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Special Issue "Translocator Protein (TSPO) in Drug Delivery and Imaging of Pathological Disorders"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2019).

Special Issue Editors

Guest Editor
Prof. Dr. Nunzio Denora

Department of Pharmacy–Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Website 1 | Website 2 | E-Mail
Phone: +39-080-544-2767
Fax: +39-080-544-2767
Interests: targeted drug delivery; micro- and nano-incapsulation; age-related formulation
Guest Editor
Prof. Dr. Giovanni Natile

Department of Chemistry, University of Bari "Aldo Moro", via E. Orabona 4, 70125 Bari, Italy
Website 1 | Website 2 | E-Mail
Phone: +39-080-544-2774
Fax: +39 080 5442230
Interests: transport of anti-tumoral platinum-based drugs and their interaction with proteins and DNA; non-classic platinum anticancer drugs; active trans-platinum compounds; platinum compounds with uncommon coordination numbers and oxidation states and activation of unsaturated ligands

Special Issue Information

Dear Colleagues,

The increasing interest in the 18-kDa mitochondrial translocator protein (TSPO), as evidenced by the success of the previous Special Issue on the latest findings on the role of TSPO in eukaryotic cells, led us to propose a second Special Issue of the International Journal of Molecular Sciences on the role of the Translocator Protein in the drug delivery and imaging of pathological disorders.

TSPO is emerging as an extremely attractive subcellular biomarker for the early detection of disease states overexpressing this protein, and for the selective delivery of drugs to mitochondria. Moreover, the design and synthesis of new, more specific and effective TSPO ligands remains a very valuable task that cannot be neglected. Submissions dealing with all of these topics are welcome.

Prof. Dr. Nunzio Denora
Prof. Dr. Giovanni Natile
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • TSPO
  • Translocator Protein 18-kDa
  • mitochondria
  • TSPO ligand
  • drug delivery
  • drug targeting
  • Apoptosis
  • Imaging
  • PET
  • Microglia
  • Neuroinflammation
  • Alzheimer
  • Steroidogenesis
  • Cancer

Related Special Issue

Published Papers (13 papers)

