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Article ; Online: The SLMAP/Striatin complex: An emerging regulator of normal and abnormal cardiac excitation-contraction coupling.

Nader, Moni

2019 Volume 858, Page(s) 172491

Abstract: The excitation-contraction (E-C) module involves a harmonized correspondence between the sarcolemma and the sarcoplasmic reticulum. This is provided by membrane proteins, which primarily shape the caveolae, the T-tubule/Sarcoplasmic reticulum (TT/SR) ... ...

Abstract	The excitation-contraction (E-C) module involves a harmonized correspondence between the sarcolemma and the sarcoplasmic reticulum. This is provided by membrane proteins, which primarily shape the caveolae, the T-tubule/Sarcoplasmic reticulum (TT/SR) junction, and the intercalated discs (ICDs). Distortion of either one of these structures impairs myocardial contraction, and subsequently translates into cardiac failure. Thus, detailed studies on the molecular cues of the E-C module are becoming increasingly necessary to pharmacologically eradicate cardiac failure Herein we reviewed the organization of caveolae, TT/SR junctions, and the ICDs in the heart, with special attention to the Sarcolemma Membrane Associated Protein (SLMAP) and striatin (STRN) in cardiac membranes biology and cardiomyocyte contraction. We emphasized on their in vivo and in vitro signaling in cardiac function/dysfunction. SLMAP is a cardiac membrane protein that plays an important role in E-C coupling and the adrenergic response of the heart. Similarly, STRN is a dynamic protein that is also involved in cardiac E-C coupling and ICD-related cardiomyopathies. Both SLMAP and STRN are linked to cardiac conditions, including heart failure, and their role in cardiomyocyte function was elucidated in our laboratory. They interact together in a protein complex that holds therapeutic potentials for cardiac dysfunction. This review is the first of its kind to conceptualize the role of the SLMAP/STRN complex in cardiac function and failure. It provides in depth information on the signaling of these two proteins and projects their interaction as a novel therapeutic target for cardiac failure.
MeSH term(s)	Animals ; Excitation Contraction Coupling ; Heart/physiology ; Heart/physiopathology ; Heart Diseases/metabolism ; Heart Diseases/pathology ; Heart Diseases/physiopathology ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Myocardium/cytology ; Myocardium/metabolism ; Myocardium/pathology
Chemical Substances	Membrane Proteins
Language	English
Publishing date	2019-06-21
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2019.172491
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Article ; Online: Age-dependent effect of insulin in the regulation of intracellular calcium in ventricular cardiomyocytes.

Bkaily, Ghassan / Al-Shahrani, Maram Ali / Nader, Moni / Jacques, Danielle

Canadian journal of physiology and pharmacology

2022 Volume 100, Issue 12, Page(s) 1106–1114

Abstract: In this study, we wanted to verify whether the effect of insulin on calcium homeostasis depends on the heart's development stage. Using a quantitative 3D confocal microscopy, we tested the effect of a high insulin concentration (100 µU) in freshly ... ...

Abstract	In this study, we wanted to verify whether the effect of insulin on calcium homeostasis depends on the heart's development stage. Using a quantitative 3D confocal microscopy, we tested the effect of a high insulin concentration (100 µU) in freshly cultured ventricular cardiomyocytes from newborn and adult rats. Our results showed that the cytosolic basal level of calcium was higher in newborn cardiomyocytes with no change in the nuclear basal calcium level compared with the adult cardiomyocytes; in addition, insulin induced a slow increase of cytosolic and nuclear calcium in newborn ventricular cardiomyocytes, followed by two phases. However, the first phase of slow cytosolic and nuclear calcium increase was absent in adult rat ventricular cardiomyocytes. Furthermore, the time to the onset of increase of cytosolic and nuclear calcium was longer in newborn cardiomyocytes compared with adults. Moreover, the time to peak of the calcium transient was shorter in newborns than in adult cardiomyocytes. These results demonstrate that insulin differently regulates calcium homeostasis in newborns than in adult cardiomyocytes. Thus, newborn rat cardiomyocytes, commonly used in research as a model for adult cardiomyocytes, should be used with caution when dealing with insulin in normal and disease conditions.
MeSH term(s)	Rats ; Animals ; Myocytes, Cardiac ; Calcium/pharmacology ; Insulin/pharmacology ; Cells, Cultured ; Heart Ventricles
Chemical Substances	Calcium (SY7Q814VUP) ; Insulin
Language	English
Publishing date	2022-10-12
Publishing country	Canada
Document type	Journal Article
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/cjpp-2022-0328
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Article ; Online: HDL levels modulate the impact of type 2 diabetes susceptibility alleles in older adults.

