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  1. Article: Gut microbiome: a balancing act between degeneration and regeneration.

    Saksena, Nitin / Keon, Matt

    Neural regeneration research

    2022  Volume 17, Issue 9, Page(s) 1967–1968

    Language English
    Publishing date 2022-02-10
    Publishing country India
    Document type Journal Article
    ZDB-ID 2388460-5
    ISSN 1876-7958 ; 1673-5374
    ISSN (online) 1876-7958
    ISSN 1673-5374
    DOI 10.4103/1673-5374.335151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Editorial: Innate immune responses to SARS-CoV-2 in infected and vaccinated individuals.

    Saksena, Nitin K / Reche, Pedro A / Bonam, Srinivasa Reddy / Mancini, Nicasio

    Frontiers in immunology

    2023  Volume 14, Page(s) 1141405

    MeSH term(s) Humans ; SARS-CoV-2 ; COVID-19 ; Immunity, Innate
    Language English
    Publishing date 2023-02-08
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1141405
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Epigenetic Lens to Visualize the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Infection in COVID-19 Pandemic.

    Saksena, Nitin / Bonam, Srinivasa Reddy / Miranda-Saksena, Monica

    Frontiers in genetics

    2021  Volume 12, Page(s) 581726

    Abstract: In <20 years, we have witnessed three different epidemics with coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 in human populations, causing widespread mortality. SARS-CoV-2, through its rapid global spread, has led to the pandemic that we call COVID- ... ...

    Abstract In <20 years, we have witnessed three different epidemics with coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 in human populations, causing widespread mortality. SARS-CoV-2, through its rapid global spread, has led to the pandemic that we call COVID-19. As of February 1, 2021, the global infections linked to SARS-CoV-2 stand at 103,503,340, with 2,236,960 deaths, and 75,108,099 recoveries. This review attempts to highlight host-pathogen interaction with particular emphasis on the role of epigenetic machinery in regulating the disease. Although researchers, since the start of the pandemic, have been intensely engaged in diverse areas to understand the mechanisms involved in SARS-CoV-2 infection to find answers that can bring about innovative ways to swiftly treat and prevent disease progression, this review provides an overview on how the host epigenetics is modulated and subverted by SARS-CoV-2 to enter the host cells and drive immunopathogenesis. Epigenetics is the study that combines genetic and non-genetic factors controlling phenotypic variation, which are primarily a consequence of external and environmental stimuli. These stimuli alter the activity of a gene without impinging on the DNA code. In viral-host interactions, DNA/RNA methylation, non-coding RNAs, chromatin remodeling, and histone modifications are known to regulate and modulate host gene expression patterns. Viruses such as Coronaviruses (an RNA virus) show intrinsic association with these processes. They have evolved the ability to tamper with host epigenetic machinery to interfere with immune sensing pathways to evade host immune response, thereby enhancing its replication and pathogenesis post-entry. These epigenetic alterations allow the virus to weaken the host's immune response to successfully spread infection. How this occurs, and what epigenetic mechanisms are altered is poorly understood both for coronaviruses and other respiratory RNA viruses. The review highlights several cutting-edge aspects of epigenetic work primarily pertinent to SARS-CoV-2, which has been published between 2019 and 2020 to showcase the current knowledge both in terms of success and failures and take lessons that will assist us in understanding the disease to develop better treatments suited to kill SARS-CoV-2.
    Language English
    Publishing date 2021-03-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2021.581726
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: SARS-CoV-2 variants, its recombinants and epigenomic exploitation of host defenses.

    Saksena, Nitin K / Reddy, Srinivasa Bonam / Miranda-Saksena, Monica / Cardoso, Thyago H S / Silva, Edson M A / Ferreira, Juliana C / Rabeh, Wael M

    Biochimica et biophysica acta. Molecular basis of disease

    2023  Volume 1869, Issue 8, Page(s) 166836

    Abstract: Since 2003, we have seen the emergence of novel viruses, such as SARS-CoV-1, MERS, ZIKA, swine flu virus H1N1, Marburg, Monkeypox, Ebola, and SARS-CoV-2, but none of them gained pandemic proportions similar to SARS-CoV-2. This could be attributed to ... ...

