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Article: Butyrate protects and synergizes with nicotine against iron- and manganese-induced toxicities in cell culture: Implications for neurodegenerative diseases.

Tizabi, Yousef / Getachew, Bruk / Aschner, Michael

Research square

2023

Abstract: Toxic exposures to heavy metals, such as iron (Fe) and manganese (Mn), can result in long-range neurological diseases and are therefore of significant environmental and medical concerns. We have previously reported that damage to neuroblastoma-derived ... ...

Abstract	Toxic exposures to heavy metals, such as iron (Fe) and manganese (Mn), can result in long-range neurological diseases and are therefore of significant environmental and medical concerns. We have previously reported that damage to neuroblastoma-derived dopaminergic cells (SH-SY5Y) by both Fe and Mn could be prevented by pre-treatment with nicotine. Moreover, butyrate, a short chain fatty acid (SCFA) provided protection against salsolinol, a selective dopaminergic toxin, in the same cell line. Here, we broadened the investigation to determine whether butyrate might also protect against Fe and/or Mn, and whether, if combined with nicotine, an additive or synergistic effect might be observed. Both butyrate and nicotine concentration-dependently blocked Fe and Mn toxicities. The ineffective concentrations of nicotine and butyrate, when combined, provided full protection against both Fe and Mn. Moreover, the effects of nicotine but not butyrate could be blocked by mecamylamine, a non-selective nicotinic antagonist. On the other hand, the effects of butyrate, but not nicotine, could be blocked by beta-hydroxy butyrate, a fatty acid-3 receptor antagonist. These results not only provide further support for neuroprotective effects of both nicotine and butyrate but indicate distinct mechanisms of action for each one. Furthermore, potential utility of the combination of butyrate and nicotine against heavy metal toxicities is suggested.
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3389904/v1
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Article ; Online: Butyrate Protects and Synergizes with Nicotine against Iron- and Manganese-induced Toxicities in Cell Culture.

Tizabi, Yousef / Getachew, Bruk / Aschner, Michael

Neurotoxicity research

2023 Volume 42, Issue 1, Page(s) 3

Abstract	Toxic exposures to heavy metals, such as iron (Fe) and manganese (Mn), can result in long-range neurological diseases and are therefore of significant environmental and medical concerns. We have previously reported that damage to neuroblastoma-derived dopaminergic cells (SH-SY5Y) by both Fe and Mn could be prevented by pre-treatment with nicotine. Moreover, butyrate, a short chain fatty acid (SCFA) provided protection against salsolinol, a selective dopaminergic toxin, in the same cell line. Here, we broadened the investigation to determine whether butyrate might also protect against Fe and/or Mn, and whether, if combined with nicotine, an additive or synergistic effect might be observed. Both butyrate and nicotine concentration-dependently blocked Fe and Mn toxicities. Ineffective concentrations of nicotine and butyrate, when combined, provided full protection against both Fe and Mn. Moreover, the effects of nicotine but not butyrate could be blocked by mecamylamine, a non-selective nicotinic antagonist. On the other hand, the effects of butyrate, but not nicotine, could be blocked by beta-hydroxy butyrate, a fatty acid-3 receptor antagonist. These results not only provide further support for neuroprotective effects of both nicotine and butyrate but also indicate distinct mechanisms of action for each one. Furthermore, potential utility of butyrate and nicotine combination against heavy metal toxicities is suggested.
MeSH term(s)	Humans ; Nicotine/toxicity ; Manganese/toxicity ; Iron/toxicity ; Butyrates/pharmacology ; Cell Line, Tumor ; Neuroblastoma ; Cell Culture Techniques
Chemical Substances	Nicotine (6M3C89ZY6R) ; Manganese (42Z2K6ZL8P) ; Iron (E1UOL152H7) ; Butyrates
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036826-4
ISSN	1476-3524 ; 1029-8428
ISSN (online)	1476-3524
ISSN	1029-8428
DOI	10.1007/s12640-023-00682-z
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Article ; Online: Ivermectin as a potential therapeutic in COVID-19.

