Publications by authors named "Ranjan Dutta"

94 Publications

Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures.

Ann Clin Transl Neurol 2021 Jun 12;8(6):1279-1291. Epub 2021 May 12.

Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, USA.

Objective: Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Though MS was initially considered to be a white matter demyelinating disease, myelin loss in cortical gray matter has been reported in all disease stages. We previously identified microRNAs (miRNAs) in white matter lesions (WMLs) that are detected in serum from MS patients. However, miRNA expression profiles in gray matter lesions (GMLs) from progressive MS brains are understudied.

Methods: We used a combination of global miRNAs and gene expression profiling of GMLs and independent validation using real-time quantitative polymerase chain reaction (RT-qPCR), immuno-in situ hybridization, and immunohistochemistry.

Results: Compared to matched myelinated gray matter (GM) regions, we identified 82 miRNAs in GMLs, of which 10 were significantly upregulated and 17 were significantly downregulated. Among these 82 miRNAs, 13 were also detected in serum and importantly were associated with brain atrophy in MS patients. The predicted target mRNAs of these miRNAs belonged to pathways associated with axonal guidance, TGF-β signaling, and FOXO signaling. Further, using state-of-the-art human protein-protein interactome network analysis, we mapped the four key GM atrophy-associated miRNAs (hsa-miR-149*, hsa-miR-20a, hsa-miR-29c, and hsa-miR-25) to their target mRNAs that were also changed in GMLs.

Interpretation: Our study identifies miRNAs altered in GMLs in progressive MS brains that correlate with atrophy measures. As these miRNAs were also detected in sera of MS patients, these could act as markers of GML demyelination in MS.
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http://dx.doi.org/10.1002/acn3.51365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164853PMC
June 2021

The BHMT-betaine methylation pathway epigenetically modulates oligodendrocyte maturation.

PLoS One 2021 11;16(5):e0250486. Epub 2021 May 11.

School of Biomedical Sciences, Kent State University, Kent, Ohio, United States of America.

Research into the epigenome is of growing importance as a loss of epigenetic control has been implicated in the development of neurodegenerative diseases. Previous studies have implicated aberrant DNA and histone methylation in multiple sclerosis (MS) disease pathogenesis. We have previously reported that the methyl donor betaine is depleted in MS and is linked to changes in histone H3 trimethylation (H3K4me3) in neurons. We have also shown that betaine increases histone methyltransferase activity by activating chromatin bound betaine homocysteine S-methyltransferase (BHMT). Here, we investigated the role of the BHMT-betaine methylation pathway in oligodendrocytes. Immunocytochemistry in the human MO3.13 cell line, primary rat oligodendrocytes, and tissue from MS postmortem brain confirmed the presence of the BHMT enzyme in the nucleus in oligodendrocytes. BHMT expression is increased 2-fold following oxidative insult, and qRT-PCR demonstrated that betaine can promote an increase in expression of oligodendrocyte maturation genes SOX10 and NKX-2.2 under oxidative conditions. Chromatin fractionation provided evidence of a direct interaction of BHMT on chromatin and co-IP analysis indicates an interaction between BHMT and DNMT3a. Our data show that both histone and DNA methyltransferase activity are increased following betaine administration. Betaine effects were shown to be dependent on BHMT expression following siRNA knockdown of BHMT. This is the first report of BHMT expression in oligodendrocytes and suggests that betaine acts through BHMT to modulate histone and DNA methyltransferase activity on chromatin. These data suggest that methyl donor availability can impact epigenetic changes and maturation in oligodendrocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112889PMC
May 2021

Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination.

Nat Commun 2021 03 26;12(1):1923. Epub 2021 Mar 26.

Department of Pharmacology and Toxicology, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.

Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.
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http://dx.doi.org/10.1038/s41467-021-22263-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998003PMC
March 2021

Post Synthetic Modification of Planar Antiaromatic Hexaphyrin (1.0.1.0.1.0) by Regio-Selective, Sequential SAr.

Molecules 2021 Feb 15;26(4). Epub 2021 Feb 15.