Sullivan, Siobhán O ' / Al Hageh, Cynthia / Henschel, Andreas / Chacar, Stephanie / Abchee, Antoine / Zalloua, Pierre / Nader, Moni

Lipids in health and disease

2024 Volume 23, Issue 1, Page(s) 56

Abstract: Background: Type 2 Diabetes (T2D) is influenced by genetic, environmental, and ageing factors. Ageing pathways exacerbate metabolic diseases. This study aimed to examine both clinical and genetic factors of T2D in older adults.: Methods: A total of 2, ...

Abstract	Background: Type 2 Diabetes (T2D) is influenced by genetic, environmental, and ageing factors. Ageing pathways exacerbate metabolic diseases. This study aimed to examine both clinical and genetic factors of T2D in older adults. Methods: A total of 2,909 genotyped patients were enrolled in this study. Genome Wide Association Study was conducted, comparing T2D patients to non-diabetic older adults aged ≥ 60, ≥ 65, or ≥ 70 years, respectively. Binomial logistic regressions were applied to examine the association between T2D and various risk factors. Stepwise logistic regression was conducted to explore the impact of low HDL (HDL < 40 mg/dl) on the relationship between the genetic variants and T2D. A further validation step using data from the UK Biobank with 53,779 subjects was performed. Results: The association of T2D with both low HDL and family history of T2D increased with the age of control groups. T2D susceptibility variants (rs7756992, rs4712523 and rs10946403) were associated with T2D, more significantly with increased age of the control group. These variants had stronger effects on T2D risk when combined with low HDL cholesterol levels, especially in older control groups. Conclusions: The findings highlight a critical role of age, genetic predisposition, and HDL levels in T2D risk. The findings suggest that individuals over 70 years who have high HDL levels without the T2D susceptibility alleles may be at the lowest risk of developing T2D. These insights can inform tailored preventive strategies for older adults, enhancing personalized T2D risk assessments and interventions.
MeSH term(s)	Humans ; Aged ; Diabetes Mellitus, Type 2/genetics ; Alleles ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; Genetic Predisposition to Disease ; Cholesterol, HDL/genetics
Chemical Substances	Cholesterol, HDL
Language	English
Publishing date	2024-02-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2091381-3
ISSN	1476-511X ; 1476-511X
ISSN (online)	1476-511X
ISSN	1476-511X
DOI	10.1186/s12944-024-02039-7
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Article ; Online: Evidence for the druggability of aldosterone targets in heart failure: A bioinformatics and data science-driven decision-making approach.

Salgado Rezende de Mendonça, Lucas / Senar, Sergio / Moreira, Luana Lorena / Silva Júnior, José Antônio / Nader, Moni / Campos, Luciana Aparecida / Baltatu, Ovidiu Constantin

Computers in biology and medicine

2024 Volume 171, Page(s) 108124

Abstract: Background: Aldosterone plays a key role in the neurohormonal drive of heart failure. Systematic prioritization of drug targets using bioinformatics and database-driven decision-making can provide a competitive advantage in therapeutic R&D. This study ... ...