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Research

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Open AccessArticle
Green Fluorescent Terbium (III) Complex Doped Silica Nanoparticles for TSPO Targeting
Int. J. Mol. Sci. 2019, 20(13), 3139; https://doi.org/10.3390/ijms20133139
Received: 26 April 2019 / Revised: 24 June 2019 / Accepted: 25 June 2019 / Published: 27 June 2019
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Abstract
The low photostability of conventional organic dyes and the toxicity of cadmium-based luminescent quantum dots have prompted the development of novel probes for in vitro and in vivo labelling. Here, a new fluorescent lanthanide probe based on silica nanoparticles is fabricated and investigated [...] Read more.
The low photostability of conventional organic dyes and the toxicity of cadmium-based luminescent quantum dots have prompted the development of novel probes for in vitro and in vivo labelling. Here, a new fluorescent lanthanide probe based on silica nanoparticles is fabricated and investigated for optically traceable in vitro translocator protein (TSPO) targeting. The targeting and detection of TSPO receptor, overexpressed in several pathological states, including neurodegenerative diseases and cancers, may provide valuable information for the early diagnosis and therapy of human disorders. Green fluorescent terbium(III)-calix[4]arene derivative complexes are encapsulated within silica nanoparticles and surface functionalized amine groups are conjugated with selective TSPO ligands based on a 2-phenylimidazo[1,2-a]pyridine acetamide structure containing derivatizable carboxylic groups. The photophysical properties of the terbium complex, promising for biological labelling, are demonstrated to be successfully conveyed to the realized nanoarchitectures. In addition, the high degree of biocompatibility, assessed by cell viability assay and the selectivity towards TSPO mitochondrial membrane receptors, proven by subcellular fractional studies, highlight targeting potential of this nanostructure for in vitro labelling of mitochondria. Full article
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Open AccessArticle
Characterization of the High-Affinity Drug Ligand Binding Site of Mouse Recombinant TSPO
Int. J. Mol. Sci. 2019, 20(6), 1444; https://doi.org/10.3390/ijms20061444
Received: 4 February 2019 / Revised: 18 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
Cited by 1 | PDF Full-text (4434 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The optimization of translocator protein (TSPO) ligands for Positron Emission Tomography as well as for the modulation of neurosteroids is a critical necessity for the development of TSPO-based diagnostics and therapeutics of neuropsychiatrics and neurodegenerative disorders. Structural hints on the interaction site and [...] Read more.
The optimization of translocator protein (TSPO) ligands for Positron Emission Tomography as well as for the modulation of neurosteroids is a critical necessity for the development of TSPO-based diagnostics and therapeutics of neuropsychiatrics and neurodegenerative disorders. Structural hints on the interaction site and ligand binding mechanism are essential for the development of efficient TSPO ligands. Recently published atomic structures of recombinant mammalian and bacterial TSPO1, bound with either the high-affinity drug ligand PK 11195 or protoporphyrin IX, have revealed the membrane protein topology and the ligand binding pocket. The ligand is surrounded by amino acids from the five transmembrane helices as well as the cytosolic loops. However, the precise mechanism of ligand binding remains unknown. Previous biochemical studies had suggested that ligand selectivity and binding was governed by these loops. We performed site-directed mutagenesis to further test this hypothesis and measured the binding affinities. We show that aromatic residues (Y34 and F100) from the cytosolic loops contribute to PK 11195 access to its binding site. Limited proteolytic digestion, circular dichroism and solution two-dimensional (2-D) NMR using selective amino acid labelling provide information on the intramolecular flexibility and conformational changes in the TSPO structure upon PK 11195 binding. We also discuss the differences in the PK 11195 binding affinities and the primary structure between TSPO (TSPO1) and its paralogous gene product TSPO2. Full article
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Open AccessArticle
Deletion of TSPO Resulted in Change of Metabolomic Profile in Retinal Pigment Epithelial Cells
Int. J. Mol. Sci. 2019, 20(6), 1387; https://doi.org/10.3390/ijms20061387
Received: 28 December 2018 / Revised: 11 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
PDF Full-text (2979 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Age-related macular degeneration is the main cause of vision loss in the aged population worldwide. Drusen, extracellular lesions formed underneath the retinal pigment epithelial (RPE) cells, are a clinical feature of AMD and associated with AMD progression. RPE cells support photoreceptor function by [...] Read more.
Age-related macular degeneration is the main cause of vision loss in the aged population worldwide. Drusen, extracellular lesions formed underneath the retinal pigment epithelial (RPE) cells, are a clinical feature of AMD and associated with AMD progression. RPE cells support photoreceptor function by providing nutrition, phagocytosing outer segments and removing metabolic waste. Dysfunction and death of RPE cells are early features of AMD. The translocator protein, TSPO, plays an important role in RPE cholesterol efflux and loss of TSPO results in increased intracellular lipid accumulation and reactive oxygen species (ROS) production. This study aimed to investigate the impact of TSPO knockout on RPE cellular metabolism by identifying the metabolic differences between wildtype and knockout RPE cells, with or without treatment with oxidized low density lipoprotein (oxLDL). Using liquid chromatography mass spectrometry (LC/MS), we differentiated several metabolic pathways among wildtype and knockout cells. Lipids amongst other intracellular metabolites were the most influenced by loss of TSPO and/or oxLDL treatment. Glucose, amino acid and nucleotide metabolism was also affected. TSPO deletion led to up-regulation of fatty acids and glycerophospholipids, which in turn possibly affected the cell membrane fluidity and stability. Higher levels of glutathione disulphide (GSSG) were found in TSPO knockout RPE cells, suggesting TSPO regulates mitochondrial-mediated oxidative stress. These data provide biochemical insights into TSPO-associated function in RPE cells and may shed light on disease mechanisms in AMD. Full article
