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Article: Targeting the Cysteine Redox Proteome in Parkinson's Disease: The Role of Glutathione Precursors and Beyond.

Martinez-Banaclocha, Marcos A

2023 Volume 12, Issue 7

Abstract: Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and ... ...

Abstract	Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson's disease.
Language	English
Publishing date	2023-06-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12071373
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: N

Martinez-Banaclocha, Marcos

Antioxidants (Basel, Switzerland)

2022 Volume 11, Issue 2

Abstract: In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic ... ...

Abstract	In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of
Language	English
Publishing date	2022-02-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11020416
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Article ; Online: N-acetyl-cysteine in Schizophrenia: Potential Role on the Sensitive Cysteine Proteome.

Martínez-Banaclocha, Marcos

Current medicinal chemistry

2020 Volume 27, Issue 37, Page(s) 6424–6439

Abstract: Background: N-acetyl-cysteine (NAC) has shown widespread utility in different psychiatric disorders, including a beneficial role in schizophrenic patients. Although the replenishment of glutathione and the antioxidant activity of NAC have been suggested ...

Abstract	Background: N-acetyl-cysteine (NAC) has shown widespread utility in different psychiatric disorders, including a beneficial role in schizophrenic patients. Although the replenishment of glutathione and the antioxidant activity of NAC have been suggested as the mechanisms that improve such a wide range of disorders, none seems to be sufficiently specific to explain these intriguing effects. A sensitive cysteine proteome is emerging as a functional and structural network of interconnected Sensitive Cysteine-containing Proteins (SCCPs) that together with reactive species and the cysteine/ glutathione cycles can regulate the bioenergetic metabolism, the redox homeostasis and the cellular growth, differentiation and survival, acting through different pathways that are regulated by the same thiol radical in cysteine residues. Objective: Since this sensitive cysteine network has been implicated in the pathogenesis of Parkinson's and Alzheimer's diseases, I have reviewed if the proteins that play a role in schizophrenia can be classified as SCCPs. Results: The results show that the principal proteins playing a role in schizophrenia can be classified as SCCPs, suggesting that the sensitive cysteine proteome (cysteinet) is defective in this type of psychosis. Conclusion: The present review proposes that there is a deregulation of the sensitive cysteine proteome in schizophrenia as the consequence of a functional imbalance among different SCCPs, which play different functions in neurons and glial cells. In this context, the role of NAC to restore and prevent schizophrenic disorders is discussed.
MeSH term(s)	Acetylcysteine/pharmacology ; Antioxidants ; Cysteine/metabolism ; Glutathione/metabolism ; Humans ; Oxidation-Reduction ; Proteome ; Schizophrenia/drug therapy
Chemical Substances	Antioxidants ; Proteome ; Glutathione (GAN16C9B8O) ; Cysteine (K848JZ4886) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2020-10-26
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867326666191015091346
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Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Targeting the Cysteine Redox Proteome in Parkinson’s Disease: The Role of Glutathione Precursors and Beyond

Martinez-Banaclocha, Marcos A.

Antioxidants. 2023 June 30, v. 12, no. 7

2023

Abstract	Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson’s disease.
Keywords	DNA replication ; Lewis bases ; active sites ; antioxidants ; cell communication ; cell senescence ; cysteine ; disulfides ; epigenetics ; glutathione ; ligands ; neurodegenerative diseases ; nucleotide sequences ; proteome ; stem cells ; telomeres ; therapeutics ; thiols ; transcription (genetics)
Language	English
Dates of publication	2023-0630
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12071373
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Interfering with the Reactive Cysteine Proteome in COVID-19.

Martinez-Banaclocha, Marcos

Current medicinal chemistry

2021 Volume 29, Issue 10, Page(s) 1657–1663

Abstract: Although vaccination against SARS-CoV-2 infection has been initiated, effective therapies for severe COVID-19 disease are still needed. A promising therapeutic strategy is using FDA-approved drugs that have the biological potential to interfere with or ... ...

Abstract	Although vaccination against SARS-CoV-2 infection has been initiated, effective therapies for severe COVID-19 disease are still needed. A promising therapeutic strategy is using FDA-approved drugs that have the biological potential to interfere with or modify some of the viral proteins capable of changing the disease's course. Recent studies highlight that some clinically safe drugs can suppress the viral life cycle while potentially promoting an adequate host inflammatory/immune response by interfering with the disease's cysteine proteome.
MeSH term(s)	COVID-19 ; Cysteine ; Humans ; Immunity ; Proteome ; SARS-CoV-2
Chemical Substances	Proteome ; Cysteine (K848JZ4886)
Language	English
Publishing date	2021-06-24
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867328666210623142811
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ab Jg. 2022: Lesesaal (EG)

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Article: N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

Martinez-Banaclocha, Marcos

Antioxidants. 2022 Feb. 18, v. 11, no. 2

2022

Abstract	In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.
Keywords	blood ; cognitive disorders ; cysteine ; diet ; disease progression ; early diagnosis ; evolution ; genomics ; glutathione ; pandemic ; pathophysiology ; prognosis ; proteome ; proteomics ; quality of life ; risk ; therapeutics
Language	English
Dates of publication	2022-0218
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11020416
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Astroglial Isopotentiality and Calcium-Associated Biomagnetic Field Effects on Cortical Neuronal Coupling.