Department of Chemistry, Kangwon National University, Chuncheon 24341, Korea.

In spite of unique structural, spectroscopic and redox properties, the synthetic variants of the planar, antiaromatic hexaphyrin (1.0.1.0.1.0) derivatives , has been limited due to the low yields and difficulty in access to the starting material. A chemical modification of the -substituents could be good alternative overcoming the synthetic barrier. Herein, we report a regio-selective nucleophilic aromatic substitution (SAr) of -pentafluorophenyl group in rosarrin with catechol. The reaction afforded benzodioxane fused rosarrin as single product with high yield. The intrinsic antiaromatic character of the starting rosarrin retained throughout the reactions. Clean, two electron reduction was achieved by treatment of with SnCl•2HO affording 26π-electron aromatic rosarrin . The synthesized compounds exhibited noticeable changes in photophysical and redox properties compared with starting rosarrin .
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http://dx.doi.org/10.3390/molecules26041025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919474PMC
February 2021

Neuronal hibernation following hippocampal demyelination.

Acta Neuropathol Commun 2021 03 1;9(1):34. Epub 2021 Mar 1.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA.

Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.
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http://dx.doi.org/10.1186/s40478-021-01130-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923530PMC
March 2021

Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination.

J Neurosci 2021 03 20;41(10):2245-2263. Epub 2021 Jan 20.

Department of Pharmacology and Toxicology, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203

The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of γ () in adult NG2 OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain. The failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease.
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http://dx.doi.org/10.1523/JNEUROSCI.0580-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018763PMC
March 2021

Multiple Sclerosis as a Syndrome-Implications for Future Management.

Front Neurol 2020 28;11:784. Epub 2020 Aug 28.

Florey Institute of Neuroscience and Mental Health, Florey Department, The University of Melbourne, Parkville, VIC, Australia.

We propose that multiple sclerosis (MS) is best characterized as a syndrome rather than a single disease because different pathogenetic mechanisms can result in the constellation of symptoms and signs by which MS is clinically characterized. We describe several cellular mechanisms that could generate inflammatory demyelination through disruption of homeostatic interactions between immune and neural cells. We illustrate that genomics is important in identifying phenocopies, in particular for primary progressive MS. We posit that molecular profiling, rather than traditional clinical phenotyping, will facilitate meaningful patient stratification, as illustrated by interactions between HLA and a regulator of homeostatic phagocytosis, MERTK. We envisage a personalized approach to MS management where genetic, molecular, and cellular information guides management.
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http://dx.doi.org/10.3389/fneur.2020.00784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483755PMC
August 2020

Tug of war: A bimanual technique for anterior circumferential proliferative vitreoretinopathy in recurrent retinal detachment.

Indian J Ophthalmol 2020 10;68(10):2155-2158

Vitreoretinal Services, Shroff Eye Centre, New Delhi, India.

Purpose: To describe a bimanual technique, "tug of war" for managing anterior circumferential proliferative vitreoretinopathy (PVR) in eyes with recurrent retinal detachment (RRD).

Methods: We retrospectively analyzed outcomes from eyes with RRD that underwent reattachment surgery using this maneuver and had a minimum of 6 months follow-up. A chandelier light was inserted for endo-illumination and the circumferential anterior PVR was tackled with two 25-gauge forceps stretching circumferential tractional membranes in opposite direction (tug of war) till they snapped.

Results: Eleven eyes of 11 patients with a mean age of 38.2 ± 19.7 years underwent surgery. All eyes had advanced PVR of Grade C A Type 4 (Circumferential). The median duration of RD from the time of first surgery was 6 months (interquartile range = 3-8 months). The tug of war maneuver was successful in relieving the anterior retinal traction leading to retinal reattachment in all eyes without the need for relaxing retinotomies or retinectomies. Small iatrogenic retina tears occurred at the time of tug of war maneuver in 3 (27%) eyes at the site of maximum traction. The mean best-corrected visual acuity (BCVA) improved from 1.87 ± 0.2 logarithm of minimum angle of resolution (logMAR) to 1.3 ± 0.4 logMAR at 6-months follow-up (P = 0.04).