    Abstract Since 2003, we have seen the emergence of novel viruses, such as SARS-CoV-1, MERS, ZIKA, swine flu virus H1N1, Marburg, Monkeypox, Ebola, and SARS-CoV-2, but none of them gained pandemic proportions similar to SARS-CoV-2. This could be attributed to unique viral traits, allowing its rapid global dissemination following its emergence in October 2019 in Wuhan, China, which appears to be primarily driven by the emergence of highly transmissible and virulent variants that also associate, in some cases, with severe disease and considerable mortality caused by fatal pneumonia, acute respiratory distress syndrome (ARDS) in infected individuals. Mechanistically, several factors are involved in viral pathogenesis, and epigenetic alterations take the front seat in host-virus interactions. The molecular basis of all viral infections, including SARS-CoV-2, tightly hinges on the transitory silencing of the host gene machinery via epigenetic modulation. SARS-CoV-2 also hijacks and subdues the host gene machinery, leading to epigenetic modulation of the critical host elements responsible for antiviral immunity. Epigenomics is a powerful, unexplored avenue that can provide a profound understanding of virus-host interactions and lead to the development of epigenome-based therapies and vaccines to counter viruses. This review discusses current developments in SARS-CoV-2 variation and its role in epigenetic modulation in infected hosts. This review provides an overview, especially in the context of emerging viral strains, their recombinants, and their possible roles in the epigenetic exploitation of host defense and viral pathogenesis. It provides insights into host-virus interactions at the molecular, genomic, and immunological levels and sheds light on the future of epigenomics-based therapies for SARS-CoV-2 infection.
    MeSH term(s) Humans ; SARS-CoV-2/genetics ; COVID-19/genetics ; Epigenomics ; Influenza A Virus, H1N1 Subtype ; Zika Virus ; Zika Virus Infection
    Language English
    Publishing date 2023-08-05
    Publishing country Netherlands
    Document type Review ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbadis.2023.166836
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy.

    Pham, Jade / Keon, Matt / Brennan, Samuel / Saksena, Nitin

    International journal of molecular sciences

    2020  Volume 21, Issue 10

    Abstract: Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)-including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)-have instigated an interest ... ...

    Abstract Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)-including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)-have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1-a non-RBP commonly associated with familial ALS (fALS)-exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics ; Humans ; MicroRNAs/genetics ; Mutation ; RNA Splicing/genetics ; RNA-Binding Protein FUS/genetics ; RNA-Binding Proteins/genetics ; Superoxide Dismutase-1/genetics
    Chemical Substances DNA-Binding Proteins ; FUS protein, human ; MicroRNAs ; RNA-Binding Protein FUS ; RNA-Binding Proteins ; SOD1 protein, human ; TARDBP protein, human ; Superoxide Dismutase-1 (EC 1.15.1.1)
    Language English
    Publishing date 2020-05-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21103464
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy

    Jade Pham / Matt Keon / Samuel Brennan / Nitin Saksena

    International Journal of Molecular Sciences, Vol 21, Iss 3464, p

    2020  Volume 3464

    Abstract: Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest ... ...

    Abstract Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1—a non-RBP commonly associated with familial ALS (fALS)—exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research.
    Keywords microRNA ; amyotrophic lateral sclerosis ; RNA metabolism ; TDP-43 ; FUS ; SOD1 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: Destination Amyotrophic Lateral Sclerosis.

    Keon, Matt / Musrie, Benjamin / Dinger, Marcel / Brennan, Samuel E / Santos, Jerran / Saksena, Nitin K

    Frontiers in neurology

    2021  Volume 12, Page(s) 596006

    Abstract: Amyotrophic Lateral Sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons both in the brain and spinal cord. The constantly evolving nature of ALS represents a fundamental dimension of ... ...

    Abstract Amyotrophic Lateral Sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons both in the brain and spinal cord. The constantly evolving nature of ALS represents a fundamental dimension of individual differences that underlie this disorder, yet it involves multiple levels of functional entities that alternate in different directions and finally converge functionally to define ALS disease progression. ALS may start from a single entity and gradually becomes multifactorial. However, the functional convergence of these diverse entities in eventually defining ALS progression is poorly understood. Various hypotheses have been proposed without any consensus between the for-and-against schools of thought. The present review aims to capture explanatory hierarchy both in terms of hypotheses and mechanisms to provide better insights on how they functionally connect. We can then integrate them within a common functional frame of reference for a better understanding of ALS and defining future treatments and possible therapeutic strategies. Here, we provide a philosophical understanding of how early leads are crucial to understanding the endpoints in ALS, because invariably, all early symptomatic leads are underpinned by neurodegeneration at the cellular, molecular and genomic levels. Consolidation of these ideas could be applied to other neurodegenerative diseases (NDs) and guide further critical thinking to unveil their roadmap of destination ALS.
    Language English
    Publishing date 2021-03-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564214-5
    ISSN 1664-2295
    ISSN 1664-2295
    DOI 10.3389/fneur.2021.596006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Prionoid Proteins in the Pathogenesis of Neurodegenerative Diseases.

    Wells, Cameron / Brennan, Samuel E / Keon, Matt / Saksena, Nitin K

    Frontiers in molecular neuroscience

    2019  Volume 12, Page(s) 271

    Abstract: There is a growing body of evidence that prionoid protein behaviors are a core element of neurodegenerative diseases (NDs) that afflict humans. Common elements in pathogenesis, pathological effects and protein-level behaviors exist between Alzheimer's ... ...