Martinez-Banaclocha, Marcos

Cells

2020 Volume 9, Issue 2

Abstract: ... stable among neighboring and distant astrocytes due to the marked bioelectric coupling between ...

Abstract	Synaptic neurotransmission is necessary but does not sufficiently explain superior cognitive faculties. Growing evidence has shown that neuron-astroglial chemical crosstalk plays a critical role in the processing of information, computation, and memory. In addition to chemical and electrical communication among neurons and between neurons and astrocytes, other nonsynaptic mechanisms called ephaptic interactions can contribute to the neuronal synchronization from different brain regions involved in the processing of information. New research on brain astrocytes has clearly shown that the membrane potential of these cells remains very stable among neighboring and distant astrocytes due to the marked bioelectric coupling between them through gap junctions. This finding raises the possibility that the neocortical astroglial network exerts a guiding template modulating the excitability and synchronization of trillions of neurons by astroglial Ca
MeSH term(s)	Astrocytes/metabolism ; Calcium/metabolism ; Cerebral Cortex/metabolism ; Humans ; Neurons/metabolism
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-02-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9020439
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Article ; Online: Proteomic Complexity in Parkinson's Disease: A Redox Signaling Perspective of the Pathophysiology and Progression.

Martinez-Banaclocha, Marcos

Neuroscience

2020 Volume 453, Page(s) 287–300

Abstract: Parkinson's disease (PD) is a prevalent age-related neurodegenerative disorder that results in the progressive impairment of motor and cognitive functions. The majority of PD cases are sporadic, and only 5% of patients are associated with mutations in a ... ...

Abstract	Parkinson's disease (PD) is a prevalent age-related neurodegenerative disorder that results in the progressive impairment of motor and cognitive functions. The majority of PD cases are sporadic, and only 5% of patients are associated with mutations in a few genes, which cause the early onset or familial PD. Environmental toxic substances and the individual genetic susceptibility play a role in sporadic cases, but despite significant efforts to treat and prevent the disease, the pathophysiological mechanisms leading to its onset and progress are not fully understood. In the last decade, genomic and proteomic studies have shown an increasing molecular complexity of sporadic PD, suggesting that a broad spectrum of biochemical pathways underlie its progression. Recent investigations and the literature review suggest the potential role of deregulation of the sensitive-cysteine proteome as a convergent pathogenic mechanism that may contribute to this complexity, opening new therapeutic opportunities.
MeSH term(s)	Genetic Predisposition to Disease ; Humans ; Mutation ; Oxidation-Reduction ; Parkinson Disease/genetics ; Proteomics ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2020-11-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2020.11.006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1215: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Potential Role of N-Acetyl-Cysteine in the Cysteine Proteome in Parkinson's Disease?

Martinez-Banaclocha, Marcos A

Clinical pharmacology and therapeutics

2019 Volume 107, Issue 5, Page(s) 1055

MeSH term(s)	Acetylcysteine ; Dopamine ; Humans ; Parkinson Disease/drug therapy ; Proteome
Chemical Substances	Proteome ; Dopamine (VTD58H1Z2X) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2019-12-10
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1709
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Zs.A 20: Show issues

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Article ; Online: Cysteinet Dysregulation in Muscular Dystrophies: A Pathogenic Network Susceptible to Therapy.

Martínez-Banaclocha, Marcos Arturo

Current medicinal chemistry

2017 Volume 24, Issue 3, Page(s) 312–330

Abstract: Background: Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious ...

Abstract	Background: Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group. Objective: Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies. Conclusion: The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.
MeSH term(s)	Acetylcysteine/pharmacokinetics ; Acetylcysteine/pharmacology ; Acetylcysteine/therapeutic use ; Animals ; Cysteine/metabolism ; Humans ; Muscular Dystrophies/drug therapy ; Muscular Dystrophies/metabolism ; Muscular Dystrophies/therapy
Chemical Substances	Cysteine (K848JZ4886) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2017
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867323666161129124549
Database	MEDical Literature Analysis and Retrieval System OnLINE

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