Conclusion: The 'tug of war' maneuver is useful for relieving circumferential anterior traction and reattaching the retina in eyes with RRD without having to resort to large relaxing retinotomies or retinectomies.
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http://dx.doi.org/10.4103/ijo.IJO_2179_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727933PMC
October 2020

Discriminative Behavior of a Donor-Acceptor-Donor Triad toward Cyanide and Fluoride: Insights into the Mechanism of Naphthalene Diimide Reduction by Cyanide and Fluoride.

Inorg Chem 2020 Sep 1;59(18):13371-13382. Epub 2020 Sep 1.

School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700 032, India.

A new molecular donor-acceptor-donor (D-A-D) triad, comprised of an electron deficient 1,4,5,8-naphthalene tetracarboxylic diimide (NDI) unit covalently connected to two flanking photosensitizers, i.e., a bis-heteroleptic Ru(II) complex of 1,10-phenanthroline and pyridine triazole hybrid ligand, is described. The single crystal X-ray structure of the perchlorate salt of the triad demonstrates that the electron deficient NDI unit can act as a host for anions via anion-π interaction. Detailed solution-state studies indicate that fluoride selectively interacts with the D-A-D triad to form a dianionic NDI, NDI, via a radical anion, NDI. On the contrary, cyanide reduces the NDI moiety to NDI, as confirmed by UV-vis, NMR, and EPR spectroscopy. Further, femtosecond transient absorption spectroscopic studies reveal a low luminescence quantum yield of the D-A-D triad attributable to the photoinduced electron transfer (PET) process from the photoactive Ru(II) center to the NDI unit. Interestingly, the triad displays "OFF-ON" luminescence behavior in the presence of fluoride by restoring the Ru(II) to phenanthroline/pyridine-triazole-based MLCT emission, whereas cyanide fails to show a similar property due to a different redox process operational in the latter. The reduction of NDI in the presence of fluoride and cyanide in different polar solvents indicates that involvement of such deprotonated solvents in the electron transfer mechanism may not be operative in our present system. Low-temperature kinetic studies support the formation of a charge transfer associative transient species, which likely allows overcoming the thermodynamically uphill barrier for the direct electron transfer mechanism.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01738DOI Listing
September 2020

Succination inactivates gasdermin D and blocks pyroptosis.

Science 2020 09 20;369(6511):1633-1637. Epub 2020 Aug 20.

Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.
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http://dx.doi.org/10.1126/science.abb9818DOI Listing
September 2020

Noncovalent Intermolecular Interaction in Cofacially Stacked 24π Antiaromatic Hexaphyrin Dimer.

Chemistry 2020 Dec 28;26(69):16434-16440. Epub 2020 Oct 28.

Department of Chemistry and Spectroscopy Laboratory for, Functional π-Electronic Systems, Yonsei University, Seoul, 03722, Korea.

π-π Stacking is omnipresent not only in nature but in a wide variety of practical fields applied to our lives. Because of its importance in a performance of natural and artificial systems, such as light harvesting system and working layer in device, many researchers have put intensive effort into identifying its underlying nature. However, for the case of π-π stacked systems composed of antiaromatic units, the understanding of the fundamental mechanisms is still unclear. Herein, we synthesized a new type of planar β,β'-phenylene-bridged hexaphyrin (1.0.1.0.1.0), referred as naphthorosarin which possesses the 24π-electron conjugated pathway. Especially, the corresponding antiaromatic porphyrinoid shows the unique property to form dimeric species adopting the face-to-face geometry which is unprecedented in cases of known annulated naphthorosarins. In order to elucidate the intriguing properties derived from the stacked dimer, the current study focuses on the experimental support to rationalize the observed π-π interactions between the two subunits.
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http://dx.doi.org/10.1002/chem.202002884DOI Listing
December 2020

Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.

Cell 2020 04 3;181(2):382-395.e21. Epub 2020 Apr 3.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address:

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426147PMC
April 2020

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation.

