Anumantha G Kanthasamy

Iowa State University, Ames, Iowa, United States

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Publications (151)569.39 Total impact

  • Daniel J Klionsky · Kotb Abdelmohsen · Akihisa Abe · Md Joynal Abedin · Hagai Abeliovich · Abraham Acevedo Arozena · Hiroaki Adachi · Christopher M Adams · Peter D Adams · Khosrow Adeli · [...] · Orsolya Kapuy · Vassiliki Karantza · Md Razaul Karim · Parimal Karmakar · Arthur Kaser · Susmita Kaushik · Thomas Kawula · A Murat Kaynar · Po-Yuan Ke · Zun-Ji Ke ·

    No preview · Dataset · Feb 2016
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    ABSTRACT: Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.
    No preview · Article · Feb 2016 · Journal of Neuroimmune Pharmacology
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    Full-text · Dataset · Jan 2016
  • Chapter: Quercetin

    No preview · Chapter · Jan 2016
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    Daniel J Klionsky · Kotb Abdelmohsen · Akihisa Abe · Md Joynal Abedin · Hagai Abeliovich · Abraham Acevedo Arozena · Hiroaki Adachi · Christopher M Adams · Peter D Adams · Khosrow Adeli · [...] · Xiao-Feng Zhu · Yuhua Zhu · Shi-Mei Zhuang · Xiaohong Zhuang · Elio Ziparo · Christos E Zois · Teresa Zoladek · Wei-Xing Zong · Antonio Zorzano · Susu M Zughaier ·
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    ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
    Full-text · Article · Jan 2016 · Autophagy
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    Dan Chen · Anumantha G. Kanthasamy · Manju B. Reddy
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    ABSTRACT: . Parkinson’s disease (PD) is a progressive neurodegenerative disease that causes severe brain dopamine depletion. Disruption of iron metabolism may be involved in the PD progression. Objective . To test the protective effect of (−)-epigallocatechin-3-gallate (EGCG) against 6-hydroxydopamine- (6-OHDA-) induced neurotoxicity by regulating iron metabolism in N27 cells. Methods . Protection by EGCG in N27 cells was assessed by SYTOX green assay, MTT, and caspase-3 activity. Iron regulatory gene and protein expression were measured by RT-PCR and Western blotting. Intracellular iron uptake was measured using 55 Fe. The EGCG protection was further tested in primary mesencephalic dopaminergic neurons by immunocytochemistry. Results . EGCG protected against 6-OHDA-induced cell toxicity. 6-OHDA treatment significantly ( p < 0.05 ) increased divalent metal transporter-1 (DMT1) and hepcidin and decreased ferroportin 1 (Fpn1) level, whereas pretreatment with EGCG counteracted the effects. The increased 55 Fe (by 96%, p < 0.01 ) cell uptake confirmed the iron burden by 6-OHDA and was reduced by EGCG by 27% ( p < 0.05 ), supporting the DMT1 results. Pretreatment with EGCG and 6-OHDA significantly increased ( p < 0.0001 ) TH + cell count (~3-fold) and neurite length (~12-fold) compared to 6-OHDA alone in primary mesencephalic neurons. Conclusions . Pretreatment with EGCG protected against 6-OHDA-induced neurotoxicity by regulating genes and proteins involved in brain iron homeostasis, especially modulating hepcidin levels.
    Preview · Article · Dec 2015 · Parkinson's Disease
  • Shivani Ghaisas · Joshua Maher · Anumantha Kanthasamy
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    ABSTRACT: The gut microbiome comprises the collective genome of the trillions of microorganisms residing in our gastrointestinal ecosystem. The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer's and Parkinson's diseases. The purpose of this review is to summarize what is known about the gut microbiome, how it is connected to the development of disease and to identify the bacterial and biochemical targets that should be the focus of future research. Understanding the mechanisms behind the activity and proliferation of the gut microbiome will provide us new insights that may pave the way for novel therapeutic strategies.
    No preview · Article · Nov 2015 · Pharmacology [?] Therapeutics
