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Article ; Online: Hsp40 overexpression in pacemaker neurons delays circadian dysfunction in a Drosophila model of Huntington's disease.

Prakash, Pavitra / Pradhan, Arpit Kumar / Sheeba, Vasu

2022 Volume 15, Issue 6

Abstract: Circadian disturbances are early features of neurodegenerative diseases, including Huntington's disease (HD). Emerging evidence suggests that circadian decline feeds into neurodegenerative symptoms, exacerbating them. Therefore, we asked whether known ... ...

Abstract	Circadian disturbances are early features of neurodegenerative diseases, including Huntington's disease (HD). Emerging evidence suggests that circadian decline feeds into neurodegenerative symptoms, exacerbating them. Therefore, we asked whether known neurotoxic modifiers can suppress circadian dysfunction. We performed a screen of neurotoxicity-modifier genes to suppress circadian behavioural arrhythmicity in a Drosophila circadian HD model. The molecular chaperones Hsp40 and HSP70 emerged as significant suppressors in the circadian context, with Hsp40 being the more potent mitigator. Upon Hsp40 overexpression in the Drosophila circadian ventrolateral neurons (LNv), the behavioural rescue was associated with neuronal rescue of loss of circadian proteins from small LNv soma. Specifically, there was a restoration of the molecular clock protein Period and its oscillations in young flies and a long-lasting rescue of the output neuropeptide Pigment dispersing factor. Significantly, there was a reduction in the expanded Huntingtin inclusion load, concomitant with the appearance of a spot-like Huntingtin form. Thus, we provide evidence implicating the neuroprotective chaperone Hsp40 in circadian rehabilitation. The involvement of molecular chaperones in circadian maintenance has broader therapeutic implications for neurodegenerative diseases. This article has an associated First Person interview with the first author of the paper.
MeSH term(s)	Animals ; Circadian Rhythm/genetics ; Drosophila ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Humans ; Huntington Disease/metabolism ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism
Chemical Substances	Drosophila Proteins
Language	English
Publishing date	2022-06-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049447
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online ; Thesis: Activation of translocator protein by XBD173 ameliorates cognitive deficits and neuropathology in an Alzheimer’s mouse model

Pradhan, Arpit Kumar [Verfasser] / Rammes, Gerhard [Akademischer Betreuer]

2023

Author's details	Arpit Kumar Pradhan ; Betreuer: Gerhard Rammes
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Publisher	Universitätsbibliothek der Ludwig-Maximilians-Universität
Publishing place	München
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Quantification of astrocytic synaptic pruning in mouse hippocampal slices in response to ex vivo Aβ treatment via colocalization analysis with C1q.

Pradhan, Arpit Kumar / Shi, Qinfang / Tartler, Katharina Johanna / Rammes, Gerhard

STAR protocols

2022 Volume 3, Issue 4, Page(s) 101687

Abstract: Quantification of synaptic engulfment is an indirect measurement of synaptic pruning. Here, we provide a detailed protocol for the volumetric rendering of individual high-resolution astrocytes in the CA1 region of hippocampus in an ex vivo model of ... ...

Abstract	Quantification of synaptic engulfment is an indirect measurement of synaptic pruning. Here, we provide a detailed protocol for the volumetric rendering of individual high-resolution astrocytes in the CA1 region of hippocampus in an ex vivo model of amyloid-beta (Aβ) treatment. The protocol includes the treatment of free-floating sections with Aβ peptide and confocal imaging of individual astrocytes. We also provide a comprehensive analysis for 3D rendering of astrocytes and assessment of synaptic engulfment via "eat-me tag" C1q protein.
MeSH term(s)	Mice ; Animals ; Astrocytes/metabolism ; Complement C1q/metabolism ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism ; Neuronal Plasticity
Chemical Substances	Complement C1q (80295-33-6) ; Amyloid beta-Peptides
Language	English
Publishing date	2022-09-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101687
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss.

Wang, Xingxing / Shi, Qinfang / Pradhan, Arpit Kumar / Ziegon, Laura / Schlegel, Martin / Rammes, Gerhard

International journal of molecular sciences

2022 Volume 23, Issue 12

Abstract: Evidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 ( ... ...

Abstract	Evidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aβ
MeSH term(s)	Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Anesthetics/pharmacology ; Animals ; Dendritic Spines/metabolism ; Hippocampus/metabolism ; Mice ; Nectins/metabolism ; Neuronal Plasticity ; Sevoflurane/pharmacology ; Xenon/metabolism ; Xenon/pharmacology
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Anesthetics ; Nectins ; Sevoflurane (38LVP0K73A) ; Xenon (3H3U766W84)
Language	English
Publishing date	2022-06-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23126637
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Article ; Online: Drug repurposing and sequence analysis in S-glycoprotein variants reveals critical signature patterns and destabilization of receptor-binding domain in omicron variant.

Liya, Devang Haresh / Anand, Nithishwer Mouroug / Jainarayanan, Ashwin Kumar / Elanchezhian, Mirudula / Seetharaman, Madhumati / Balakannan, Dhanuush / Pradhan, Arpit Kumar

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 16, Page(s) 7931–7948

Abstract: The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected ... ...