J Clin Invest 2020 07;130(7):3467-3482

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
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http://dx.doi.org/10.1172/JCI129401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324171PMC
July 2020

Cytoplasmic-predominant Pten increases microglial activation and synaptic pruning in a murine model with autism-like phenotype.

Mol Psychiatry 2021 05 13;26(5):1458-1471. Epub 2020 Feb 13.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Germline mutations in PTEN account for ~10% of cases of autism spectrum disorder (ASD) with coincident macrocephaly. To explore the importance of nuclear PTEN in the development of ASD and macrocephaly, we previously generated a mouse model with predominantly cytoplasmic localization of Pten (Pten).Cytoplasmic predominant Pten localization results in a phenotype of extreme macrocephaly and autistic-like traits. Transcriptomic analysis of the Pten cortex found upregulated gene pathways related to myeloid cell activation, myeloid cell migration, and phagocytosis. These transcriptomic findings were used to direct in vitro assays on Pten wild-type and Pten microglia. We found increased Iba1 and C1q expression with enhanced phagocytic capacity in Pten microglia, indicating microglial activation. Moreover, through a series of neuron-microglia co-culture experiments, we found Pten microglia are more efficient at synaptic pruning compared with wild-type controls. In addition, we found evidence for neuron-microglia cross-talk, where Pten neurons elicit enhanced pruning from innately activated microglia. Subsequent in vivo studies validated our in vitro findings. We observed a concurrent decline in the expression of Pten and synaptic markers in the Pten cortex. At ~3 weeks of age, with a 50% drop in Pten expression compared with wild-type levels, we observed enhanced activation of microglia in the Pten brain. Collectively, our data provide evidence that dysregulated Pten in microglia has an etiological role in microglial activation, phagocytosis, and synaptic pruning, creating avenues for future studies on the importance of PTEN in maintaining microglia homeostasis.
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http://dx.doi.org/10.1038/s41380-020-0681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159731PMC
May 2021

Strapped calix[4]pyrroles: from syntheses to applications.

Chem Soc Rev 2020 Feb 20;49(3):865-907. Epub 2020 Jan 20.

Department of Chemistry, The University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, Texas 78712, USA. and Center for Supramolecular Chemistry and Catalysis, Shanghai University, Shanghai 200444, P. R. China.

Supramolecular chemistry is a central topic in modern chemistry. It touches on many traditional disciplines, such as organic chemistry, inorganic chemistry, physical chemistry, materials chemistry, environmental chemistry, and biological chemistry. Supramolecular hosts, inter alia macrocyclic hosts, play critical roles in supramolecular chemistry. Calix[4]pyrroles, non-aromatic tetrapyrrolic macrocycles defined by sp hybridized meso bridges, have proved to be versatile receptors for neutral species, anions, and cations, as well as ion pairs. Compared to the parent system, octamethylcalix[4]pyrrole and its derivatives bearing simple appended functionalities, strapped calix[4]pyrroles typically display enhanced binding affinities and selectivities. In this review, we summarize advances in the design and synthesis of strapped calix[4]pyrroles, as well as their broad utility in molecular recognition, supramolecular extraction, separation technology, ion transport, and as agents capable of inhibiting cancer cell proliferation. Future challenges within this sub-field are also discussed.
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http://dx.doi.org/10.1039/c9cs00528eDOI Listing
February 2020

A robust bis-rhodium(i) complex of π-extended planar, anti-aromatic hexaphyrin[1.0.1.0.1.0].

Chem Commun (Camb) 2020 Jan 17;56(5):758-761. Epub 2019 Dec 17.

Department of Chemistry, Kangwon National University, Chuncheon 24341, Korea.

β,β'-Phenylene bridged hexaphyrin[1.0.1.0.1.0] (naphthorosarin), an expanded porphyrin possessing C-symmetry, has been shown to possess unique electronic features. We now report a bimetallic Rh(i)-complex of naphthorosarin retaining 24 π-antiaromatic characteristics. The two Rh(i) cations reside on opposite sides of the macrocyclic π-system and are separated at a distance consistent with a possible Rh(i)-Rh(i) metallic bond interaction.
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http://dx.doi.org/10.1039/c9cc09221hDOI Listing
January 2020

Oligodendrocyte Intrinsic miR-27a Controls Myelination and Remyelination.

