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  1. Article: Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator.

    Ortega, Joseph Thomas / Jastrzebska, Beata

    Pharmaceutics

    2021  Volume 13, Issue 11

    Abstract: The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a ... ...

    Abstract The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP.
    Language English
    Publishing date 2021-11-16
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics13111935
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor

    Joseph Thomas Ortega / Beata Jastrzebska / Hector Rafael Rangel

    Pathogens, Vol 11, Iss 45, p

    An In Silico Analysis

    2022  Volume 45

    Abstract: The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the ... ...

    Abstract The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the SARS-CoV-2 Omicron variant and whether these changes modulate the interactions with the angiotensin-converting enzyme 2 (ACE2) host receptor. The mutations associated with the Omicron variant were retrieved from the GISAID and covariants.org databases, and a structural model was built using the SWISS-Model server. The interaction between the spike and the human ACE2 was evaluated using two different docking software, Zdock and Haddock. We found that the binding free energy was lower for the Omicron variant as compared to the WT spike. In addition, the Omicron spike protein showed an increased number of electrostatic interactions with ACE2 than the WT spike, especially the interactions related to charged residues. This study contributes to a better understanding of the changes in the interaction between the Omicron spike and the human host ACE2 receptor.
    Keywords omicron ; SARS-CoV-2 ; spike ; variants ; binding affinity ; Medicine ; R
    Subject code 612
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis.

    Ortega, Joseph Thomas / Jastrzebska, Beata / Rangel, Hector Rafael

    Pathogens (Basel, Switzerland)

    2021  Volume 11, Issue 1

    Abstract: The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the ... ...

    Abstract The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the SARS-CoV-2 Omicron variant and whether these changes modulate the interactions with the angiotensin-converting enzyme 2 (ACE2) host receptor. The mutations associated with the Omicron variant were retrieved from the GISAID and covariants.org databases, and a structural model was built using the SWISS-Model server. The interaction between the spike and the human ACE2 was evaluated using two different docking software, Zdock and Haddock. We found that the binding free energy was lower for the Omicron variant as compared to the WT spike. In addition, the Omicron spike protein showed an increased number of electrostatic interactions with ACE2 than the WT spike, especially the interactions related to charged residues. This study contributes to a better understanding of the changes in the interaction between the Omicron spike and the human host ACE2 receptor.
    Language English
    Publishing date 2021-12-31
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens11010045
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  4. Article: Mutations in the SARS-CoV-2 spike protein modulate the virus affinity to the human ACE2 receptor, an

    Ortega, Joseph Thomas / Pujol, Flor Helene / Jastrzebska, Beata / Rangel, Hector R

    EXCLI journal

    2021  Volume 20, Page(s) 585–600

    Abstract: The increasing number of SARS-CoV-2 variants associated with highly transmissible phenotypes is a health-public concern in the current pandemic scenario. Herein, we developed a ... ...

    Abstract The increasing number of SARS-CoV-2 variants associated with highly transmissible phenotypes is a health-public concern in the current pandemic scenario. Herein, we developed a comprehensive
    Language English
    Publishing date 2021-03-08
    Publishing country Germany
    Document type Journal Article
    ISSN 1611-2156
    ISSN 1611-2156
    DOI 10.17179/excli2021-3471
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis

    Ortega, Joseph Thomas / Jastrzebska, Beata / Rangel, Hector Rafael

    Pathogens. 2021 Dec. 31, v. 11, no. 1

    2021  

    Abstract: The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the ... ...

