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  1. Article ; Online: Interplay between hypoxia and inflammation contributes to the progression and severity of respiratory viral diseases.

    Bhattacharya, Sulagna / Agarwal, Sakshi / Shrimali, Nishith M / Guchhait, Prasenjit

    Molecular aspects of medicine

    2021  Volume 81, Page(s) 101000

    Abstract: History of pandemics is dominated by viral infections and specifically respiratory viral diseases like influenza and COVID-19. Lower respiratory tract infection is the fourth leading cause of death worldwide. Crosstalk between resultant inflammation and ... ...

    Abstract History of pandemics is dominated by viral infections and specifically respiratory viral diseases like influenza and COVID-19. Lower respiratory tract infection is the fourth leading cause of death worldwide. Crosstalk between resultant inflammation and hypoxic microenvironment may impair ventilatory response of lungs. This reduces arterial partial pressure of oxygen, termed as hypoxemia, which is observed in a section of patients with respiratory virus infections including SARS-CoV-2 (COVID-19). In this review, we describe the interplay between inflammation and hypoxic microenvironment in respiratory viral infection and its contribution to disease pathogenesis.
    MeSH term(s) COVID-19 ; Humans ; Hypoxia ; Inflammation ; Pandemics ; SARS-CoV-2
    Language English
    Publishing date 2021-07-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 197640-0
    ISSN 1872-9452 ; 0098-2997
    ISSN (online) 1872-9452
    ISSN 0098-2997
    DOI 10.1016/j.mam.2021.101000
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    Zs.A 1189: Show issues Location:
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  2. Article ; Online: Gain-of-function Tibetan PHD2

    Bhattacharya, Sulagna / Shrimali, Nishith M / Mohammad, Ghulam / Koul, Parvaiz A / Prchal, Josef T / Guchhait, Prasenjit

    EBioMedicine

    2021  Volume 68, Page(s) 103418

    Abstract: Background: We have previously described an evolutionarily selected Tibetan prolyl hydroxylase-2 (PHD2: Methods: We genotyped the Tibetans using DNA isolated from whole blood. Thereafter immunophenotying was performed on PBMCs from homozygous PHD2: ...

    Abstract Background: We have previously described an evolutionarily selected Tibetan prolyl hydroxylase-2 (PHD2
    Methods: We genotyped the Tibetans using DNA isolated from whole blood. Thereafter immunophenotying was performed on PBMCs from homozygous PHD2
    Findings: We report that homozygous PHD2
    Interpretation: Our report suggests that gain-of-function PHD2
    Funding: This study is supported by the Department of Biotechnology, Government of India.
    MeSH term(s) Adult ; Altitude Sickness/chemically induced ; Altitude Sickness/genetics ; Altitude Sickness/prevention & control ; Animals ; Case-Control Studies ; Disease Models, Animal ; Female ; Gain of Function Mutation ; Humans ; Hypertension, Pulmonary/chemically induced ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/prevention & control ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Immunophenotyping ; Ketoglutaric Acids/adverse effects ; Male ; Mice ; Travel ; U937 Cells ; Young Adult
    Chemical Substances Ketoglutaric Acids ; EGLN1 protein, human (EC 1.14.11.2) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
    Language English
    Publishing date 2021-06-05
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2021.103418
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Inhibition of cellular activation induced by platelet factor 4 via the CXCR3 pathway ameliorates Japanese encephalitis and dengue viral infections.

    Singh, Anamika / Ghosh, Riya / Asuru, Tejeswara Rao / Prajapat, Surendra K / Joshi, Garima / Gaur, Kishan K / Shrimali, Nishith M / Ojha, Amrita / Vikram, Naval K / Poncz, Mortimer / Kalia, Manjula / Guchhait, Prasenjit

    Journal of thrombosis and haemostasis : JTH

    2023  Volume 22, Issue 3, Page(s) 818–833

    Abstract: Background: Activated platelets secrete platelet factor 4 (PF4), which contributes to viral pathogenesis. Recently, we reported the proviral role of PF4 in replication of closely related flaviviruses, Japanese encephalitis virus (JEV) and dengue virus ( ... ...

    Abstract Background: Activated platelets secrete platelet factor 4 (PF4), which contributes to viral pathogenesis. Recently, we reported the proviral role of PF4 in replication of closely related flaviviruses, Japanese encephalitis virus (JEV) and dengue virus (DENV).
    Objectives: This study aimed to investigate the detailed mechanism of PF4-mediated virus replication.
    Methods: PF4
    Results: PF4
    Conclusion: These studies suggest that PF4 deficiency or inhibition of the PF4:CXCR3 pathway prevents JEV and DENV infection. The studies also highlight the PF4:CXCR3 axis as a potential target to develop treatment regimens against flaviviruses.
    MeSH term(s) Animals ; Humans ; Mice ; Acetamides ; Dengue/drug therapy ; Dengue/metabolism ; Encephalitis Virus, Japanese/physiology ; Encephalitis, Japanese/drug therapy ; Immunologic Factors ; Platelet Factor 4 ; Pyrimidinones ; Receptors, CXCR3
    Chemical Substances Acetamides ; CXCR3 protein, human ; Immunologic Factors ; N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido(2,3-d)pyrimidin-2-yl)ethyl)-N-pyridin-3-ylmethyl-2-(4-trifluoromethoxyphenyl)acetamide ; Platelet Factor 4 (37270-94-3) ; Pyrimidinones ; Receptors, CXCR3 ; Pf4 protein, mouse
    Language English
    Publishing date 2023-11-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1016/j.jtha.2023.11.015
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  4. Article ; Online: α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt.