Cell Rep 2019 10;29(4):904-919.e9

Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA; Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA. Electronic address:

Remyelination requires the generation of new oligodendrocytes (OLs), which are derived from oligodendrocyte progenitor cells (OPCs). Maturation of OPCs into OLs is a multi-step process. Here, we describe a microRNA expressed by OLs, miR-27a, as a regulator of OL development and survival. Increased levels of miR-27a were found in OPCs associated with multiple sclerosis (MS) lesions and in animal models of demyelination. Increased levels of miR-27a led to inhibition of OPC proliferation by cell-cycle arrest, as well as impaired differentiation of human OPCs (hOPCs) and myelination by dysregulating the Wnt-β-catenin signaling pathway. In vivo administration of miR-27a led to suppression of myelinogenic signals, leading to loss of endogenous myelination and remyelination. Our findings provide evidence supporting a critical role for a steady-state level of OL-specific miR-27a in supporting multiple steps in the complex process of OPC maturation and remyelination.
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http://dx.doi.org/10.1016/j.celrep.2019.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874400PMC
October 2019

Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination.

Nat Commun 2019 08 29;10(1):3887. Epub 2019 Aug 29.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.
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http://dx.doi.org/10.1038/s41467-019-11638-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715717PMC
August 2019

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis.

J Vis Exp 2019 07 19(149). Epub 2019 Jul 19.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic;

We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 days a year. Participants consent to donate their brain and spinal cord. Most patients were followed by neurologists at the Cleveland Clinic Mellen Center for MS Treatment and Research. Their clinical courses and neurological disabilities are well-characterized. Soon after death, the body is transported to the MS Imaging Center, where the brain is scanned in situ by 3 T magnetic resonance imaging (MRI). The body is then transferred to the autopsy room, where the brain and spinal cord are removed. The brain is divided into two hemispheres. One hemisphere is immediately placed in a slicing box and alternate 1 cm-thick slices are either fixed in 4% paraformaldehyde for two days or rapidly frozen in dry ice and 2-methylbutane. The short-fixed brain slices are stored in a cryopreservation solution and used for histological analyses and immunocytochemical detection of sensitive antigens. Frozen slices are stored at -80 °C and used for molecular, immunocytochemical, and in situ hybridization/RNA scope studies. The other hemisphere is placed in 4% paraformaldehyde for several months, placed in the slicing box, re-scanned in the 3 T magnetic resonance (MR) scanner and sliced into centimeter-thick slices. Postmortem in situ MR images (MRIs) are co-registered with 1 cm-thick brain slices to facilitate MRI-pathology correlations. All brain slices are photographed and brain white-matter lesions are identified. The spinal cord is cut into 2 cm segments. Alternate segments are fixed in 4% paraformaldehyde or rapidly frozen. The rapid procurement of postmortem MS tissues allows pathological and molecular analyses of MS brains and spinal cords and pathological correlations of brain MRI abnormalities. The quality of these rapidly-processed postmortem tissues (usually within 6 h of death) is of great value to MS research and has resulted in many high-impact discoveries.
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http://dx.doi.org/10.3791/59511DOI Listing
July 2019

meso-Alkylidenyl dibenzihexaphyrins: synthesis and protonation studies.

Chem Commun (Camb) 2019 Aug 26;55(65):9693-9696. Epub 2019 Jul 26.

Department of Chemistry, Kangwon National University, Chun Cheon, Korea24341.

The synthesis and characterization of the alkylidenyl-dibenzihexaphyrins bearing four indanedionyl groups at the meso-positions linked via four meso-exocyclic double bonds is reported. Treatment with trifluoroacetic acid at 50 °C leads to C(α)-protonation of the two indanedionyl groups resulting increased macrocyclic conjugation with dramatic red shifted absorption spectra.
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http://dx.doi.org/10.1039/c9cc04607kDOI Listing
August 2019

pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis.