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Open AccessArticle
The TSPO Ligands 2-Cl-MGV-1, MGV-1, and PK11195 Differentially Suppress the Inflammatory Response of BV-2 Microglial Cell to LPS
Int. J. Mol. Sci. 2019, 20(3), 594; https://doi.org/10.3390/ijms20030594
Received: 17 December 2018 / Revised: 16 January 2019 / Accepted: 18 January 2019 / Published: 30 January 2019
Cited by 3 | PDF Full-text (4667 KB) | HTML Full-text | XML Full-text
Abstract
The 18 kDa Translocator Protein (TSPO) is a marker for microglial activation as its expression is enhanced in activated microglia during neuroinflammation. TSPO ligands can attenuate neuroinflammation and neurotoxicity. In the present study, we examined the efficacy of new TSPO ligands designed by [...] Read more.
The 18 kDa Translocator Protein (TSPO) is a marker for microglial activation as its expression is enhanced in activated microglia during neuroinflammation. TSPO ligands can attenuate neuroinflammation and neurotoxicity. In the present study, we examined the efficacy of new TSPO ligands designed by our laboratory, MGV-1 and 2-Cl-MGV-1, in mitigating an in vitro neuroinflammatory process compared to the classic TSPO ligand, PK 11195. We exposed BV-2 microglial cells to lipopolysaccharide (LPS) for 24 h to induce inflammatory response and added the three TSPO ligands: (1) one hour before LPS treatment (pretreatment), (2) simultaneously with LPS (cotreatment), and (3) one hour after LPS exposure (post-treatment). We evaluated the capability of TSPO ligands to reduce the levels of three glial inflammatory markers: cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO). We compared the effects of the two novel ligands to PK 11195. Both 2-Cl-MGV-1 and MGV-1 reduced the levels of glial COX-2, iNOS, and NO in LPS-treated BV-2 cells more efficiently than PK 11195. Notably, even when added after exposure to LPS, all ligands were able to suppress the inflammatory response. Due to their pronounced anti-inflammatory activity, 2-Cl-MGV-1 and MGV-1 may serve as potential therapeutics in neuroinflammatory and neurodegenerative diseases. Full article
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Open AccessCommunication
Binding Affinity of Some Endogenous and Synthetic TSPO Ligands Regarding the rs6971 Polymorphism
Int. J. Mol. Sci. 2019, 20(3), 563; https://doi.org/10.3390/ijms20030563
Received: 4 January 2019 / Revised: 22 January 2019 / Accepted: 24 January 2019 / Published: 29 January 2019
Cited by 1 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text
Abstract
An intriguing target involved in several pathophysiological processes is the 18 kDa translocator protein (TSPO), of which exact functions remained elusive until now. A single nucleotide polymorphism in the TSPO gene influences the binding affinity of endogenous and synthetic TSPO ligands by facilitating [...] Read more.
An intriguing target involved in several pathophysiological processes is the 18 kDa translocator protein (TSPO), of which exact functions remained elusive until now. A single nucleotide polymorphism in the TSPO gene influences the binding affinity of endogenous and synthetic TSPO ligands by facilitating a lower-affinity conformation, which modifies a potential ligand binding site, ultimately leading to a binding profile classification according to each genotype. For instance, some clinical effects of the distinctive binding affinity profile of cholesterol toward the TSPO of individuals with different genotypes have been extensively discussed. Therefore, we conducted an investigation based on a radioligand binding assay, to determine the inhibition constants of some reported endogenous TSPO ligands (diazepam binding inhibitor and protoporphyrin IX), as well as synthetic ligands (disulfiram and derivatives). We observed no dependency of the polymorphism on the binding affinity of the evaluated endogenous ligands, whereas a high dependency on the binding affinity of the tested synthetic ligands was evident. Full article
Open AccessArticle
TSPO Ligands Promote Cholesterol Efflux and Suppress Oxidative Stress and Inflammation in Choroidal Endothelial Cells
Int. J. Mol. Sci. 2018, 19(12), 3740; https://doi.org/10.3390/ijms19123740
Received: 16 October 2018 / Revised: 16 November 2018 / Accepted: 21 November 2018 / Published: 24 November 2018
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Abstract
Choroidal endothelial cells supply oxygen and nutrients to retinal pigment epithelial (RPE) cells and photoreceptors, recycle metabolites, and dispose of metabolic waste through the choroidal blood circulation. Death of the endothelial cells of the choroid may cause abnormal deposits including unesterified and esterified [...] Read more.
Choroidal endothelial cells supply oxygen and nutrients to retinal pigment epithelial (RPE) cells and photoreceptors, recycle metabolites, and dispose of metabolic waste through the choroidal blood circulation. Death of the endothelial cells of the choroid may cause abnormal deposits including unesterified and esterified cholesterol beneath RPE cells and within Bruch’s membrane that contribute to the progression of age-related macular degeneration (AMD), the most prevalent cause of blindness in older people. Translocator protein (TSPO) is a cholesterol-binding protein that is involved in mitochondrial cholesterol transport and other cellular functions. We have investigated the role of TSPO in choroidal endothelial cells. Immunocytochemistry showed that TSPO was localized to the mitochondria of choroidal endothelial cells. Choroidal endothelial cells exposed to TSPO ligands (Etifoxine or XBD-173) had significantly increased cholesterol efflux, higher expression of cholesterol homeostasis genes (LXRα, CYP27A1, CYP46A1, ABCA1 and ABCG1), and reduced biosynthesis of cholesterol and phospholipids from [14C]acetate, when compared to untreated controls. Treatment with TSPO ligands also resulted in reduced production of reactive oxygen species (ROS), increased antioxidant capacity, and reduced release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and VEGF) induced by oxidized LDL. These data suggest TSPO ligands may offer promise for the treatment of AMD. Full article