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    ABSTRACT: Complex biological barriers are major obstacles for preventing and treating disease. Nano-carriers are designed to overcome such obstacles by enhancing drug delivery through physiochemical barriers and improving therapeutic indices. This review critically examines both biological barriers and nano-carrier payloads for a variety of drug delivery applications. A spectrum of nano-carriers is discussed that have been successfully developed for improving tissue penetration for preventing or treating a range of infectious, inflammatory, and degenerative diseases. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · Journal of Controlled Release
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    ABSTRACT: We recently identified a compensatory survival role for protein kinase D1 (PKD1) in protecting dopaminergic neurons from oxidative insult. To investigate the molecular mechanism of Prkd1 gene expression, we cloned the 5'-flanking region (1620-bp) of the mouse Prkd1 gene. Deletion analyses revealed that the -250/+113 promoter region contains full promoter activity in MN9D dopaminergic neuronal cells. In silico analysis of the Prkd1 promoter uncovered binding sites for key redox transcription factors including Sp1 and NF-κB. Overexpression of Sp1, Sp3, and NF-κB-p65 proteins stimulated Prkd1 promoter activity. Binding of Sp3 and NF-κB-p65 to the Prkd1 promoter was confirmed using chromatin immunoprecipitation. Treatment with the Sp inhibitor mithramycin-A significantly attenuated Prkd1 promoter activity and PKD1 mRNA and protein expression. Further mechanistic studies revealed that inhibition of histone acetylation and DNA methylation upregulates PKD1 mRNA expression. Importantly, negative modulation of PKD1 signaling by pharmacological inhibition or shRNA knockdown increased dopaminergic neuronal sensitivity to oxidative damage in a human mesencephalic neuronal cell model. Collectively, our findings demonstrate that Sp1, Sp3 and NF-κB-p65 can transactivate the mouse Prkd1 promoter and that epigenetic mechanisms, such as DNA methylation and histone modification, are key regulatory events controlling the expression of pro-survival kinase PKD1 in dopaminergic neuronal cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Neurochemistry
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    ABSTRACT: Unlabelled: Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson's disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-characterized inflammogens LPS and TNFα rapidly activated Fyn kinase in microglia. Immunocytochemical studies revealed that activated Fyn preferentially localized to the microglial plasma membrane periphery and the nucleus. Furthermore, activated Fyn phosphorylated PKCδ at tyrosine residue 311, contributing to an inflammogen-induced increase in its kinase activity. Notably, the Fyn-PKCδ signaling axis further activated the LPS- and TNFα-induced MAP kinase phosphorylation and activation of the NFκB pathway, implying that Fyn is a major upstream regulator of proinflammatory signaling. Functional studies in microglia isolated from wild-type (Fyn(+/+)) and Fyn knock-out (Fyn(-/-)) mice revealed that Fyn is required for proinflammatory responses, including cytokine release as well as iNOS activation. Interestingly, a prolonged inflammatory insult induced Fyn transcript and protein expression, indicating that Fyn is upregulated during chronic inflammatory conditions. Importantly, in vivo studies using MPTP, LPS, or 6-OHDA models revealed a greater attenuation of neuroinflammatory responses in Fyn(-/-) and PKCδ (-/-) mice compared with wild-type mice. Collectively, our data demonstrate that Fyn is a major upstream signaling mediator of microglial neuroinflammatory processes in PD. Significance statement: Parkinson's disease (PD) is a complex multifactorial disease characterized by the progressive loss of midbrain dopamine neurons. Sustained microglia-mediated neuroinflammation has been recognized as a major pathophysiological contributor to chronic degenerative processes in PD; however, the key molecular signaling mechanisms underlying microglial activation are not entirely clear. Herein, we identified a novel role for the non-receptor tyrosine kinase Fyn in regulating neuroinflammatory responses in microglia. Our data clearly suggest that the Fyn-PKCδ signaling axis acts as a major upstream signaling mediator of the sustained neuroinflammatory processes in cell culture and animal models of PD. Our finding has important clinical significance to PD because it identifies Fyn as a potential translational target for intervention of progressive neurodegenerative processes in PD.
