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Article ; Online: Neuroprotective Effects of Neuropeptide Y on Human Neuroblastoma SH-SY5Y Cells in Glutamate Excitotoxicity and ER Stress Conditions.

Palanivel, Viswanthram / Gupta, Vivek / Mirshahvaladi, Seyed Shahab Oddin / Sharma, Samridhi / Gupta, Veer / Chitranshi, Nitin / Mirzaei, Mehdi / Graham, Stuart L / Basavarajappa, Devaraj

Cells

2022 Volume 11, Issue 22

Abstract: Neuropeptide Y (NPY), a sympathetic neurotransmitter, is involved in various physiological functions, and its dysregulation is implicated in several neurodegenerative diseases. Glutamate excitotoxicity, endoplasmic reticulum (ER) stress, and oxidative ... ...

Abstract	Neuropeptide Y (NPY), a sympathetic neurotransmitter, is involved in various physiological functions, and its dysregulation is implicated in several neurodegenerative diseases. Glutamate excitotoxicity, endoplasmic reticulum (ER) stress, and oxidative stress are the common mechanisms associated with numerous neurodegenerative illnesses. The present study aimed to elucidate the protective effects of NPY against glutamate toxicity and tunicamycin-induced ER stress in the human neuroblastoma SH-SY5Y cell line. We exposed the SH-SY5Y cells to glutamate and tunicamycin for two different time points and analyzed the protective effects of NPY at different concentrations. The protective effects of NPY treatments were assessed by cell viability assay, and the signalling pathway changes were evaluated by biochemical techniques such as Western blotting and immunofluorescence assays. Our results showed that treatment of SH-SY5Y cells with NPY significantly increased the viability of the cells in both glutamate toxicity and ER stress conditions. NPY treatments significantly attenuated the glutamate-induced pro-apoptotic activation of ERK1/2 and JNK/BAD pathways. The protective effects of NPY were further evident against tunicamycin-induced ER stress. NPY treatments significantly suppressed the ER stress activation by downregulating BiP, phospho-eIF2α, and CHOP expression. In addition, NPY alleviated the Akt/FoxO3a pathway in acute oxidative conditions caused by glutamate and tunicamycin in SH-SY5Y cells. Our results demonstrated that NPY is neuroprotective against glutamate-induced cell toxicity and tunicamycin-induced ER stress through anti-apoptotic actions.
MeSH term(s)	Humans ; Neuroprotective Agents/pharmacology ; Neuropeptide Y/pharmacology ; Neuroblastoma ; Glutamic Acid/toxicity ; Tunicamycin/pharmacology ; Cell Line, Tumor
Chemical Substances	Neuroprotective Agents ; Neuropeptide Y ; Glutamic Acid (3KX376GY7L) ; Tunicamycin (11089-65-9)
Language	English
Publishing date	2022-11-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11223665
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Article ; Online: Anti-inflammatory Effects of Siponimod in a Mouse Model of Excitotoxicity-Induced Retinal Injury.

Basavarajappa, Devaraj / Gupta, Vivek / Chitranshi, Nitin / Viswanathan, Deepa / Gupta, Veer / Vander Wall, Roshana / Palanivel, Viswanthram / Mirzaei, Mehdi / You, Yuyi / Klistorner, Alexander / Graham, Stuart L

Molecular neurobiology

2023 Volume 60, Issue 12, Page(s) 7222–7237

Abstract: Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D- ... ...

Abstract	Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina. Siponimod is an immunomodulatory drug for multiple sclerosis and is a selective modulator of S1PR subtypes 1 and 5 and has been shown to have beneficial effects on the central nervous system (CNS) in degenerative conditions. Our previous study showed that mice administered orally with siponimod protected inner retinal structure and function against acute NMDA excitotoxicity. To elucidate the molecular mechanisms behind these protective effects, we investigated the inflammatory pathways affected by siponimod treatment in NMDA excitotoxicity model. NMDA excitotoxicity resulted in the activation of glial cells coupled with upregulation of the inflammatory NF-kB pathway and increased expression of TNFα, IL1-β, and IL-6. Siponimod treatment significantly reduced glial activation and suppressed the pro-inflammatory pathways. Furthermore, NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) were significantly diminished with siponimod treatment. Our data demonstrated that siponimod induces anti-inflammatory effects via suppression of glial activation and inflammatory singling pathways that could protect the retina against acute excitotoxicity conditions. These findings provide insights into the anti-inflammatory effects of siponimod in the CNS and suggest a potential therapeutic strategy for neuroinflammatory conditions.
MeSH term(s)	Mice ; Animals ; N-Methylaspartate/metabolism ; Neuroinflammatory Diseases ; Retina/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Glaucoma/metabolism ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Anti-Inflammatory Agents/metabolism
Chemical Substances	N-Methylaspartate (6384-92-5) ; siponimod (RR6P8L282I) ; Receptors, N-Methyl-D-Aspartate ; Anti-Inflammatory Agents
Language	English
Publishing date	2023-08-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-023-03535-0
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Article ; Online: Mumbai mayhem of COVID-19 pandemic reveals important factors that influence susceptibility to infection.