Abstract	The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected to be relatively neutral, mutations at the Spike region of the genome have shown to have a major impact on the viral transmission and infection in humans. Therefore, it is crucial to survey the structures of spike protein across the global virus population to contextualize the rate of therapeutic success against these variants. In this study, high-frequency mutational variants from different geographic regions were pooled in order to study the structural evolution of the spike protein through drug docking and MD simulations. We investigated the mutational burden in the spike subregions and have observed that the different variants harbour unique signature patterns in the spike subregions, with certain domains being highly prone to mutations. Further, the MD simulations and docking study revealed that different variants show differential stability when docked for the same set of drug targets. This work sheds light on the mutational burden and the stability landscape of the spike protein across the variants from different geographical regions.Communicated by Ramaswamy H. Sarma.
Language	English
Publishing date	2022-09-29
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2127902
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Article ; Online: Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer's disease.

Pradhan, Arpit Kumar / Neumüller, Tatjana / Klug, Claudia / Fuchs, Severin / Schlegel, Martin / Ballmann, Markus / Tartler, Katharina Johanna / Pianos, Antoine / Garcia, Maria Sanchez / Liere, Philippe / Schumacher, Michael / Kreuzer, Matthias / Rupprecht, Rainer / Rammes, Gerhard

Translational psychiatry

2023 Volume 13, Issue 1, Page(s) 332

Abstract: Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis ... ...

Abstract	Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABA
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/drug therapy ; Receptors, GABA/metabolism ; Nervous System Diseases ; Mice, Transgenic ; Carrier Proteins ; Amyloid beta-Peptides/metabolism ; Ligands ; Cognition ; Disease Models, Animal
Chemical Substances	N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide ; Receptors, GABA ; Carrier Proteins ; Amyloid beta-Peptides ; Ligands
Language	English
Publishing date	2023-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02630-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A comprehensive SARS-CoV-2 genomic analysis identifies potential targets for drug repurposing.

Anand, Nithishwer Mouroug / Liya, Devang Haresh / Pradhan, Arpit Kumar / Tayal, Nitish / Bansal, Abhinav / Donakonda, Sainitin / Jainarayanan, Ashwin Kumar

PloS one

2021 Volume 16, Issue 3, Page(s) e0248553

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory ... ...

Abstract	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory tract illness. Its higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. One of the major concerns involving the SARS-COV-2 is the mutation rate, which enhances the virus evolution and genome variability, thereby making the design of therapeutics difficult. In this study, we identified the most common haplotypes from the haplotype network. The conserved genes and population level variants were analysed. Non-Structural Protein 10 (NSP10), Nucleoprotein, Papain-like protease (Plpro or NSP3) and 3-Chymotrypsin like protease (3CLpro or NSP5), which were conserved at the highest threshold, were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs, which are suggested for further pre-clinical and clinical trials. This particular study provides a comprehensive targeting of the conserved genes. We also identified the mutation frequencies across the viral genome.
MeSH term(s)	COVID-19/virology ; Drug Discovery/methods ; Drug Repositioning/methods ; Genome, Viral ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation Rate ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism ; COVID-19 Drug Treatment
Chemical Substances	Viral Proteins
Language	English
Publishing date	2021-03-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0248553
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Neurosteroids and translocator protein 18 kDa (TSPO) in depression: implications for synaptic plasticity, cognition, and treatment options.

Rupprecht, Rainer / Pradhan, Arpit Kumar / Kufner, Marco / Brunner, Lisa Marie / Nothdurfter, Caroline / Wein, Simon / Schwarzbach, Jens / Puig, Xenia / Rupprecht, Christian / Rammes, Gerhard

European archives of psychiatry and clinical neuroscience

2022 Volume 273, Issue 7, Page(s) 1477–1487

Abstract: There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of ... ...

Abstract	There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABA
MeSH term(s)	Humans ; Female ; Neurosteroids/pharmacology ; Anti-Anxiety Agents/therapeutic use ; Pregnanolone/pharmacology ; Ligands ; Depression ; Depression, Postpartum/drug therapy ; Depressive Disorder, Major/drug therapy ; Neurotransmitter Agents/pharmacology ; Neurotransmitter Agents/metabolism ; Receptors, GABA-A ; Benzodiazepines ; Carrier Proteins ; Neuronal Plasticity ; Cognition ; gamma-Aminobutyric Acid ; Receptors, GABA/metabolism
Chemical Substances	Neurosteroids ; Anti-Anxiety Agents ; Pregnanolone (BXO86P3XXW) ; Ligands ; Neurotransmitter Agents ; Receptors, GABA-A ; Benzodiazepines (12794-10-4) ; Carrier Proteins ; gamma-Aminobutyric Acid (56-12-2) ; Receptors, GABA ; TSPO protein, human
Language	English
Publishing date	2022-12-27
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1045583-8
ISSN	1433-8491 ; 0175-758X ; 0940-1334
ISSN (online)	1433-8491
ISSN	0175-758X ; 0940-1334
DOI	10.1007/s00406-022-01532-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Neurosteroids and translocator protein 18 kDa (TSPO) in depression

Rupprecht, Rainer / Pradhan, Arpit Kumar / Kufner, Marco / Brunner, Lisa Marie / Nothdurfter, Caroline / Wein, Simon / Schwarzbach, Jens / Puig, Xenia / Rupprecht, Christian / Rammes, Gerhard

European Archives of Psychiatry and Clinical Neuroscience

Implications for synaptic plasticity, cognition, and treatment options

2023 Volume 273, Issue 7, Page(s) 1477–1487

Abstract: There is need for novel fast acting treatment options in affective disorders. 3alpha-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABAA receptors and target also extrasynaptic receptors. Their synthesis is ...