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Open AccessArticle
Induction of ATP Release, PPIX Transport, and Cholesterol Uptake by Human Red Blood Cells Using a New Family of TSPO Ligands
Int. J. Mol. Sci. 2018, 19(10), 3098; https://doi.org/10.3390/ijms19103098
Received: 31 August 2018 / Revised: 5 October 2018 / Accepted: 7 October 2018 / Published: 10 October 2018
Cited by 2 | PDF Full-text (1371 KB) | HTML Full-text | XML Full-text
Abstract
Two main isoforms of the Translocator Protein (TSPO) have been identified. TSPO1 is ubiquitous and is mainly present at the outer mitochondrial membrane of most eukaryotic cells, whereas, TSPO2 is specific to the erythroid lineage, located at the plasma membrane, the nucleus, and [...] Read more.
Two main isoforms of the Translocator Protein (TSPO) have been identified. TSPO1 is ubiquitous and is mainly present at the outer mitochondrial membrane of most eukaryotic cells, whereas, TSPO2 is specific to the erythroid lineage, located at the plasma membrane, the nucleus, and the endoplasmic reticulum. The design of specific tools is necessary to determine the molecular associations and functions of TSPO, which remain controversial nowadays. We recently demonstrated that TSPO2 is involved in a supramolecular complex of the erythrocyte membrane, where micromolar doses of the classical TSPO ligands induce ATP release and zinc protoporphyrin (ZnPPIX) transport. In this work, three newly-designed ligands (NCS1016, NCS1018, and NCS1026) were assessed for their ability to modulate the functions of various erythrocyte’s and compare them to the TSPO classical ligands. The three new ligands were effective in reducing intraerythrocytic Plasmodium growth, without compromising erythrocyte survival. While NCS1016 and NCS1018 were the most effective ligands in delaying sorbitol-induced hemolysis, NCS1016 induced the highest uptake of ZnPPIX and NCS1026 was the only ligand inhibiting the cholesterol uptake. Differential effects of ligands are probably due, not only, to ligand features, but also to the dynamic interaction of TSPO with various partners at the cell membrane. Further studies are necessary to fully understand the mechanisms of the TSPO’s complex activation. Full article
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Open AccessArticle
Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain
Int. J. Mol. Sci. 2018, 19(9), 2707; https://doi.org/10.3390/ijms19092707
Received: 4 August 2018 / Revised: 9 September 2018 / Accepted: 9 September 2018 / Published: 11 September 2018
Cited by 3 | PDF Full-text (2859 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The inducible expression of the mitochondrial translocator protein 18 kDa (TSPO) by activated microglia is a prominent, regular feature of acute and chronic-progressive brain pathology. This expression is also the rationale for the continual development of new TSPO binding molecules for the diagnosis [...] Read more.
The inducible expression of the mitochondrial translocator protein 18 kDa (TSPO) by activated microglia is a prominent, regular feature of acute and chronic-progressive brain pathology. This expression is also the rationale for the continual development of new TSPO binding molecules for the diagnosis of “neuroinflammation” by molecular imaging. However, there is in the normal brain an ill-defined, low-level constitutive expression of TSPO. Taking advantage of healthy TSPO knockout mouse brain tissue to validate TSPO antibody specificity, this study uses immunohistochemistry to determine the regional distribution and cellular sources of TSPO in the normal mouse brain. Fluorescence microscopy revealed punctate TSPO immunostaining in vascular endothelial cells throughout the brain. In the olfactory nerve layers and glomeruli of the olfactory bulb, choroid plexus and ependymal layers, we confirm constitutive TSPO expression levels similar to peripheral organs, while some low TSPO expression is present in regions of known neurogenesis, as well as cerebellar Purkinje cells. The distributed-sparse expression of TSPO in endothelial mitochondria throughout the normal brain can be expected to give rise to a low baseline signal in TSPO molecular imaging studies. Finally, our study emphasises the need for valid and methodologically robust verification of the selectivity of TSPO ligands through the use of TSPO knockout tissues. Full article
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Open AccessArticle
Structural Prediction of the Dimeric Form of the Mammalian Translocator Membrane Protein TSPO: A Key Target for Brain Diagnostics
Int. J. Mol. Sci. 2018, 19(9), 2588; https://doi.org/10.3390/ijms19092588
Received: 25 July 2018 / Revised: 21 August 2018 / Accepted: 28 August 2018 / Published: 31 August 2018
Cited by 3 | PDF Full-text (2399 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers—the suggested functional state of the protein—is limited to a solid-state nuclear [...] Read more.
Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers—the suggested functional state of the protein—is limited to a solid-state nuclear magnetic resonance (NMR) study and to a model based on the previously-deposited solution NMR structure of the monomeric mouse protein. Computational studies performed here suggest that the NMR-solved structure in the presence of detergents is not prone to dimer formation and is furthermore unstable in its native membrane environment. We, therefore, propose a new model of the functionally-relevant dimeric form of the mouse protein, based on a prokaryotic homologue. The model, fully consistent with solid-state NMR data, is very different from the previous predictions. Hence, it provides, for the first time, structural insights into this pharmaceutically-important target which are fully consistent with experimental data. Full article
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Open AccessArticle