Yadav, Radha / Acharjee, Arup / Salkar, Akanksha / Bankar, Renuka / Palanivel, Viswanthram / Agrawal, Sachee / Shastri, Jayanthi / Sabnis, Sanjeev V / Srivastava, Sanjeeva

EClinicalMedicine

2021 Volume 35, Page(s) 100841

Abstract: Background: COVID-19 severity is disproportionately high in the elderly and people with comorbidities. However, other factors that predispose individuals to increased chances of infection are unclear.: Methods: Data from 18,600 people screened for ... ...

Abstract	Background: COVID-19 severity is disproportionately high in the elderly and people with comorbidities. However, other factors that predispose individuals to increased chances of infection are unclear. Methods: Data from 18,600 people screened for COVID-19 in Mumbai during the outbreak's initial phase, March 7 to June 30, 2020, were used to assess risk factors associated with COVID-19 using the odds ratio analysis. Findings: Males aged ≥60 years having both diabetes and hypertension were at the highest risk of COVID-19 infection (M vs Interpretation: Our research indicates that the risk of getting COVID-19 disease is not equal. When considering sex, age, and comorbidity together, we found that males aged ≥60 years and having both diabetes and hypertension had a significantly high risk of COVID-19 infection. Therefore, remedial measures such as vaccination programs should be prioritized for at-risk individuals. Funding: SERB, India: SB/S1/COVID-2/2020 and Seed grant RD/0520-IRCCHC0-006 from IRCC, IIT Bombay.
Language	English
Publishing date	2021-04-25
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2021.100841
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Article: Rapid Classification of COVID-19 Severity by ATR-FTIR Spectroscopy of Plasma Samples

Banerjee, Arghya / Gokhale, Abhiram / Bankar, Renuka / Palanivel, Viswanthram / Salkar, Akanksha / Robinson, Harley / Shastri, Jayanthi S. / Agrawal, Sachee / Hartel, Gunter / Hill, Michelle M. / Srivastava, Sanjeeva

Analytical chemistry. 2021 July 19, v. 93, no. 30

2021

Abstract: The coronavirus disease 2019 (COVID-19) pandemic continues to ravage the world, with many hospitals overwhelmed by the large number of patients presenting during major outbreaks. A rapid triage for COVID-19 patient requiring hospitalization and intensive ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic continues to ravage the world, with many hospitals overwhelmed by the large number of patients presenting during major outbreaks. A rapid triage for COVID-19 patient requiring hospitalization and intensive care is urgently needed. Age and comorbidities have been associated with a higher risk of severe COVID-19 but are not sufficient to triage patients. Here, we investigated the potential of attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy as a rapid blood test for classification of COVID-19 disease severity using a cohort of 160 COVID-19 patients. A simple plasma processing and ATR-FTIR data acquisition procedure was established using 75% ethanol for viral inactivation. Next, partial least-squares-discriminant analysis (PLS-DA) models were developed and tested using data from 130 and 30 patients, respectively. Addition of the ATR-FTIR spectra to the clinical parameters (age, sex, diabetes mellitus, and hypertension) increased the area under the ROC curve (C-statistics) for both the training and test data sets, from 69.3% (95% CI 59.8–78.9%) to 85.7% (78.6–92.8%) and 77.8% (61.3–94.4%) to 85.1% (71.3–98.8%), respectively. The independent test set achieved 69.2% specificity (42.4–87.3%) and 94.1% sensitivity (73.0–99.0%). Diabetes mellitus was the strongest predictor in the model, followed by FTIR regions 1020–1090 and 1588–1592 cm–¹. In summary, this study demonstrates the potential of ATR-FTIR spectroscopy as a rapid, low-cost COVID-19 severity triage tool to facilitate COVID-19 patient management during an outbreak.
Keywords	COVID-19 infection ; analytical chemistry ; data collection ; diabetes mellitus ; disease severity ; ethanol ; hematologic tests ; hypertension ; models ; pandemic ; patients ; reflectance ; risk
Language	English
Dates of publication	2021-0719
Size	p. 10391-10396.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.1c00596
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Article: Proteomic Investigation of COVID-19 Severity During the Tsunamic Second Wave in Mumbai.