Title translation	Neurosteroide und das Translokatorprotein 18 kDa (TSPO) bei Depressionen: Auswirkungen auf synaptische Plastizität, Kognition und Behandlungsmöglichkeiten. (DeepL)
Abstract	There is need for novel fast acting treatment options in affective disorders. 3alpha-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABAA receptors and target also extrasynaptic receptors. Their synthesis is mediated by the translocator protein 18 kDa (TSPO). TSPO ligands not only promote endogenous neurosteroidogenesis, but also exert a broad spectrum of functions involving modulation of mitochondrial activity and acting as anti-inflammatory and neuroregenerative agents. Besides affective symptoms, in depression cognitive impairment can be frequently observed, which may be ameliorated through targeting of extrasynaptic GABAA receptors either via TSPO ligands or exogenously administered 3alpha-reduced neurosteroids. Interestingly, recent findings indicate an enhanced activation of the complement system, e.g., enhanced expression of C1q, both in depression and dementia. It is of note that benzodiazepines have been shown to reduce long-term potentiation and to cause cognitive decline. Intriguingly, TSPO may be crucial in mediating the effects of benzodiazepines on synaptic pruning. Here, we discuss how benzodiazepines and TSPO may interfere with synaptic pruning. Moreover, we highlight recent developments of TSPO ligands and 3alpha-reduced neurosteroids as therapeutic agents. Etifoxine is the only clinically available TSPO ligand so far and has been studied in anxiety disorders. Regarding 3alpha-reduced neurosteroids, brexanolone, an intravenous formulation of allopregnanolone, has been approved for the treatment of postpartum depression and zuranolone, an orally available 3alpha-reduced neurosteroid, is currently being studied in major depressive disorder and postpartum depression. As such, 3alpha-reduced neurosteroids and TSPO ligands may constitute promising treatment approaches for affective disorders. (c) The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022
Keywords	Benzodiazepine ; Benzodiazepines ; Major Depression ; Postpartum Depression ; Proteine ; Proteins ; Synaptic Plasticity ; Synaptische Plastizität ; Therapie ; Treatment ; Wochenbettdepression
Language	English
Document type	Article
ZDB-ID	1045583-8
ISSN	0940-1334
ISSN	0940-1334
DOI	10.1007/s00406-022-01532-3
Database	PSYNDEX

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Book ; Online: A Comprehensive SARS-CoV-2 Genomic Analysis Identifies Potential Targets for Drug Repurposing

Mouroug Anand, Nithishwer / Haresh Liya, Devang / Pradhan, Arpit Kumar / Tayal, Nitish / Bansal, Abhinav / Donakonda, Sainitin / Jainarayanan, Ashwin Kumar

2020

Abstract: ... Background: ... The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract ... ...

Abstract	Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract illness. It’s higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. With 6,529,240 cases and about 385,264 deaths, this pandemic has become a global concern with certain drugs and vaccines failing at later clinical trials. Materials and Methods: Phylogenetic Analysis, Haplotype Network, Analysis of conserved genes and population-level variants, Using conserved genes as targets for drug designing, Docking studies and Molecular Dynamics (MD) simulations to predict the stability of Drug-Ligand Complex. Results: We identified the most common haplotypes from the haplotype network and at least seven different clusters were found signifying seven different viral lineages across the globe. We studied the mutation frequency across the SARS-CoV-2 viral genome. The conserved genes and population level variants were analyzed and NSP10, Nucleoprotein, Plpro and 3CLpro which were conserved at the highest threshold were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs which are suggested for further pre-clinical and clinical trials. Significance: This particular study provides a comprehensive targeting of the conserved genes as a novel approach for drug targeting. The conserved gene approach could also be of a big use while designing vaccines and cure. Mutations in the viral genome make the designing of the drugs a challenging task which has a higher risk of failure at later clinical trials. This approach of targeting the stable genes for drug discovery would provide a better therapeutic approach and confidence in the successive clinical trials. We also identified the global level spread of SARS-CoV-2 and mutation frequencies across the viral genome. Our study gives insights of the origin and global spread of the SARS-CoV-2. The data provided in this study can further be used by other groups to understand and combat Covid 19.
Keywords	covid19
Publisher	American Chemical Society (ACS)
Publishing country	us
Document type	Book ; Online
DOI	10.26434/chemrxiv.12430919.v1
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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