Translocator Protein (TSPO) as a Potential Biomarker in Human Cancers
Int. J. Mol. Sci. 2018, 19(8), 2176; https://doi.org/10.3390/ijms19082176
Received: 30 May 2018 / Revised: 21 June 2018 / Accepted: 24 June 2018 / Published: 25 July 2018
Cited by 2 | PDF Full-text (9531 KB) | HTML Full-text | XML Full-text
Abstract
TSPO is a receptor involved in the regulation of cellular proliferation, apoptosis and mitochondrial functions. Previous studies showed that the expression of TSPO protein correlated positively with tumour malignancy and negatively with patient survival. The aim of this study was to determine the [...] Read more.
TSPO is a receptor involved in the regulation of cellular proliferation, apoptosis and mitochondrial functions. Previous studies showed that the expression of TSPO protein correlated positively with tumour malignancy and negatively with patient survival. The aim of this study was to determine the transcription of Tspo mRNA in various types of normal and cancer tissues. In situ hybridization was performed to localise the Tspo mRNA in various human normal and cancer tissues. The relative level of Tspo mRNA was quantified using fluorescent intensity and visual estimation of colorimetric staining. RT-PCR was used to confirm these mRNA levels in normal lung, lung cancer, liver cancer, and cervical cancer cell lines. There was a significant increase in the level of transcription in liver, prostate, kidney, and brain cancers while a significant decrease was observed in cancers of the colon and lung. Quantitative RT-PCR confirmed that the mRNA levels of Tspo are higher in a normal lung cell line than in a lung cancer cell line. An increase in the expression levels of Tspo mRNA is not necessarily a good diagnostic biomarker in most cancers with changes not being large enough to be significantly different when detected by in situ hybridisation. Full article
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Open AccessArticle
Delivery of Proapoptotic Agents in Glioma Cell Lines by TSPO Ligand–Dextran Nanogels
Int. J. Mol. Sci. 2018, 19(4), 1155; https://doi.org/10.3390/ijms19041155
Received: 2 March 2018 / Revised: 7 April 2018 / Accepted: 8 April 2018 / Published: 11 April 2018
Cited by 3 | PDF Full-text (21992 KB) | HTML Full-text | XML Full-text
Abstract
Translocator protein 18-kDa (TSPO) is a versatile mitochondrial target for molecular imaging and therapy. Moreover, selective TSPO ligands have been widely investigated for diagnostic purposes and explored to target drug delivery systems directed to cancer cells overexpressing TSPO. Indeed, poly(d,l [...] Read more.
Translocator protein 18-kDa (TSPO) is a versatile mitochondrial target for molecular imaging and therapy. Moreover, selective TSPO ligands have been widely investigated for diagnostic purposes and explored to target drug delivery systems directed to cancer cells overexpressing TSPO. Indeed, poly(d,l-lactic-co-glycolic acid (PLGA) polymers and nanocarriers decorated with TSPO ligands are capable of transporting TSPO ligands inside cancer cells, inducing survival inhibition in cancer cells and producing mitochondrial morphology modification. The aim of this work was to prepare nanogels (NGs) made with TSPO ligand dextran conjugates (TSPO-Dex) that are useful as potential delivery systems of two TSPO ligands as apoptotic agents. Synthesis and complete characterization of TSPO–dextran conjugates, an average molecular weights analysis, TSPO ligand release profiles, thermal behaviour and swelling studies were achieved. NG preparation, characterization and in vitro biological studies were also performed. The release of TSPO ligands released from dextran conjugates at 37 °C occurred in human serum at a faster rate than that detected in phosphate buffer. Cytotoxicity studies demonstrated that NGs produced from TSPO ligand–dextran conjugates induce survival inhibition in rat C6 glioma cell lines. Cellular uptake was also proven by fluorescence microscopy. Full article
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Open AccessArticle
Assessment of TSPO in a Rat Experimental Autoimmune Myocarditis Model: A Comparison Study between [18F]Fluoromethyl-PBR28 and [18F]CB251
Int. J. Mol. Sci. 2018, 19(1), 276; https://doi.org/10.3390/ijms19010276
Received: 27 November 2017 / Revised: 11 January 2018 / Accepted: 15 January 2018 / Published: 17 January 2018
PDF Full-text (2909 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Overexpression of the 18-kDa translocator protein (TSPO) is closely linked to inflammatory responses in the heart, including myocarditis, which can lead to myocardial necrosis. In vivo assessment of inflammatory responses has enabled the precise diagnosis of myocarditis to improve clinical outcomes. Here, we [...] Read more.
Overexpression of the 18-kDa translocator protein (TSPO) is closely linked to inflammatory responses in the heart, including myocarditis, which can lead to myocardial necrosis. In vivo assessment of inflammatory responses has enabled the precise diagnosis of myocarditis to improve clinical outcomes. Here, we evaluated TSPO overexpression in a rat model of experimental autoimmune myocarditis (EAM) compared to healthy rats using two TSPO radiotracers, [18F]fluoromethyl-PBR28 ([18F]1) and [18F]CB251 ([18F]2). All radiolabeling methods were successfully applied to an automated module for the reproducible preparation of TSPO radiotracers. Both radiotracers were directly compared in an EAM rat model, as well as in healthy rats to determine whether either radiotracer provides a more promising assessment of in vivo TSPO overexpression. [18F]2 provided more specific TSPO-uptake in the heart of the EAM rats (1.32-fold that of the heart-to-lung uptake ratio versus healthy controls), while [18F]1 did not show a significant difference between the two groups. Histopathological characterization revealed that a prominent positron emission tomography (PET) signal of [18F]2 in the EAM rats corresponded to the presence of a higher density of TSPO compared to the healthy controls. These results suggest that the imidazole[1,2-a]pyridine-based radiotracer [18F]2 is a sensitive tool for noninvasively diagnosing myocarditis related to inflammation of the heart muscle by assessing abnormal TSPO expression. Full article
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Review