    Abstract The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the SARS-CoV-2 Omicron variant and whether these changes modulate the interactions with the angiotensin-converting enzyme 2 (ACE2) host receptor. The mutations associated with the Omicron variant were retrieved from the GISAID and covariants.org databases, and a structural model was built using the SWISS-Model server. The interaction between the spike and the human ACE2 was evaluated using two different docking software, Zdock and Haddock. We found that the binding free energy was lower for the Omicron variant as compared to the WT spike. In addition, the Omicron spike protein showed an increased number of electrostatic interactions with ACE2 than the WT spike, especially the interactions related to charged residues. This study contributes to a better understanding of the changes in the interaction between the Omicron spike and the human host ACE2 receptor.
    Keywords Gibbs free energy ; Severe acute respiratory syndrome coronavirus 2 ; computer simulation ; computer software ; haddock ; humans ; models ; pathogenicity ; peptidyl-dipeptidase A ; viruses
    Language English
    Dates of publication 2021-1231
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens11010045
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Flavonoids improve the stability and function of P23H rhodopsin slowing down the progression of retinitis pigmentosa in mice.

    Ortega, Joseph Thomas / Parmar, Tanu / Carmena-Bargueño, Miguel / Pérez-Sánchez, Horacio / Jastrzebska, Beata

    Journal of neuroscience research

    2022  Volume 100, Issue 4, Page(s) 1063–1083

    Abstract: The balanced homeostasis of the G protein-coupled receptor (GPCR), rhodopsin (Rho), is required for vision. Misfolding mutations in Rho cause photoreceptor death, leading to retinitis pigmentosa (RP) and consequently blindness. With no cure currently ... ...

    Abstract The balanced homeostasis of the G protein-coupled receptor (GPCR), rhodopsin (Rho), is required for vision. Misfolding mutations in Rho cause photoreceptor death, leading to retinitis pigmentosa (RP) and consequently blindness. With no cure currently available, the development of efficient therapy for RP is an urgent need. Pharmacological supplementation with molecular chaperones, including flavonoids, improves stability, folding, and membrane targeting of the RP Rho mutants in vitro. Thus, we hypothesized that flavonoids by binding to P23H Rho and enhancing its conformational stability could mitigate detrimental effects of this mutation on retinal health. In this work, we evaluated the pharmacological potential of two model flavonoids, quercetin and myricetin, by using in silico, in vitro, and in vivo models of P23H Rho. Our computational analysis showed that quercetin could interact within the orthosteric binding pocket of P23H Rho and shift the conformation of its N-terminal loop toward the wild type (WT)-like state. Quercetin added to the NIH-3T3 cells stably expressing P23H Rho increased the stability of this receptor and improved its function. Systemic administration of quercetin to P23H Rho knock-in mice substantially improved retinal morphology and function, which was associated with an increase in levels of Rho and cone opsins. In addition, treatment with quercetin resulted in downregulation of the UPR signaling and oxidative stress-related markers. This study unravels the pharmacological potential of quercetin to slow down the progression of photoreceptor death in Rho-related RP and highlights its prospective as a lead compound to develop a novel therapeutic remedy to counter RP pathology.
    MeSH term(s) Animals ; Disease Models, Animal ; Mice ; Mutation ; Prospective Studies ; Quercetin/metabolism ; Quercetin/pharmacology ; Quercetin/therapeutic use ; Retina/metabolism ; Retinitis Pigmentosa/drug therapy ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/metabolism ; Rhodopsin/genetics ; Rhodopsin/metabolism
    Chemical Substances Rhodopsin (9009-81-8) ; Quercetin (9IKM0I5T1E)
    Language English
    Publishing date 2022-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 195324-2
    ISSN 1097-4547 ; 0360-4012
    ISSN (online) 1097-4547
    ISSN 0360-4012
    DOI 10.1002/jnr.25021
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  7. Article: Unrevealing sequence and structural features of novel coronavirus using

    Ortega, Joseph Thomas / Serrano, Maria Luisa / Pujol, Flor Helene / Rangel, Hector Rafael

    EXCLI journal

    2020  Volume 19, Page(s) 400–409

    Abstract: Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. ... ...