    Full-text · Article · Jul 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Tebufenpyrad and pyridaben are two agro-chemically important acaricides that function like the known mitochondrial toxicant rotenone. Although these two compounds have been commonly used to kill populations of mites and ticks in commercial greenhouses, their neurotoxic profiles remain largely unknown. Therefore, we investigated the effects of these two pesticides on mitochondrial structure and function in an in vitro cell culture model using the Seahorse bioanalyzer and confocal fluorescence imaging. The effects were compared with rotenone. Exposing rat dopaminergic neuronal cells (N27 cells) to tebufenpyrad and pyridaben for 3h induced dose-dependent cell death with an EC50 of 3.98μM and 3.77μM, respectively. Also, tebufenpyrad and pyridaben (3μM) exposure induced reactive oxygen species (ROS) generation and m-aconitase damage, suggesting that the pesticide toxicity is associated with oxidative damage. Morphometric image analysis with the MitoTracker red fluorescent probe indicated that tebufenpyrad and pyridaben, as well as rotenone, caused abnormalities in mitochondrial morphology, including reduced mitochondrial length and circularity. Functional bioenergetic experiments using the Seahorse XF96 analyzer revealed that tebufenpyrad and pyridaben very rapidly suppressed the basal mitochondrial oxygen consumption rate similar to that of rotenone. Further analysis of bioenergetic curves also revealed dose-dependent decreases in ATP-linked respiration and respiratory capacity. The luminescence-based ATP measurement further confirmed that pesticide-induced mitochondrial inhibition of respiration is accompanied by the loss of cellular ATP. Collectively, our results suggest that exposure to the pesticides tebufenpyrad and pyridaben induces neurotoxicity by rapidly initiating mitochondrial dysfunction and oxidative damage in dopaminergic neuronal cells. Our findings also reveal that monitoring the kinetics of mitochondrial respiration with Seahorse could be used as an early neurotoxicological high-throughput index for assessing the risk that pesticides pose to the dopaminergic neuronal system. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jun 2015 · NeuroToxicology
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    ABSTRACT: Parkinson's disease (PD) is the second most common progressive neu-rodegenerative disorder that is characterized by the progressive loss of substan-tia nigral dopaminergic neurons resulting in the pronounced depletion of striatal DA levels which subsequently leads to the expression of cardinal features of PD including tremor, bradykinesia, rigidity and postural instability. The mechanisms underlying the selective loss of dopaminergic neurons remain poorly understood; however, studies conducted in post mortem PD brains and experimental PD models have implicated oxidative stress and mitochondrial dysfunction in the mechanism of dopaminergic neurodegeneration. In recent years, the etiology of several neurodegenerative diseases including PD has been linked to low dose and chronic exposure to a variety of agrochemicals including paraquat, rotenone and dieldrin. Here we discuss how several of these pesticides share common mechanistic events, including oxidative stress, mitochondrial impairment/complex I inhibition, abnormal protein aggregation and post translational modifications (PTMs) of proteins including α-synuclein, as well as dopaminergic cell death. Furthermore, intersecting and parallel effects of environmental neurotoxicants on protein clearance mechanisms and mitochondrial function are addressed and hence provide novel insights that might be beneficial in the development of targeted therapies for PD.
    Full-text · Chapter · May 2015