Jump to: Research

Open AccessReview
TSPO: An Evolutionarily Conserved Protein with Elusive Functions
Int. J. Mol. Sci. 2018, 19(6), 1694; https://doi.org/10.3390/ijms19061694
Received: 15 May 2018 / Accepted: 18 May 2018 / Published: 7 June 2018
Cited by 6 | PDF Full-text (3317 KB) | HTML Full-text | XML Full-text
Abstract
TSPO (18 kDa translocator protein) was identified decades ago in a search for peripheral tissue binding sites for benzodiazepines, and was formerly called the peripheral benzodiazepine receptor. TSPO is a conserved protein throughout evolution and it is implicated in the regulation of many [...] Read more.
TSPO (18 kDa translocator protein) was identified decades ago in a search for peripheral tissue binding sites for benzodiazepines, and was formerly called the peripheral benzodiazepine receptor. TSPO is a conserved protein throughout evolution and it is implicated in the regulation of many cellular processes, including inflammatory responses, oxidative stress, and mitochondrial homeostasis. TSPO, apart from its broad expression in peripheral tissues, is highly expressed in neuroinflammatory cells, such as activated microglia. In addition, emerging studies employing the ligands of TSPO suggest that TSPO plays an important role in neuropathological settings as a biomarker and therapeutic target. However, the precise molecular function of this protein in normal physiology and neuropathology remains enigmatic. This review provides an overview of recent advances in our understanding of this multifaceted molecule and identifies the knowledge gap in the field for future functional studies. Full article
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