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Article: RGD-binding integrins and TGF-β in SARS-CoV-2 infections - novel targets to treat COVID-19 patients?

Carvacho, Ingrid / Piesche, Matthias

2021 Volume 10, Issue 3, Page(s) e1240

Abstract: The new coronavirus SARS-CoV-2 is a global pandemic and a severe public health crisis. SARS-CoV-2 is highly contagious and shows high mortality rates, especially in elderly and patients with pre-existing medical conditions. At the current stage, no ... ...

Abstract	The new coronavirus SARS-CoV-2 is a global pandemic and a severe public health crisis. SARS-CoV-2 is highly contagious and shows high mortality rates, especially in elderly and patients with pre-existing medical conditions. At the current stage, no effective drugs are available to treat these patients. In this review, we analyse the rationale of targeting RGD-binding integrins to potentially inhibit viral cell infection and to block TGF-β activation, which is involved in the severity of several human pathologies, including the complications of severe COVID-19 cases. Furthermore, we demonstrate the correlation between ACE2 and TGF-β expression and the possible consequences for severe COVID-19 infections. Finally, we list approved drugs or drugs in clinical trials for other diseases that also target the RGD-binding integrins or TGF-β. These drugs have already shown a good safety profile and, therefore, can be faster brought into a trial to treat COVID-19 patients.
Language	English
Publishing date	2021-03-18
Publishing country	Australia
Document type	Journal Article ; Review
ZDB-ID	2694482-0
ISSN	2050-0068
ISSN	2050-0068
DOI	10.1002/cti2.1240
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Adipose tissue macrophages as a therapeutic target in obesity‐associated diseases

Herrada, Andrés A / Olate‐Briones, Alexandra / Rojas, Armando / Liu, Chaohong / Escobedo, Noelia / Piesche, Matthias

Obesity reviews. 2021 June, v. 22, no. 6

2021

Abstract: Obesity is an increasing problem in developed and developing countries. Individuals with obesity have a higher risk of several diseases, such as cardiovascular disease, increased risk of insulin resistance, type 2 diabetes, infertility, degenerative ... ...

Abstract	Obesity is an increasing problem in developed and developing countries. Individuals with obesity have a higher risk of several diseases, such as cardiovascular disease, increased risk of insulin resistance, type 2 diabetes, infertility, degenerative disorders, and also certain types of cancer. Adipose tissue (AT) is considered an extremely active endocrine organ, and the expansion of AT is accompanied by the infiltration of different types of immune cells, which induces a state of low‐grade, chronic inflammation and metabolic dysregulation. Even though the exact mechanism of this low‐grade inflammation is not fully understood, there is clear evidence that AT‐infiltrating macrophages (ATMs) play a significant role in the pro‐inflammatory state and dysregulated metabolism. ATMs represent the most abundant class of leukocytes in AT, constituting 5% of the cells in AT in individuals with normal weight. However, this percentage dramatically increases up to 50% in individuals with obesity, suggesting an important role of ATMs in obesity and its associated complications. In this review, we discuss current knowledge of the function of ATMs during steady‐state and obesity and analyze its contribution to different obesity‐associated diseases, highlighting the potential therapeutic target of ATMs in these pathological conditions.
Keywords	adipose tissue ; cardiovascular diseases ; inflammation ; insulin resistance ; macrophages ; metabolism ; noninsulin-dependent diabetes mellitus ; obesity ; risk ; therapeutics
Language	English
Dates of publication	2021-06
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; REVIEW
ZDB-ID	2147980-X
ISSN	1467-789X ; 1467-7881
ISSN (online)	1467-789X
ISSN	1467-7881
DOI	10.1111/obr.13200
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Adipose tissue macrophages as a therapeutic target in obesity-associated diseases.

Herrada, Andrés A / Olate-Briones, Alexandra / Rojas, Armando / Liu, Chaohong / Escobedo, Noelia / Piesche, Matthias

Obesity reviews : an official journal of the International Association for the Study of Obesity