Rajoria, Sakshi / Nair, Divya / Suvarna, Kruthi / Pai, Medha Gayathri J / Salkar, Akanksha / Palanivel, Viswanthram / Verma, Ayushi / Barpanda, Abhilash / Awasthi, Gaurav / Doshi, Hastyn / Dhara, Vivek / Burli, Ananya / Agrawal, Sachee / Shrivastav, Om / Shastri, Jayanthi / Srivastava, Sanjeeva

Advances in experimental medicine and biology

2023 Volume 1412, Page(s) 175–195

Abstract: Maharashtra was severely affected during the noxious second wave of COVID-19, with the highest number of cases recorded across India. The emergence of new symptoms and dysregulation of multiple organs resulted in high disease severity during the second ... ...

Abstract	Maharashtra was severely affected during the noxious second wave of COVID-19, with the highest number of cases recorded across India. The emergence of new symptoms and dysregulation of multiple organs resulted in high disease severity during the second wave which led to increased difficulties in understanding the molecular mechanisms behind the disease pathology. Exploring the underlying factors can help to relieve the burden on the medical communities to some extent by prioritizing the patients and, at the same time, opening avenues for improved treatments. In the current study, we have performed a mass-spectrometry-based proteomic analysis to investigate the disease pathology using nasopharyngeal swab samples collected from the COVID-19 patients in the Mumbai region of Maharashtra over the period of March-June 2021, the peak of the second wave. A total of 59 patients, including 32 non-severe and 27 severe cases, were considered for this proteomic study. We identified 23 differentially regulated proteins in severe patients as a host response to infection. In addition to the previously identified innate mechanisms of neutrophil and platelet degranulation, this study revealed significant alterations of anti-microbial peptide pathways in severe conditions, illustrating its role in the severity of the infectious strain of COVID-19 during the second wave. Furthermore, myeloperoxidase, cathepsin G, and profilin-1 were identified as potential therapeutic targets of the FDA-approved drugs dabrafenib, ZINC4097343, and ritonavir. This study has enlightened the role of the anti-microbial peptide pathway associated with the second wave in India and proposed its importance in potential therapeutics for COVID-19.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Proteomics/methods ; India/epidemiology ; Ritonavir
Chemical Substances	Ritonavir (O3J8G9O825)
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-031-28012-2_9
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Article ; Online: Rapid Classification of COVID-19 Severity by ATR-FTIR Spectroscopy of Plasma Samples.

Banerjee, Arghya / Gokhale, Abhiram / Bankar, Renuka / Palanivel, Viswanthram / Salkar, Akanksha / Robinson, Harley / Shastri, Jayanthi S / Agrawal, Sachee / Hartel, Gunter / Hill, Michelle M / Srivastava, Sanjeeva

Analytical chemistry

2021 Volume 93, Issue 30, Page(s) 10391–10396

Abstract	The coronavirus disease 2019 (COVID-19) pandemic continues to ravage the world, with many hospitals overwhelmed by the large number of patients presenting during major outbreaks. A rapid triage for COVID-19 patient requiring hospitalization and intensive care is urgently needed. Age and comorbidities have been associated with a higher risk of severe COVID-19 but are not sufficient to triage patients. Here, we investigated the potential of attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy as a rapid blood test for classification of COVID-19 disease severity using a cohort of 160 COVID-19 patients. A simple plasma processing and ATR-FTIR data acquisition procedure was established using 75% ethanol for viral inactivation. Next, partial least-squares-discriminant analysis (PLS-DA) models were developed and tested using data from 130 and 30 patients, respectively. Addition of the ATR-FTIR spectra to the clinical parameters (age, sex, diabetes mellitus, and hypertension) increased the area under the ROC curve (C-statistics) for both the training and test data sets, from 69.3% (95% CI 59.8-78.9%) to 85.7% (78.6-92.8%) and 77.8% (61.3-94.4%) to 85.1% (71.3-98.8%), respectively. The independent test set achieved 69.2% specificity (42.4-87.3%) and 94.1% sensitivity (73.0-99.0%). Diabetes mellitus was the strongest predictor in the model, followed by FTIR regions 1020-1090 and 1588-1592 cm
MeSH term(s)	Ataxia Telangiectasia Mutated Proteins ; COVID-19 ; Discriminant Analysis ; Humans ; Least-Squares Analysis ; SARS-CoV-2 ; Spectroscopy, Fourier Transform Infrared
Chemical Substances	ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2021-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.1c00596
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Article ; Online: A Multi-omics Longitudinal Study Reveals Alteration of the Leukocyte Activation Pathway in COVID-19 Patients.