Proc Natl Acad Sci U S A 2019 07 18;116(30):15216-15225. Epub 2019 Jun 18.

Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany;

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.
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http://dx.doi.org/10.1073/pnas.1901283116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660731PMC
July 2019

Expression of disease-related miRNAs in white-matter lesions of progressive multiple sclerosis brains.

Ann Clin Transl Neurol 2019 May 21;6(5):854-862. Epub 2019 Mar 21.

Department of Neurosciences Cleveland Clinic Cleveland Ohio.

Background: MicroRNA (miRNA) expression in the serum of multiple sclerosis (MS) patients has been correlated with white matter (WM) magnetic resonance imaging (MRI) abnormalities. The expression levels and cellular specificity of the target genes of these miRNAs are unknown in MS brain.

Objective: The aim of this study was to analyze and validate the expression of miRNAs, previously reported as dysregulated in sera of MS patients, in white-matter lesions (WMLs) of progressive MS brains.

Methods: We performed global miRNA expression profiling analysis in demyelinated WMLs of progressive MS brains ( = 5) and compared the significantly altered miRNAs to previously identified miRNAs from sera of MS patients. Top dysregulated miRNAs common between the two datasets were validated in an independent cohort of MS brains by quantitative PCR (qPCR) and in situ hybridization.

Results: Among the miRNAs that were significantly changed in WML tissues, 11 were similar to pathogenic and 12 were common to protective miRNAs previously identified in sera and correlating with WM MRI abnormalities. Importantly, the expression levels of 58% of the protective miRNAs (7 of 12) were decreased in MS lesions compared to surrounding normal-appearing tissue. Target genes of these miRNAs were also altered in MS lesions and queries of cell-specific databases identified astrocytes and microglia as the key cellular expressers of these genes in MS brains.

Conclusions: We identified miRNAs that correlate with MRI abnormalities in lesioned tissue from MS brains.
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http://dx.doi.org/10.1002/acn3.750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530016PMC
May 2019

Proteomic Approaches to Decipher Mechanisms Underlying Pathogenesis in Multiple Sclerosis Patients.

Proteomics 2019 08 21;19(16):e1800335. Epub 2019 Jun 21.

Department of Neurosciences, Cleveland Clinic, Cleveland, OH, 44195, USA.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). The cause of MS is unknown, with no effective therapies available to halt the progressive neurological disability. Development of new and improvement of existing therapeutic strategies therefore require a better understanding of MS pathogenesis, especially during the progressive phase of the disease. This can be achieved through development of biomarkers that can help to identify disease pathophysiology and monitor disease progression. Proteomics is a powerful and promising tool to accelerate biomarker detection and contribute to novel therapeutics. In this review, an overview of how proteomic technology using CNS tissues and biofluids from MS patients has provided important clues to the pathogenesis of MS is provided. Current publications, pitfalls, as well as directions of future research involving proteomic approaches to understand the pathogenesis of MS are discussed.
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http://dx.doi.org/10.1002/pmic.201800335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690771PMC
August 2019

meso-Bis(ethynyl) Versus meso-Bis(aryl) Calix[4]pyrroles: Dimensionally Well-Modulated Receptors That Can Regulate the Anion Binding Domains.

J Org Chem 2019 06 23;84(11):6851-6857. Epub 2019 May 23.

Department of Chemistry , Kangwon National University , Chun Cheon 24341 , Korea.

meso-Substituted calix[4]pyrroles 2-6 containing a direct meso-ethynyl linker displayed high binding affinities and unique conformational features on halide anion binding. A general conformational bias for the equatorial alignments of the meso-(aryl)ethynyl groups was observed in the host-halide complexes which was attributed to the repulsive anion-alkyne interactions and released steric strain. Such conformational features of host-halide complexes persisted even in the case of calix[4]pyrrole 6 bearing cationic meso components, which displayed the highest binding affinity for chloride anions among known meso-aryl calix[4]pyrroles. Synthetic details, conformational features, and comparative halide anion binding properties of this series of calix[4]pyrroles are described.
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http://dx.doi.org/10.1021/acs.joc.9b00639DOI Listing
June 2019

Trapping of Stable [4n+1] π-Electron Species from Peripherally Substituted, Conformationally Rigid, Antiaromatic Hexaphyrins.

