cells nearby or distant via circulation and reprogram them by introducing their cargo. This consists of different molecules among which are microRNAs (miRNAs) and molecular chaperones, the focus of this article. miRNAs modify target cells in the immune system to avoid antitumor reaction and chaperones are key survival molecules for the tumor cell. Extracellular vesicles cargo reflects the composition and metabolism of the original tumor cell; therefore, it is a source of markers, including the miRNAs and chaperones discussed in this article, with potential diagnostic and prognostic value. This and their relatively easy availability by minimally invasive procedures (e.g., drawing venous blood) illustrate the potential of extracellular vesicles as useful materials to manage brain tumor patients. Furthermore, understanding extracellular vesicles circulation and interaction with target cells will provide the basis for using this vesicle for delivering therapeutic compounds to selected tumor cells. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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Graphical abstract

28 pages, 745 KiB  
Review
Extracellular Chaperones as Novel Biomarkers of Overall Cancer Progression and Efficacy of Anticancer Therapy
by Malgorzata Anna Krawczyk, Agata Pospieszynska, Małgorzata Styczewska, Ewa Bien, Sambor Sawicki, Antonella Marino Gammazza, Alberto Fucarino and Magdalena Gorska-Ponikowska
Appl. Sci. 2020, 10(17), 6009; https://doi.org/10.3390/app10176009 - 30 Aug 2020
Cited by 4 | Viewed by 3687
Abstract
Exosomal heat shock proteins (Hsps) are involved in intercellular communication both in physiological and pathological conditions. They play a role in key processes of carcinogenesis including immune system regulation, cell differentiation, vascular homeostasis and metastasis formation. Thus, exosomal Hsps are emerging biomarkers of [...] Read more.
Exosomal heat shock proteins (Hsps) are involved in intercellular communication both in physiological and pathological conditions. They play a role in key processes of carcinogenesis including immune system regulation, cell differentiation, vascular homeostasis and metastasis formation. Thus, exosomal Hsps are emerging biomarkers of malignancies and possible therapeutic targets. Adolescents and young adults (AYAs) are patients aged 15–39 years. This age group, placed between pediatric and adult oncology, pose a particular challenge for cancer management. New biomarkers of cancer growth and progression as well as prognostic factors are desperately needed in AYAs. In this review, we attempted to summarize the current knowledge on the role of exosomal Hsps in selected solid tumors characteristic for the AYA population and/or associated with poor prognosis in this age group. These included malignant melanoma, brain tumors, and breast, colorectal, thyroid, hepatocellular, lung and gynecological tract carcinomas. The studies on exosomal Hsps in these tumors are limited; however; some have provided promising results. Although further research is needed, there is potential for future clinical applications of exosomal Hsps in AYA cancers, both as novel biomarkers of disease presence, progression or relapse, or as therapeutic targets or tools for drug delivery. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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21 pages, 971 KiB  
Review
Biogenesis, Biologic Function and Clinical Potential of Exosomes in Different Diseases
by Amany Magdy Beshbishy, Saad Alghamdi, ThankGod E. Onyiche, Muhammad Zahoor, Nallely Rivero-Perez, Adrian Zaragoza-Bastida, Mohamed A. Ghorab, Ahmed Kh. Meshaal, Mohamed A. El-Esawi, Helal F. Hetta and Gaber El-Saber Batiha
Appl. Sci. 2020, 10(13), 4428; https://doi.org/10.3390/app10134428 - 27 Jun 2020
Cited by 15 | Viewed by 4664
Abstract
Exosomes are extracellular vesicles (EVs) belonging to the nanovesicles family that function as signaling molecules between cells. After their first description in the late 1960s, interest in their potential as a research target has steadily increased. They are small secreted organelles with a [...] Read more.
Exosomes are extracellular vesicles (EVs) belonging to the nanovesicles family that function as signaling molecules between cells. After their first description in the late 1960s, interest in their potential as a research target has steadily increased. They are small secreted organelles with a single membrane that are well enriched in lipids, proteins, nucleic acids, and glycoconjugates. Exosomes take part in a larger communication network in which cells communicate between one another by DNA shuttling, proteins, RNA, and membrane-bound factors. The machinery of protein quality control occurs through the process termed “exosome biogenesis”. Furthermore, the pathway involved in intercellular movement of vesicles is vital in various aspects of human health and diseases. Due to their inherent properties, exosomes are currently being developed as potential therapeutic agents in a wide range of diseases including infectious and non-infectious diseases. Exosomes and other EVs sourced from Mesenchymal stem cells (MSCs) have been shown in different studies to possess therapeutic effects in diverse disease models either in vivo or in vitro. Some mechanisms and/or pathways that MSC-derived exosomes use to illustrate their therapeutic effect against some diseases have also been summarized. This review aims to highlight the recent findings and potential therapeutic application of exosomes in different diseases such as autoimmune, cardiovascular, obesity, neural, soft tissues, bone, and cartilage. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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Other

10 pages, 819 KiB  
Brief Report
A Pilot Longitudinal Evaluation of MicroRNAs for Monitoring the Cognitive Impairment in Pediatric Multiple Sclerosis
by Nicoletta Nuzziello, Arianna Consiglio, Rosa Gemma Viterbo, Flavio Licciulli, Sabino Liuni, Maria Trojano and Maria Liguori
Appl. Sci. 2020, 10(22), 8274; https://doi.org/10.3390/app10228274 - 22 Nov 2020
Cited by 2 | Viewed by 2276
Abstract
MicroRNAs (miRNAs), a class of non-coding RNAs, seem to play a key role in complex diseases like multiple sclerosis (MS), as well as in many cognitive functions associated with the disease. In a previous cross-sectional evaluation on pediatric MS (PedMS) patients, the expression [...] Read more.
MicroRNAs (miRNAs), a class of non-coding RNAs, seem to play a key role in complex diseases like multiple sclerosis (MS), as well as in many cognitive functions associated with the disease. In a previous cross-sectional evaluation on pediatric MS (PedMS) patients, the expression of some miRNAs and their target genes were found to be associated with the scores of some neuropsychiatric tests, thus suggesting that they may be involved in early processes of cognitive impairment. To verify these data, we asked the same patients to be re-evaluated after a 1-year interval; unfortunately, only nine of them agreed to this further clinical and molecular analysis. The main results showed that 13 differentially expressed miRNAs discriminated the two time-points. Among them, the expression of miR-182-5p, miR-320a-3p, miR-744-5p and miR-192-5p significantly correlated with the attention and information processing speed performances, whereas the expression of miR-182-5p, miR-451a, miR-4742-3p and miR-320a-3p correlated with the expressive language performances. The analysis of mRNA expression uncovered 58 predicted and/or validated miRNA-target pairs, including 23 target genes, some of them already associated with cognitive impairment, such as the transducing beta like 1 X-linked receptor-1 gene (TBL1XR1), correlated to disorders of neurodevelopment; the Snf2 related CREBBP activator protein gene (SRCAP) that was found implicated in a rare form of dementia; and the glia maturation factor beta gene (GMFB), which has been reported to be implicated in neurodegeneration and neuroinflammation. No molecular pathways involving the most targeted genes survived the adjustment for multiple data. Although preliminary, these findings showed the feasibility of the methods also applied to longitudinal investigations, as well as the reliability of the obtained results. These findings should be confirmed in larger PedMS cohorts in order to identify early markers of cognitive impairment, towards which more efficient therapeutic efforts can be addressed. Full article
(This article belongs to the Special Issue Extracellular Chaperones and Related miRNA as Diagnostic Tools of Chronic Diseases)
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