Abstract	Background: Aldosterone plays a key role in the neurohormonal drive of heart failure. Systematic prioritization of drug targets using bioinformatics and database-driven decision-making can provide a competitive advantage in therapeutic R&D. This study investigated the evidence on the druggability of these aldosterone targets in heart failure. Methods: The target disease predictability of mineralocorticoid receptors (MR) and aldosterone synthase (AS) in cardiac failure was evaluated using Open Targets target-disease association scores. The Open Targets database collections were downloaded to MongoDB and queried according to the desired aggregation level, and the results were retrieved from the Europe PMC (data type: text mining), ChEMBL (data type: drugs), Open Targets Genetics Portal (data type: genetic associations), and IMPC (data type: genetic associations) databases. The target tractability of MR and AS in the cardiovascular system was investigated by computing activity scores in a curated ChEMBL database using supervised machine learning. Results: The medians of the association scores of the MR and AS groups were similar, indicating a comparable predictability of the target disease. The median of the MR activity scores group was significantly lower than that of AS, indicating that AS has higher target tractability than MR [Hodges-Lehmann difference 0.62 (95%CI 0.53-0.70, p < 0.0001]. The cumulative distributions of the overall multiplatform association scores of cardiac diseases with MR were considerably higher than with AS, indicating more advanced investigations on a wider range of disorders evaluated for MR (Kolmogorov-Smirnov D = 0.36, p = 0.0009). In curated ChEMBL, MR had a higher cumulative distribution of activity scores in experimental cardiovascular assays than AS (Kolmogorov-Smirnov D = 0.23, p < 0.0001). Documented clinical trials for MR in heart failures surfaced in database searches, none for AS. Conclusions: Although its clinical development has lagged behind that of MR, our findings indicate that AS is a promising therapeutic target for the treatment of cardiac failure. The multiplatform-integrated identification used in this study allowed us to comprehensively explore the available scientific evidence on MR and AS for heart failure therapy.
MeSH term(s)	Humans ; Aldosterone ; Data Science ; Heart Failure/drug therapy ; Heart ; Enzyme Inhibitors ; Cardiotonic Agents ; Computational Biology
Chemical Substances	Aldosterone (4964P6T9RB) ; Enzyme Inhibitors ; Cardiotonic Agents
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	127557-4
ISSN	1879-0534 ; 0010-4825
ISSN (online)	1879-0534
ISSN	0010-4825
DOI	10.1016/j.compbiomed.2024.108124
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Article: Editorial: Trends post-COVID-19 attack: the cardiocerebral system safety remains of utmost concern.

Nader, Moni / Haddad, George / Elies, Jacobo / Kentamneni, Sriharsha / AlBadarin, Firas

Frontiers in physiology

2023 Volume 14, Page(s) 1224550

Language	English
Publishing date	2023-07-11
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1224550
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Article: Structural and Electrical Remodeling of the Sinoatrial Node in Diabetes: New Dimensions and Perspectives.

Al Kury, Lina T / Chacar, Stephanie / Alefishat, Eman / Khraibi, Ali A / Nader, Moni

Frontiers in endocrinology

2022 Volume 13, Page(s) 946313

Abstract: The sinoatrial node (SAN) is composed of highly specialized cells that mandate the spontaneous beating of the heart through self-generation of an action potential (AP). Despite this automaticity, the SAN is under the modulation of the autonomic nervous ... ...

Abstract	The sinoatrial node (SAN) is composed of highly specialized cells that mandate the spontaneous beating of the heart through self-generation of an action potential (AP). Despite this automaticity, the SAN is under the modulation of the autonomic nervous system (ANS). In diabetes mellitus (DM), heart rate variability (HRV) manifests as a hallmark of diabetic cardiomyopathy. This is paralleled by an impaired regulation of the ANS, and by a pathological remodeling of the pacemaker structure and function. The direct effect of diabetes on the molecular signatures underscoring this pathology remains ill-defined. The recent focus on the electrical currents of the SAN in diabetes revealed a repressed firing rate of the AP and an elongation of its tracing, along with conduction abnormalities and contractile failure. These changes are blamed on the decreased expression of ion transporters and cell-cell communication ports at the SAN (i.e., HCN4, calcium and potassium channels, connexins 40, 45, and 46) which further promotes arrhythmias. Molecular analysis crystallized the RGS4 (regulator of potassium currents), mitochondrial thioredoxin-2 (reactive oxygen species; ROS scavenger), and the calcium-dependent calmodulin kinase II (CaMKII) as metabolic culprits of relaying the pathological remodeling of the SAN cells (SANCs) structure and function. A special attention is given to the oxidation of CaMKII and the generation of ROS that induce cell damage and apoptosis of diabetic SANCs. Consequently, the diabetic SAN contains a reduced number of cells with significant infiltration of fibrotic tissues that further delay the conduction of the AP between the SANCs. Failure of a genuine generation of AP and conduction of their derivative waves to the neighboring atrial myocardium may also occur as a result of the anti-diabetic regiment (both acute and/or chronic treatments). All together, these changes pose a challenge in the field of cardiology and call for further investigations to understand the etiology of the structural/functional remodeling of the SANCs in diabetes. Such an understanding may lead to more adequate therapies that can optimize glycemic control and improve health-related outcomes in patients with diabetes.
MeSH term(s)	Atrial Remodeling ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/pharmacology ; Diabetes Mellitus ; Humans ; Reactive Oxygen Species/metabolism ; Sinoatrial Node/physiology
Chemical Substances	Reactive Oxygen Species ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-07-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2022.946313
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Article ; Online: Role of CaMKII in diabetes induced vascular injury and its interaction with anti-diabetes therapy.