Chemistry 2019 Mar 13;25(14):3525-3531. Epub 2019 Feb 13.

Department of Chemistry, Kangwon National University, Chuncheon, 24341, Korea.

Peripherally substituted antiaromatic naphthorosarins have been synthesized for the first time. The synthesis was accomplished by acid-catalyzed condensation of naphthobipyrrole building blocks with aromatic aldehydes. The naphthobipyrrole building blocks were synthesized by simple oxidative coupling of the corresponding pyrrole substituted aromatics. Solid-state structural analyses of the synthesized naphthorosarins revealed that the presence of meso-2,6-dichlorophenyl- and 5,6-difluoro-substitution substantially alter the geometry and properties of the naphthorosarins. The substituents affect the redox potentials as well and, in turn, the proton-coupled electron-transfer processes leading to the formation of one- and two-electron reduced forms of the corresponding naphthorosarins. One particular naphthorosarin that bears both peripheral fluorine and meso-2,6-dichlorophenyl substituents forms a stable 25 π-electron species upon treating with TFA that was characterized by single-crystal X-ray diffraction analysis. The current study underscores how structural modifications can be used to fine-tune the electronic features of naphthorosarins, including stabilization of odd electron species.
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http://dx.doi.org/10.1002/chem.201900022DOI Listing
March 2019

Constitutional mislocalization of Pten drives precocious maturation in oligodendrocytes and aberrant myelination in model of autism spectrum disorder.

Transl Psychiatry 2019 01 17;9(1):13. Epub 2019 Jan 17.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

There is a strong genetic association between germline PTEN mutation and autism spectrum disorder (ASD), making Pten-mutant models exemplary for the study of ASD pathophysiology. We developed the Pten mouse, where Pten is largely restricted from the nucleus, which recapitulates patient-like, autism-related phenotypes: behavioral changes, macrocephaly, and white matter abnormalities. This study aimed to investigate the contribution of oligodendrocyte (OL) lineage differentiation and functional changes in myelination to the white matter phenotype. OL lineage differentiation and myelination in Pten mice was studied using immunohistochemical and electron microscopic analyses. We also used primary oligodendrocyte progenitor cells (OPCs) to determine the effect of the Pten mutation on OPC proliferation, migration and maturation. Finally, we assessed the myelinating competency of mutant OLs via co-culture with wildtype dorsal root ganglia (DRG) neurons. The in vivo analyses of Pten murine brains showed deficits in proteolipid protein (Plp) trafficking in myelinating OLs. Despite the increased expression of myelin proteins in the brain, myelin deposition was observed to be abnormal, often occurring adjacent to, rather than around axons. Mutant primary OPCs showed enhanced proliferation and migration. Furthermore, mutant OPCs matured precociously, exhibiting aberrant myelination in vitro. Mutant OPCs, when co-cultured with wildtype DRG neurons, showed an inability to properly ensheath axons. Our findings provide evidence that the Pten mutation disrupts the differentiation and myelination programs of developing OLs. OL dysfunction in the Pten model explains the leukodystrophy phenotype, a feature commonly associated with autism, and highlights the growing importance of glial dysfunction in autism pathogenesis.
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http://dx.doi.org/10.1038/s41398-018-0364-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341090PMC
January 2019

Bimanual 25-gauge chandelier technique for direct perfluorocarbon liquid-silicone oil exchange in retinal detachments associated with giant retinal tear.

Indian J Ophthalmol 2018 Dec;66(12):1849-1851

Shroff Eye Centre, New Delhi, India.