Suvarna, Kruthi / Salkar, Akanksha / Palanivel, Viswanthram / Bankar, Renuka / Banerjee, Nirjhar / Gayathri J Pai, Medha / Srivastava, Alisha / Singh, Avinash / Khatri, Harsh / Agrawal, Sachee / Shrivastav, Om / Shastri, Jayanthi / Srivastava, Sanjeeva

Journal of proteome research

2021 Volume 20, Issue 10, Page(s) 4667–4680

Abstract: Severe coronavirus disease 2019 (COVID-19) infection may lead to lung injury, multi-organ failure, and eventually death. Cytokine storm due to excess cytokine production has been associated with fatality in severe infections. However, the specific ... ...

Abstract	Severe coronavirus disease 2019 (COVID-19) infection may lead to lung injury, multi-organ failure, and eventually death. Cytokine storm due to excess cytokine production has been associated with fatality in severe infections. However, the specific molecular signatures associated with the elevated immune response are yet to be elucidated. We performed a mass-spectrometry-based proteomic and metabolomic analysis of COVID-19 plasma samples collected at two time points. Using Orbitrap Fusion LC-MS/MS-based label-free proteomic analysis, we identified around 10 significant proteins, 32 significant peptides, and 5 metabolites that were dysregulated at the severe time points. Few of these proteins identified by quantitative proteomics were validated using the multiple reaction monitoring (MRM) assay. Integrated pathway analysis using distinct proteomic and metabolomic signatures revealed alterations in complement and coagulation cascade, platelet aggregation, myeloid leukocyte activation pathway, and arginine metabolism. Further, we highlight the role of leukocyte activation and arginine metabolism in COVID-19 pathogenesis and targeting these pathways for COVID-19 therapeutics.
MeSH term(s)	COVID-19 ; Chromatography, Liquid ; Humans ; Leukocytes ; Longitudinal Studies ; Proteomics ; SARS-CoV-2 ; Tandem Mass Spectrometry
Language	English
Publishing date	2021-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00215
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Article: A Multi-omics Longitudinal Study Reveals Alteration of the Leukocyte Activation Pathway in COVID-19 Patients

Journal of proteome research. 2021 Aug. 11, v. 20, no. 10

2021

Abstract	Severe coronavirus disease 2019 (COVID-19) infection may lead to lung injury, multi-organ failure, and eventually death. Cytokine storm due to excess cytokine production has been associated with fatality in severe infections. However, the specific molecular signatures associated with the elevated immune response are yet to be elucidated. We performed a mass-spectrometry-based proteomic and metabolomic analysis of COVID-19 plasma samples collected at two time points. Using Orbitrap Fusion LC–MS/MS-based label-free proteomic analysis, we identified around 10 significant proteins, 32 significant peptides, and 5 metabolites that were dysregulated at the severe time points. Few of these proteins identified by quantitative proteomics were validated using the multiple reaction monitoring (MRM) assay. Integrated pathway analysis using distinct proteomic and metabolomic signatures revealed alterations in complement and coagulation cascade, platelet aggregation, myeloid leukocyte activation pathway, and arginine metabolism. Further, we highlight the role of leukocyte activation and arginine metabolism in COVID-19 pathogenesis and targeting these pathways for COVID-19 therapeutics.
Keywords	COVID-19 infection ; arginine ; coagulation ; complement ; cytokines ; death ; immune response ; leukocytes ; longitudinal studies ; lungs ; metabolism ; metabolites ; metabolomics ; multiomics ; pathogenesis ; platelet aggregation ; proteome ; proteomics ; research ; therapeutics
Language	English
Dates of publication	2021-0811
Size	p. 4667-4680.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00215
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Article ; Online: Proteomic investigation reveals dominant alterations of neutrophil degranulation and mRNA translation pathways in patients with COVID-19.