2021 Volume 22, Issue 6, Page(s) e13200

Abstract	Obesity is an increasing problem in developed and developing countries. Individuals with obesity have a higher risk of several diseases, such as cardiovascular disease, increased risk of insulin resistance, type 2 diabetes, infertility, degenerative disorders, and also certain types of cancer. Adipose tissue (AT) is considered an extremely active endocrine organ, and the expansion of AT is accompanied by the infiltration of different types of immune cells, which induces a state of low-grade, chronic inflammation and metabolic dysregulation. Even though the exact mechanism of this low-grade inflammation is not fully understood, there is clear evidence that AT-infiltrating macrophages (ATMs) play a significant role in the pro-inflammatory state and dysregulated metabolism. ATMs represent the most abundant class of leukocytes in AT, constituting 5% of the cells in AT in individuals with normal weight. However, this percentage dramatically increases up to 50% in individuals with obesity, suggesting an important role of ATMs in obesity and its associated complications. In this review, we discuss current knowledge of the function of ATMs during steady-state and obesity and analyze its contribution to different obesity-associated diseases, highlighting the potential therapeutic target of ATMs in these pathological conditions.
MeSH term(s)	Adipose Tissue ; Diabetes Mellitus, Type 2 ; Humans ; Inflammation ; Insulin Resistance ; Macrophages ; Obesity/complications
Language	English
Publishing date	2021-01-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2147980-X
ISSN	1467-789X ; 1467-7881
ISSN (online)	1467-789X
ISSN	1467-7881
DOI	10.1111/obr.13200
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Integrin/TGF-β1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells which could attenuate disease severity.

Huntington, Kelsey E / Carlsen, Lindsey / So, Eui-Young / Piesche, Matthias / Liang, Olin / El-Deiry, Wafik S

medRxiv : the preprint server for health sciences

2022

Abstract: As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target ...

Abstract	As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced inhibition of pseudovirus infection by GLPG-0187. Because integrins activate TGF-β signaling, we compared plasma levels of active and total TGF-β in COVID-19+ patients. Plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. In our preclinical studies, Omicron infects lower airway lung cells less efficiently than other COVID-19 variants. Moreover, inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
Language	English
Publishing date	2022-01-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.01.02.22268641
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity.

Huntington, Kelsey E / Carlsen, Lindsey / So, Eui-Young / Piesche, Matthias / Liang, Olin / El-Deiry, Wafik S

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 5

Abstract: As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects ... ...

Abstract	As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. Because integrins activate transforming growth factor beta (TGF-β) signaling, we compared the plasma levels of active and total TGF-β in COVID-19+ patients. The plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. Moreover, the inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and it may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
Language	English
Publishing date	2022-05-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15050618
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Article ; Online: Integrin/TGF-Beta1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells which could attenuate disease severity

Huntington, Kelsey E. / Carlsen, Lindsey / So, Eui-Young / Piesche, Matthias / Liang, Olin / El-Deiry, Wafik

medRxiv

Abstract	As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced inhibition of pseudovirus infection by GLPG-0187. Because integrins activate TGF-beta; signaling, we compared plasma levels of active and total TGF-beta; in COVID-19+ patients. Plasma TGF-beta1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-beta1 levels correlated with activated TGF-beta1 levels. In our preclinical studies, Omicron infects lower airway lung cells less efficiently than other COVID-19 variants. Moreover, inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and may mitigate COVID-19 severity through decreased TGF-beta1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
Keywords	covid19
Language	English
Publishing date	2022-01-03
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2022.01.02.22268641
Database	COVID19

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Article: Ion Channel Function During Oocyte Maturation and Fertilization.

Carvacho, Ingrid / Piesche, Matthias / Maier, Thorsten J / Machaca, Khaled

Frontiers in cell and developmental biology

2018 Volume 6, Page(s) 63

Abstract: The proper maturation of both male and female gametes is essential for supporting fertilization and the early embryonic divisions. In the ovary, immature fully-grown oocytes that are arrested in prophase I of meiosis I are not able to support ... ...

Abstract	The proper maturation of both male and female gametes is essential for supporting fertilization and the early embryonic divisions. In the ovary, immature fully-grown oocytes that are arrested in prophase I of meiosis I are not able to support fertilization. Acquiring fertilization competence requires resumption of meiosis which encompasses the remodeling of multiple signaling pathways and the reorganization of cellular organelles. Collectively, this differentiation endows the egg with the ability to activate at fertilization and to promote the egg-to-embryo transition. Oocyte maturation is associated with changes in the electrical properties of the plasma membrane and alterations in the function and distribution of ion channels. Therefore, variations on the pattern of expression, distribution, and function of ion channels and transporters during oocyte maturation are fundamental to reproductive success. Ion channels and transporters are important in regulating membrane potential, but also in the case of calcium (Ca
Language	English
Publishing date	2018-06-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2018.00063
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online ; Thesis: Identifikation und immunologische Charakterisierung von MHC-Klasse-II-Peptidepitopen in humanen Leukämie- und Lymphom-assoziierten Antigenen

Piesche, Matthias

2006

Abstract: CD4+ T-Zellen spielen durch verschiedene Mechanismen eine wichtige Rolle bei der Tumorbekämpfung. Vor allem helfen sie bei der Induktion und Aufrechterhaltung von CTL-Antworten. Tierexperimente haben gezeigt, dass Antigen-spezifische CD4+ T-Zellen ... ...