Direct perfluorocarbon liquid (PFCL)-silicone oil exchange presents its own set of challenges in the micro incision vitreous surgery era. We propose a simple bimanual technique to circumvent this problem. Thirteen eyes of patients with retinal detachment associated with giant retinal tears underwent vitrectomy followed by self-retaining endo illuminator (Chandelier) assisted direct PFCL-silicone exchange. No intra or postoperative complications related to the surgical technique were noted. All patients had attached retinas and satisfactory visual recovery at 6 months. Direct bimanual PFCL silicone oil exchange using a Chandelier seems to be a safe and effective technique.
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http://dx.doi.org/10.4103/ijo.IJO_440_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256879PMC
December 2018

Current advancements in promoting remyelination in multiple sclerosis.

Mult Scler 2019 01 1;25(1):7-14. Epub 2018 Oct 1.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Current multiple sclerosis (MS) therapies are effective in reducing relapse rate, short-term measures of disability, and magnetic resonance imaging (MRI) measures of inflammation in relapsing remitting MS (RRMS), whereas in progressive/degenerative disease phases these medications are of little or no benefit. Therefore, the development of new therapies aimed at reversing neurodegeneration is of great interest. Remyelination, which is usually a spontaneous endogenous process, is achieved when myelin-producing oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs). Even though these precursor cells are abundant in MS brains, their regeneration capacity is limited. Enhancing the generation of myelin-producing cells is therefore a major focus of MS research. Here we present an overview of the different advancements in the field of remyelination, including suitable animal models for testing remyelination therapies, approved medications with a proposed role in regeneration, myelin repair treatments under investigation in clinical trials, as well as future therapeutics aimed at facilitating myelin repair.
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http://dx.doi.org/10.1177/1352458518800827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389436PMC
January 2019

Unexpected halide anion binding modes in meso-bis-ethynyl picket-calix[4]pyrroles: effects of meso-π (ethynyl) extension.

Chem Commun (Camb) 2018 Jul;54(57):7936-7939

Department of Chemistry, Kangwon National University, Chun Cheon 24341, Korea.

meso-Ethynyl extended aryl-picket calix[4]pyrroles 2 and 3 are designed and synthesized by directly anchoring arylethynyl groups at diametrically opposed meso-positions. The critical roles of direct ethynyl linkers are manifested through the isolation of unexpected host-anion conformers of meso-arylethynyl calix[4]pyrroles and a significant enhancement in halide binding affinities.
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http://dx.doi.org/10.1039/c8cc04393kDOI Listing
July 2018

CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways.

Neurobiol Dis 2019 06 23;126:47-61. Epub 2018 Jun 23.

Departments of Neurosciences, Cleveland Clinic, Cleveland, OH 44195, United States of America. Electronic address:

White matter (WM) is injured in most strokes, which contributes to functional deficits during recovery. Casein kinase 2 (CK2) is a protein kinase that is expressed in brain, including WM. To assess the impact of CK2 inhibition on axon recovery following oxygen glucose deprivation (OGD), mouse optic nerves (MONs), which are pure WM tracts, were subjected to OGD with or without the selective CK2 inhibitor CX-4945. CX-4945 application preserved axon function during OGD and promoted axon function recovery when applied before or after OGD. This protective effect of CK2 inhibition correlated with preservation of oligodendrocytes and conservation of axon structure and axonal mitochondria. To investigate the pertinent downstream signaling pathways, siRNA targeting the CK2α subunit identified CDK5 and AKT as downstream molecules. Consequently, MK-2206 and roscovitine, which are selective AKT and CDK5 inhibitors, respectively, protected young and aging WM function only when applied before OGD. However, a novel pan-AKT allosteric inhibitor, ARQ-092, which targets both the inactive and active conformations of AKT, conferred protection to young and aging axons when applied before or after OGD. These results suggest that AKT and CDK5 signaling contribute to the WM functional protection conferred by CK2 inhibition during ischemia, while inhibition of activated AKT signaling plays the primary role in post-ischemic protection conferred by CK2 inhibition in WM independent of age. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, our results will provide rationale for repurposing these drugs as therapeutic options for stroke patients by adding novel targets.
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http://dx.doi.org/10.1016/j.nbd.2018.05.011DOI Listing
June 2019