    Shrimali, Nishith M / Agarwal, Sakshi / Kaur, Simrandeep / Bhattacharya, Sulagna / Bhattacharyya, Sankar / Prchal, Josef T / Guchhait, Prasenjit

    EBioMedicine

    2021  Volume 73, Page(s) 103672

    Abstract: Background: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated ... ...

    Abstract Background: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity.
    Methods: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2.
    Findings: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals.
    Interpretation: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs.
    Funding: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).
    MeSH term(s) Animals ; Blood Platelets/cytology ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; COVID-19/pathology ; COVID-19/prevention & control ; COVID-19/veterinary ; COVID-19/virology ; Cricetinae ; Dietary Supplements ; Down-Regulation/drug effects ; Humans ; Ketoglutaric Acids/pharmacology ; Ketoglutaric Acids/therapeutic use ; Lung/metabolism ; Lung/pathology ; Mesocricetus ; Mice ; Mice, Inbred BALB C ; Monocytes/cytology ; Monocytes/drug effects ; Monocytes/metabolism ; Phosphorylation ; Platelet Aggregation/drug effects ; Prolyl Hydroxylases/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/physiology ; Thrombosis/chemically induced ; Thrombosis/pathology ; Thrombosis/prevention & control ; Thrombosis/veterinary
    Chemical Substances Ketoglutaric Acids ; Protein Isoforms ; Prolyl Hydroxylases (EC 1.14.11.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2021-11-02
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2021.103672
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  5. Article ; Online: Dietary alpha-ketoglutarate inhibits SARS CoV-2 infection and rescues inflamed lungs to restore O

    Agarwal, Sakshi / Kaur, Simrandeep / Asuru, Tejeswara Rao / Joshi, Garima / Shrimali, Nishith M / Singh, Anamika / Singh, Oinam Ningthemmani / Srivastva, Puneet / Shrivastava, Tripti / Vrati, Sudhanshu / Surjit, Milan / Guchhait, Prasenjit

    Clinical and translational medicine

    2022  Volume 12, Issue 9, Page(s) e1041

    MeSH term(s) COVID-19 ; Humans ; Ketoglutaric Acids/pharmacology ; Lung ; Severe Acute Respiratory Syndrome ; Virus Replication
    Chemical Substances Ketoglutaric Acids
    Language English
    Publishing date 2022-09-19
    Publishing country United States
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2697013-2
    ISSN 2001-1326 ; 2001-1326
    ISSN (online) 2001-1326
    ISSN 2001-1326
    DOI 10.1002/ctm2.1041
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  6. Article ; Online: Dietary αKG inhibits SARS CoV-2 infection and rescues inflamed lungs to restore normal O2 saturation in animals

    Agarwal, Sakshi / Kaur, Simrandeep / Asuru, Tejeswara Rao / Joshi, Garima / Shrimali, Nishith M / Singh, Anamika / Singh, Oinam N / Srivastva, Puneet / Shrivastava, Tripti / Vrati, Sudhanshu / Surjit, Milan / Guchhait, Prasenjit

    bioRxiv

    Abstract: Our recent works described the rescue effect of α-ketoglutarate (αKG, a metabolite of Krebs cycle) on thrombosis and inflammation in animals. αKG augments activity of prolyl hydroxylase 2 (PHD2), which in turn degrades proline residues of substrates like ...

    Abstract Our recent works described the rescue effect of α-ketoglutarate (αKG, a metabolite of Krebs cycle) on thrombosis and inflammation in animals. αKG augments activity of prolyl hydroxylase 2 (PHD2), which in turn degrades proline residues of substrates like phosphorylated Akt (pAkt) and hypoxia inducible factor (HIF)α. Here we describe the inhibitory effect of octyl αKG on pAkt as well as on HIF1α/HIF2α, and in turn decreasing SARS CoV-2 replication in Vero E6 cells. αKG failed to inhibit the viral replication and Akt phosphorylation in PHD2-knockdown U937 cells transiently expressing ACE2. Contrastingly, triciribine (TCN, an Akt-inhibitor) inhibited viral replication alongside a downmodulation of pAkt in PHD2-KD cells. Dietary αKG significantly inhibited viral infection and rescued hamsters from thrombus formation and inflammation in lungs, the known causes of acute respiratory distress syndrome (ARDS) in COVID-19. αKG supplementation also reduced the apoptotic death of lung tissues in infected animals, alongside a downmodulation of pAkt and HIF2α. αKG supplementation neither affected IgG levels against SARS CoV-2 RBD protein nor altered the neutralization antibody response against SARS CoV-2. It did not interfere with the percentage of interferon-γ positive (IFNγ+) CD4+ and IFNγ+CD8+ T cells in infected animals. The extended work in balb/c mice transiently expressing ACE2 showed a similar effect of αKG in reducing accumulation of inflammatory immune cells and cytokines, including IL6, IL1β and TNFα, in lungs as well as in circulation of infected animals. Pro-thrombotic markers like platelet microparticles and platelet-leukocyte aggregates were reduced significantly in infected mice after αKG supplementation. Importantly, αKG supplementation restored the O2 saturation (SpO2) in circulation of SARS CoV-2 infected hamsters and mice, suggesting a potential therapeutic role of this metabolite in COVID-19 treatment.
    Keywords covid19
    Language English
    Publishing date 2022-04-03
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.04.02.486853
    Database COVID19

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