    Abstract Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. Based on that and using an
    Keywords covid19
    Language English
    Publishing date 2020-03-17
    Publishing country Germany
    Document type Journal Article
    ISSN 1611-2156
    ISSN 1611-2156
    DOI 10.17179/excli2020-1189
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  8. Article: Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An

    Ortega, Joseph Thomas / Serrano, Maria Luisa / Pujol, Flor Helene / Rangel, Hector Rafael

    EXCLI journal

    2020  Volume 19, Page(s) 410–417

    Abstract: Many human viral diseases are a consequence of a zoonotic event. Some of the diseases caused by these zoonotic events have affected millions of people around the world, some of which have resulted in high rates of morbidity/mortality in humans. Changes ... ...

    Abstract Many human viral diseases are a consequence of a zoonotic event. Some of the diseases caused by these zoonotic events have affected millions of people around the world, some of which have resulted in high rates of morbidity/mortality in humans. Changes in the viral proteins that function as ligands of the host receptor may promote the spillover between species. The most recent of these zoonotic events that have caused an ongoing epidemic of high magnitude is the Covid-19 epidemics caused by SARS-CoV-2. The aim of this study was to determine the mutation(s) in the sequence of the spike protein of the SARS-CoV-2 that might be favoring human to human transmission. An
    Keywords covid19
    Language English
    Publishing date 2020-03-18
    Publishing country Germany
    Document type Journal Article
    ISSN 1611-2156
    ISSN 1611-2156
    DOI 10.17179/excli2020-1167
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  9. Article ; Online: Effectiveness of Clopidogrel vs Alternative P2Y

    Thomas, Cameron D / Franchi, Francesco / Rossi, Joseph S / Keeley, Ellen C / Anderson, R David / Beitelshees, Amber L / Duarte, Julio D / Ortega-Paz, Luis / Gong, Yan / Kerensky, Richard A / Kulick, Natasha / McDonough, Caitrin W / Nguyen, Anh B / Wang, Yehua / Winget, Marshall / Yang, William E / Johnson, Julie A / Winterstein, Almut G / Stouffer, George A /
    Angiolillo, Dominick J / Lee, Craig R / Cavallari, Larisa H

    Journal of the American College of Cardiology

    2024  Volume 83, Issue 15, Page(s) 1370–1381

    Abstract: Background: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear.: Objectives! ...

    Abstract Background: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear.
    Objectives: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y
    Methods: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y
    Results: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885).
    Conclusions: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.
    MeSH term(s) Humans ; Clopidogrel ; Platelet Aggregation Inhibitors ; Cytochrome P-450 CYP2C19/genetics ; Percutaneous Coronary Intervention/adverse effects ; Ticagrelor/therapeutic use ; Treatment Outcome ; Genotype
    Chemical Substances Clopidogrel (A74586SNO7) ; Platelet Aggregation Inhibitors ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1) ; Ticagrelor (GLH0314RVC)
    Language English
    Publishing date 2024-04-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 605507-2
    ISSN 1558-3597 ; 0735-1097
    ISSN (online) 1558-3597
    ISSN 0735-1097
    DOI 10.1016/j.jacc.2024.02.015
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  10. Article ; Online: Trauma as an Entry Point to the Health Care System.

    Spruce, Marguerite W / Thomas, Debi M / Anderson, Jamie E / Ortega, Joanna C / Mortazavi, Kevin / Galante, Joseph M

    JAMA surgery

    2020  Volume 155, Issue 10, Page(s) 982–984

    MeSH term(s) Adolescent ; Adult ; Aged ; California ; Female ; Health Services Accessibility ; Humans ; Male ; Middle Aged ; Prevalence ; Retrospective Studies ; Risk Factors ; Wounds and Injuries/complications ; Wounds and Injuries/epidemiology ; Young Adult
    Language English
    Publishing date 2020-08-02
    Publishing country United States
    Document type Letter
    ZDB-ID 2701841-6
    ISSN 2168-6262 ; 2168-6254
    ISSN (online) 2168-6262
    ISSN 2168-6254
    DOI 10.1001/jamasurg.2020.2178
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