Chacar, Stephanie / Abdi, Abdulhamid / Almansoori, Khalifa / Alshamsi, Jawaher / Al Hageh, Cynthia / Zalloua, Pierre / Khraibi, Ali A / Holt, Stephen G / Nader, Moni

Reviews in endocrine & metabolic disorders

2023 Volume 25, Issue 2, Page(s) 369–382

Abstract: Diabetes mellitus is a metabolic disorder denoted by chronic hyperglycemia that drives maladaptive structural changes and functional damage to the vasculature. Attenuation of this pathological remodeling of blood vessels remains an unmet target owing to ... ...

Abstract	Diabetes mellitus is a metabolic disorder denoted by chronic hyperglycemia that drives maladaptive structural changes and functional damage to the vasculature. Attenuation of this pathological remodeling of blood vessels remains an unmet target owing to paucity of information on the metabolic signatures of this process. Ca
MeSH term(s)	Animals ; Humans ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Vascular System Injuries ; Diabetes Mellitus ; Signal Transduction
Chemical Substances	Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
Language	English
Publishing date	2023-12-08
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2185718-0
ISSN	1573-2606 ; 1389-9155
ISSN (online)	1573-2606
ISSN	1389-9155
DOI	10.1007/s11154-023-09855-9
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Article: Striatin translocates to the cytosol of apoptotic cells and is proteolytically cleaved in a caspase 3-dependent manner.

Nader, Moni / Khalil, Bariaa / Kattuah, Wejdan / Dzimiri, Nduna / Bakheet, Dana

Heliyon

2020 Volume 6, Issue 9, Page(s) e04990

Abstract: Striatin (STRN) is a multivalent protein holding great therapeutic potentials in view of its interaction with dynamic partners implicated in apoptosis. Although striatin-3 and striatin-4, that share high structural similarities with STRN, have been ... ...

Abstract	Striatin (STRN) is a multivalent protein holding great therapeutic potentials in view of its interaction with dynamic partners implicated in apoptosis. Although striatin-3 and striatin-4, that share high structural similarities with STRN, have been linked to apoptosis, the dynamics of STRN in apoptotic cells remain unclear. Herein, we report that the amount of STRN (110 kDa) is reduced in apoptotic cells, in response to various chemotherapeutic agents, thereby yielding a major polypeptide fragment at ~65 kDa, and three minor products at lower molecular weights. While STRN siRNA reduced the 65 kDa derivative fragment, the overexpression of a Myc-tagged STRN precipitated a novel fragment that was detected slightly higher than 65 kDa (due to the Myc-DDK tag on the cleaved fragment), confirming the cleavage of STRN during apoptosis. Interestingly, STRN cleavage was abrogated by the general caspase inhibitor Z-VAD.fmk. Cell fractionation revealed that the STRN pool, mainly distributed in the non-cytosolic fragment of naïve cells, translocates to the cytosol where it is proteolytically cleaved during apoptosis. Interestingly, the ectopic expression of caspase 3 in MCF-7 cells (deprived of caspase 3) induced STRN cleavage under apoptotic conditions. Inhibition of caspase 3 (Ac-DEVD-CHO) conferred a dose-dependent protection against the proteolytic cleavage of STRN. Collectively, our data provide cogent proofs that STRN translocates to the cytosol where it undergoes proteolytic cleavage in a caspase 3-dependent manner during apoptosis. Thus, this study projects the cleavage of STRN as a novel marker for apoptosis to serve pharmacological strategies targeting this particular form of cell death.
Language	English
Publishing date	2020-09-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2020.e04990
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Article ; Online: Interaction of SARS-CoV-2 with cardiomyocytes: Insight into the underlying molecular mechanisms of cardiac injury and pharmacotherapy.

Abdi, Abdulhamid / AlOtaiby, Shahad / Badarin, Firas Al / Khraibi, Ali / Hamdan, Hamdan / Nader, Moni

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2021 Volume 146, Page(s) 112518

Abstract: SARS-CoV-2 causes respiratory illness with a spectrum of systemic complications. However, the mechanism for cardiac infection and cardiomyocyte injury in COVID-19 patients remains unclear. The current literature supports the notion that SARS-CoV-2 ... ...