    Abstract There is a growing body of evidence that prionoid protein behaviors are a core element of neurodegenerative diseases (NDs) that afflict humans. Common elements in pathogenesis, pathological effects and protein-level behaviors exist between Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). These extend beyond the affected neurons to glial cells and processes. This results in a complicated system of disease progression, which often takes advantage of protective processes to promote the propagation of pathological protein aggregates. This review article provides a current snapshot of knowledge on these proteins and their intrinsic role in the pathogenesis and disease progression seen across NDs.
    Language English
    Publishing date 2019-11-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2019.00271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Therapeutic potential of metal ions for COVID-19: insights from the papain-like protease of SARS-CoV-2.

    Shetler, Cameron Lee / Ferreira, Juliana C / Cardoso, Thyago H S / Silva, Edson M A / Saksena, Nitin K / Rabeh, Wael M

    The Biochemical journal

    2022  Volume 479, Issue 20, Page(s) 2175–2193

    Abstract: Coronaviruses have been responsible for multiple challenging global pandemics, including coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Papain-like protease (PLpro), one of two ... ...

    Abstract Coronaviruses have been responsible for multiple challenging global pandemics, including coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Papain-like protease (PLpro), one of two cysteine proteases responsible for the maturation and infectivity of SARS-CoV-2, processes and liberates functional proteins from the viral polyproteins and cleaves ubiquitin and ISG15 modifications to inhibit innate immune sensing. Consequently, PLpro is an attractive target for developing COVID-19 therapies. PLpro contains a zinc-finger domain important for substrate binding and structural stability. However, the impact of metal ions on the activity and biophysical properties of SARS-CoV-2 PLpro has not been comprehensively studied. Here, we assessed the impacts of metal ions on the catalytic activity of PLpro. Zinc had the largest inhibitory effect on PLpro, followed by manganese. Calcium, magnesium, and iron had smaller or no effects on PLpro activity. EDTA at a concentration of 0.5 mM was essential for PLpro activity, likely by chelating trace metals that inhibit PLpro. IC50 values for ZnCl2, ZnSO4, and MnCl2 of 0.42 ± 0.02 mM, 0.35 ± 0.01 mM, and 2.6 ± 0.3 mM were obtained in the presence of 0.5 mM EDTA; in the absence of EDTA, the estimated IC50 of ZnCl2 was 14 µM. Tryptophan intrinsic fluorescence analysis confirmed the binding of zinc and manganese to PLpro, and differential scanning calorimetry revealed that zinc but not manganese reduced ΔHcal of PLpro. The results of this study provide a reference for further work targeting PLpro to prevent and treat COVID-19.
    MeSH term(s) Humans ; SARS-CoV-2 ; Papain/chemistry ; Papain/metabolism ; Peptide Hydrolases/metabolism ; Magnesium ; Calcium ; Tryptophan ; Edetic Acid ; Ubiquitin/metabolism ; Polyproteins ; Ions ; Zinc ; Iron ; COVID-19 Drug Treatment
    Chemical Substances Papain (EC 3.4.22.2) ; zinc chloride (86Q357L16B) ; Peptide Hydrolases (EC 3.4.-) ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP) ; Tryptophan (8DUH1N11BX) ; Edetic Acid (9G34HU7RV0) ; Ubiquitin ; Polyproteins ; Ions ; Zinc (J41CSQ7QDS) ; Iron (E1UOL152H7)
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220380
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Pathomechanisms of Blood-Brain Barrier Disruption in ALS.

    Kakaroubas, Nicholas / Brennan, Samuel / Keon, Matthew / Saksena, Nitin K

    Neuroscience journal

    2019  Volume 2019, Page(s) 2537698

    Abstract: The blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are responsible for controlling the microenvironment within neural tissues in humans. These barriers are fundamental to all neurological processes as they provide the extreme ... ...

    Abstract The blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are responsible for controlling the microenvironment within neural tissues in humans. These barriers are fundamental to all neurological processes as they provide the extreme nutritional demands of neural tissue, remove wastes, and maintain immune privileged status. Being a semipermeable membrane, both the BBB and BSCB allow the diffusion of certain molecules, whilst restricting others. In amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, these barriers become hyperpermeable, allowing a wider variety of molecules to pass through leading to more severe and more rapidly progressing disease. The intention of this review is to discuss evidence that BBB hyperpermeability is potentially a disease driving feature in ALS and other neurodegenerative diseases. The various biochemical, physiological, and genomic factors that can influence BBB permeability in ALS and other neurodegenerative diseases are also discussed, in addition to novel therapeutic strategies centred upon the BBB.
    Language English
    Publishing date 2019-07-10
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2738360-X
    ISSN 2314-4270 ; 2314-4262
    ISSN (online) 2314-4270
    ISSN 2314-4262
    DOI 10.1155/2019/2537698
    Database MEDical Literature Analysis and Retrieval System OnLINE

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