Bankar, Renuka / Suvarna, Kruthi / Ghantasala, Saicharan / Banerjee, Arghya / Biswas, Deeptarup / Choudhury, Manisha / Palanivel, Viswanthram / Salkar, Akanksha / Verma, Ayushi / Singh, Avinash / Mukherjee, Amrita / Pai, Medha Gayathri J / Roy, Jyotirmoy / Srivastava, Alisha / Badaya, Apoorva / Agrawal, Sachee / Shrivastav, Om / Shastri, Jayanthi / Srivastava, Sanjeeva

iScience

2021 Volume 24, Issue 3, Page(s) 102135

Abstract: The altered molecular proteins and pathways in response to COVID-19 infection are still unclear. Here, we performed a comprehensive proteomics-based investigation of nasopharyngeal swab samples from patients with COVID-19 to study the host response by ... ...

Abstract	The altered molecular proteins and pathways in response to COVID-19 infection are still unclear. Here, we performed a comprehensive proteomics-based investigation of nasopharyngeal swab samples from patients with COVID-19 to study the host response by employing simple extraction strategies. Few of the host proteins such as interleukin-6, L-lactate dehydrogenase, C-reactive protein, Ferritin, and aspartate aminotransferase were found to be upregulated only in COVID-19-positive patients using targeted multiple reaction monitoring studies. The most important pathways identified by enrichment analysis were neutrophil degranulation, interleukin-12 signaling pathways, and mRNA translation of proteins thus providing the detailed investigation of host response in COVID-19 infection. Thus, we conclude that mass spectrometry-detected host proteins have a potential for disease severity progression; however, suitable validation strategies should be deployed for the clinical translation. Furthermore, the
Language	English
Publishing date	2021-02-04
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.102135
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Article: Proteomics and Machine Learning Approaches Reveal a Set of Prognostic Markers for COVID-19 Severity With Drug Repurposing Potential.

Suvarna, Kruthi / Biswas, Deeptarup / Pai, Medha Gayathri J / Acharjee, Arup / Bankar, Renuka / Palanivel, Viswanthram / Salkar, Akanksha / Verma, Ayushi / Mukherjee, Amrita / Choudhury, Manisha / Ghantasala, Saicharan / Ghosh, Susmita / Singh, Avinash / Banerjee, Arghya / Badaya, Apoorva / Bihani, Surbhi / Loya, Gaurish / Mantri, Krishi / Burli, Ananya /

Roy, Jyotirmoy / Srivastava, Alisha / Agrawal, Sachee / Shrivastav, Om / Shastri, Jayanthi / Srivastava, Sanjeeva

Frontiers in physiology

2021 Volume 12, Page(s) 652799

Abstract: The pestilential pathogen SARS-CoV-2 has led to a seemingly ceaseless pandemic of COVID-19. The healthcare sector is under a tremendous burden, thus necessitating the prognosis of COVID-19 severity. This in-depth study of plasma proteome alteration ... ...

Abstract	The pestilential pathogen SARS-CoV-2 has led to a seemingly ceaseless pandemic of COVID-19. The healthcare sector is under a tremendous burden, thus necessitating the prognosis of COVID-19 severity. This in-depth study of plasma proteome alteration provides insights into the host physiological response towards the infection and also reveals the potential prognostic markers of the disease. Using label-free quantitative proteomics, we performed deep plasma proteome analysis in a cohort of 71 patients (20 COVID-19 negative, 18 COVID-19 non-severe, and 33 severe) to understand the disease dynamics. Of the 1200 proteins detected in the patient plasma, 38 proteins were identified to be differentially expressed between non-severe and severe groups. The altered plasma proteome revealed significant dysregulation in the pathways related to peptidase activity, regulated exocytosis, blood coagulation, complement activation, leukocyte activation involved in immune response, and response to glucocorticoid biological processes in severe cases of SARS-CoV-2 infection. Furthermore, we employed supervised machine learning (ML) approaches using a linear support vector machine model to identify the classifiers of patients with non-severe and severe COVID-19. The model used a selected panel of 20 proteins and classified the samples based on the severity with a classification accuracy of 0.84. Putative biomarkers such as angiotensinogen and SERPING1 and ML-derived classifiers including the apolipoprotein B, SERPINA3, and fibrinogen gamma chain were validated by targeted mass spectrometry-based multiple reaction monitoring (MRM) assays. We also employed an
Language	English
Publishing date	2021-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.652799
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