  • No preview · Article · May 2015 · Neurotoxicology and Teratology

  • No preview · Article · Apr 2015 · Prion

  • No preview · Article · Apr 2015 · Prion
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    ABSTRACT: Numerous studies have suggested a positive association between pesticide exposure and the risk of developing Parkinson’s disease (PD). Previous studies indicated that dichlorvos (DCV), an organophosphate (OP) pesticide induced nigrostriatal dopaminergic neuronal death; however, the molecular mechanisms underlying DCV-induce cell death remains elusive. Using multiple approaches including, subcellular fractionation, immunofluorescence analysis, enzymatic assays, gene silencing technology we show that Abelson murine leukemia (c-Abl) tyrosine kinase is linked to DCV-induced dopaminergic cell death. Exposure of N27 mesencephalic dopaminergic neuronal cells to DCV, induced cell death via the upregulation of c-Abl, proteolytic cleavage and phosphorylation of PKC, mitochondrial dysfunction, and apoptotic events involving Bax upregulation, activation of caspase-9 and 3; and DNA fragmentation. Furthermore, a concomitant impairment in mitochondrial biogenesis (decreased TFAM & PGC1 levels); and protein clearance mechanisms, as assessed by the accumulation of ubiquitinated aggregates and enhancement of autophagic markers (LC3IIB & BECN-1) were found to precede DCV-induced cell death. In order to examine the role of c-Abl in DCV-induced cell death we used Dasatinib, a pharmacological inhibitor of c-Abl and gene silencing of c-Abl via siRNA. Both strategies ameliorated DCV-induced apoptotic cell death by attenuating the afore mentioned deficits namely mitochondrial dysfunction, protein clearance mechanisms, and mitochondrial biogenesis. Importantly, an increase in the levels of c-Abl and autophagy related markers were evidenced in the substantia nigra of MPTP treated mice. Our findings identify c-Abl tyrosine kinase as a novel upstream regulator of mitochondrial homeostasis and that phosphorylation of PKCδ by c-Abl is a key posttranslational modification that is pivotal for the deregulation of mitochondrial biogenesis and protein clearance machinery, thereby leading to the induction of cell death in N27 cells exposed to DCV (Supported by NIHES1058667).
    No preview · Conference Paper · Mar 2015
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    ABSTRACT: Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics are immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Nanomedicine Nanotechnology Biology and Medicine
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    ABSTRACT: Parkinson's diseaseParkinson's disease (PDPD ) is mainly characterized by a progressive degeneration of dopaminergicdopaminergic neuronsdopaminergic neurons in the substantia nigrasubstantia nigra resulting in chronic deficits in motor functions. Administration of the neurotoxinneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPMPTP ) produces PD symptoms and recapitulates the main features of PD in human and animal modelsanimal models . MPTP is converted to 1-methyl-4-phenylpyridine1-methyl-4-phenylpyridine (MPP(+) MPP(+) ), which is the active toxic compound that selectively destroys dopaminergic neurons. Here, we describe methods and protocols to evaluate MPTP/MPP(+)-induced dopaminergic neurodegenerationneurodegeneration in both murine primary mesencephalicmesencephalic culturesprimary mesencephalic cultures and animal models. The ability of MPTP/MPP(+) to cause dopaminergic neuronal cell deathcell death is assessed by immunostaining of tyrosine hydroxylasetyrosine hydroxylase (THTH ).
    Full-text · Article · Jan 2015 · Methods in molecular biology (Clifton, N.J.)
  • H. Jin · D.S. Harischandra · C. Choi · D. Martin · V. Anantharam · A. Kanthasamy · A.G. Kanthasamy

    No preview · Article · Jan 2015 · Issues in Toxicology
  • Yiwen Meng · Ravi Hadimani · Vellareddy Anantharam · Anumantha Kanthasamy · David Jiles

    No preview · Article · Jan 2015

Publication Stats

6k Citations
569.39 Total Impact Points

Institutions

  • 2002-2015
    • Iowa State University
      • Department of Biomedical Sciences
      Ames, Iowa, United States
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2008
    • CUNY Graduate Center
      New York City, New York, United States
  • 2000
    • Long Beach Memorial Medical Center
      Long Beach, California, United States
  • 1996-1999
    • University of California, Irvine
      • Division of Neurology
      Irvine, California, United States
  • 1991-1997
    • Purdue University
      • Department of Medicinal Chemistry and Molecular Pharmacology (MCMP)
      West Lafayette, Indiana, United States