Abstract	SARS-CoV-2 causes respiratory illness with a spectrum of systemic complications. However, the mechanism for cardiac infection and cardiomyocyte injury in COVID-19 patients remains unclear. The current literature supports the notion that SARS-CoV-2 particles access the heart either by the circulating blood cells or by extracellular vesicles, originating from the inflamed lungs, and encapsulating the virus along with its receptor (ACE2). Both cardiomyocytes and pericytes (coronary arteries) express the necessary accessory proteins for access of SARS-CoV-2 particles (i.e. ACE2, NRP-1, TMPRSS2, CD147, integrin α5β1, and CTSB/L). These proteins facilitate the SARS-CoV-2 interaction and entry into the pericytes and cardiomyocytes thus leading to cardiac manifestations. Subsequently, various signaling pathways are altered in the infected cardiomyocytes (i.e. increased ROS production, reduced contraction, impaired calcium homeostasis), causing cardiac dysfunction. The currently adopted pharmacotherapy in severe COVID-19 subjects exhibited side effects on the heart, often manifested by electrical abnormalities. Nonetheless, cardiovascular adverse repercussions have been associated with the advent of some of the SARS-CoV-2 vaccines with no clear mechanisms underlining these complications. We provide herein an overview of the pathways involved with cardiomyocyte in COVID-19 subjects to help promoting pharmacotherapies that can protect against SARS-CoV-2-induced cardiac injuries.
MeSH term(s)	Animals ; Antiviral Agents/administration & dosage ; Antiviral Agents/metabolism ; COVID-19/epidemiology ; COVID-19/metabolism ; COVID-19 Vaccines/administration & dosage ; COVID-19 Vaccines/metabolism ; Heart Diseases/drug therapy ; Heart Diseases/epidemiology ; Heart Diseases/metabolism ; Humans ; Myocardium/metabolism ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/metabolism ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; COVID-19 Vaccines
Language	English
Publishing date	2021-12-09
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2021.112518
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Article: Striatin translocates to the cytosol of apoptotic cells and is proteolytically cleaved in a caspase 3-dependent manner

Nader, Moni / Khalil, Bariaa / Kattuah, Wejdan / Dzimiri, Nduna / Bakheet, Dana

Heliyon. 2020 Sept., v. 6, no. 9

2020

Abstract	Striatin (STRN) is a multivalent protein holding great therapeutic potentials in view of its interaction with dynamic partners implicated in apoptosis. Although striatin-3 and striatin-4, that share high structural similarities with STRN, have been linked to apoptosis, the dynamics of STRN in apoptotic cells remain unclear. Herein, we report that the amount of STRN (110 kDa) is reduced in apoptotic cells, in response to various chemotherapeutic agents, thereby yielding a major polypeptide fragment at ~65 kDa, and three minor products at lower molecular weights. While STRN siRNA reduced the 65 kDa derivative fragment, the overexpression of a Myc-tagged STRN precipitated a novel fragment that was detected slightly higher than 65 kDa (due to the Myc-DDK tag on the cleaved fragment), confirming the cleavage of STRN during apoptosis. Interestingly, STRN cleavage was abrogated by the general caspase inhibitor Z-VAD.fmk. Cell fractionation revealed that the STRN pool, mainly distributed in the non-cytosolic fragment of naïve cells, translocates to the cytosol where it is proteolytically cleaved during apoptosis. Interestingly, the ectopic expression of caspase 3 in MCF-7 cells (deprived of caspase 3) induced STRN cleavage under apoptotic conditions. Inhibition of caspase 3 (Ac-DEVD-CHO) conferred a dose-dependent protection against the proteolytic cleavage of STRN. Collectively, our data provide cogent proofs that STRN translocates to the cytosol where it undergoes proteolytic cleavage in a caspase 3-dependent manner during apoptosis. Thus, this study projects the cleavage of STRN as a novel marker for apoptosis to serve pharmacological strategies targeting this particular form of cell death.
Keywords	apoptosis ; caspase-3 ; cell fractionation ; cytosol ; dose response ; drug therapy ; polypeptides ; proteolysis
Language	English
Dates of publication	2020-09
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2020.e04990
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