Title variant	Identification and immunological characterization of MHC-class-II-peptide epitopes and antigens in human leukemia- and lymphoma-associated proteins
Author's details	vorgelegt von Matthias Piesche
Abstract	CD4+ T-Zellen spielen durch verschiedene Mechanismen eine wichtige Rolle bei der Tumorbekämpfung. Vor allem helfen sie bei der Induktion und Aufrechterhaltung von CTL-Antworten. Tierexperimente haben gezeigt, dass Antigen-spezifische CD4+ T-Zellen wichtig für die Eliminierung von Tumoren sind. Ein interessanter Weg zur Bekämpfung von Tumoren bei Patienten liegt in der Peptid-Vakzinierung. Bisherige Anstrengungen zielten auf die Induktion von CTL-Antworten ab; um eine Verbesserung der Tumor-Vakzinierung zu erzielen, sollten CD4+ T-Zellepitope aus demselben Tumorantigen miteinbezogen werden. Das Hauptziel dieser Arbeit war es, MHC Klasse-II Peptidepitope in den Proteinen zu identifizieren, welche eine tumor-assoziierte Expression aufweisen und die bereits bekannte Zielantigene von zytotoxischen T-Zellreaktionen sind ...
Language	German
Size	Online-Ressource, Ill., graph. Darst
Publisher	Niedersächsische Staats- und Universitätsbibliothek
Publishing place	Göttingen
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Göttingen, 2006
Database	Former special subject collection: coastal and deep sea fishing

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Book ; Thesis: Identifikation und immunologische Charakterisierung von MHC-Klasse-II-Peptidepitopen in humanen Leukämie- und Lymphom-assoziierten Antigenen

Piesche, Matthias

2006

Author's details	vorgelegt von Matthias Piesche
Language	German
Size	XI, 139 Bl., Ill., graph. Darst
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Göttingen, 2006
Note	Auch als elektronisches Dokument vorh. ; Zsfassung in engl. Sprache
Database	Former special subject collection: coastal and deep sea fishing

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Article: Effects of Interleukin-1β in Glycinergic Transmission at the Central Amygdala.

Solorza, Jocelyn / Oliva, Carolina A / Castillo, Karen / Amestica, Gabriela / Maldifassi, María Constanza / López-Cortés, Xaviera A / Barra, Rafael / Stehberg, Jimmy / Piesche, Matthias / Sáez-Briones, Patricio / González, Wendy / Arenas-Salinas, Mauricio / Mariqueo, Trinidad A

Frontiers in pharmacology

2021 Volume 12, Page(s) 613105

Abstract: Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In ... ...

Abstract	Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1β is released by glial cells in regions associated with pain processing during neuropathic pain. It also has important roles in neuroinflammation and in regulating NMDA receptor activity required for learning and memory. The modulation of glycine-mediated inhibitory activity via IL-1β may play a critical role in the perception of different levels of pain. The central nucleus of the amygdala (CeA) participates in receiving and processing pain information. Interestingly, this nucleus is enriched in the regulatory auxiliary glycine receptor (GlyR) β subunit (βGlyR); however, no studies have evaluated the effect of IL-1β on glycinergic neurotransmission in the brain. Hence, we hypothesized that IL-1β may modulate GlyR-mediated inhibitory activity via interactions with the βGlyR subunit. Our results show that the application of IL-1β (10 ng/ml) to CeA brain slices has a biphasic effect; transiently increases and then reduces sIPSC amplitude of CeA glycinergic currents. Additionally, we performed molecular docking, site-directed mutagenesis, and whole-cell voltage-clamp electrophysiological experiments in HEK cells transfected with GlyRs containing different GlyR subunits. These data indicate that IL-1β modulates GlyR activity by establishing hydrogen bonds with at least one key amino acid residue located in the back of the loop C at the ECD domain of the βGlyR subunit. The present results suggest that IL-1β in the CeA controls glycinergic neurotransmission, possibly via interactions with the βGlyR subunit. This effect could be relevant for understanding how IL-1β released by glia modulates central processing of pain, learning and memory, and is involved in neuroinflammation.
Language	English
Publishing date	2021-03-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.613105
Database	MEDical Literature Analysis and Retrieval System OnLINE

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