Segura-Aguilar, Juan / Tizabi, Yousef

Clinical pharmacology and translational medicine

2020 Volume 4, Issue 1, Page(s) 160–161

Language	English
Publishing date	2020-12-29
Publishing country	United States
Document type	Journal Article
ISSN	2572-7656
ISSN (online)	2572-7656
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Article ; Online: Vitamin D and COVID-19: Role of ACE2, age, gender, and ethnicity.

Getachew, Bruk / Tizabi, Yousef

Journal of medical virology

2021 Volume 93, Issue 9, Page(s) 5285–5294

Abstract: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, disproportionally targets older people, particularly men, ethnic minorities, and individuals with underlying diseases such as compromised ... ...

Abstract	Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, disproportionally targets older people, particularly men, ethnic minorities, and individuals with underlying diseases such as compromised immune system, cardiovascular disease, and diabetes. The discrepancy in COVID-19 incidence and severity is multifaceted and likely involves biological, social, as well as nutritional status. Vitamin D deficiency, notably common in Black and Brown people and elderly, is associated with an increased susceptibility to many of the diseases comorbid with COVID-19. Vitamin D deficiency can cause over-activation of the pulmonary renin-angiotensin system (RAS) leading to the respiratory syndrome. RAS is regulated in part at least by angiotensin-converting enzyme 2 (ACE2), which also acts as a primary receptor for SARS-CoV-2 entry into the cells. Hence, vitamin D deficiency can exacerbate COVID-19, via its effects on ACE2. In this review we focus on influence of age, gender, and ethnicity on vitamin D-ACE2 interaction and susceptibility to COVID-19.
MeSH term(s)	Age Factors ; Angiotensin-Converting Enzyme 2/immunology ; COVID-19/epidemiology ; Ethnicity ; Humans ; Risk Factors ; Sex Factors ; Vitamin D Deficiency
Chemical Substances	ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-05-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.27075
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Article ; Online: Adolescent alcohol drinking interaction with the gut microbiome: implications for adult alcohol use disorder.

Getachew, Bruk / Hauser, Sheketha R / Bennani, Samia / El Kouhen, Nacer / Sari, Youssef / Tizabi, Yousef

Advances in drug and alcohol research

2024 Volume 4

Abstract: Reciprocal communication between the gut microbiota and the brain, commonly referred to as the "gut-brain-axis" is crucial in maintaining overall physiological homeostasis. Gut microbiota development and brain maturation (neuronal connectivity and ... ...

Abstract	Reciprocal communication between the gut microbiota and the brain, commonly referred to as the "gut-brain-axis" is crucial in maintaining overall physiological homeostasis. Gut microbiota development and brain maturation (neuronal connectivity and plasticity) appear to be synchronized and to follow the same timeline during childhood (immature), adolescence (expansion) and adulthood (completion). It is important to note that the mesolimbic reward circuitry develops early on, whereas the maturation of the inhibitory frontal cortical neurons is delayed. This imbalance can lead to increased acquirement of reward-seeking and risk-taking behaviors during adolescence, and consequently eventuate in heightened risk for substance abuse. Thus, there is high initiation of alcohol drinking in early adolescence that significantly increases the risk of alcohol use disorder (AUD) in adulthood. The underlying causes for heightened AUD risk are not well understood. It is suggested that alcohol-associated gut microbiota impairment during adolescence plays a key role in AUD neurodevelopment in adulthood. Furthermore, alcohol-induced dysregulation of microglia, either directly or indirectly through interaction with gut microbiota, may be a critical neuroinflammatory pathway leading to neurodevelopmental impairments and AUD. In this review article, we highlight the influence of adolescent alcohol drinking on gut microbiota, gut-brain axis and microglia, and eventual manifestation of AUD. Furthermore, novel therapeutic interventions via gut microbiota manipulations are discussed briefly.
Language	English
Publishing date	2024-01-15
Publishing country	Switzerland
Document type	Journal Article
ISSN	2674-0001
ISSN (online)	2674-0001
DOI	10.3389/adar.2024.11881
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Article ; Online: Dihydromyricetin Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line: Role of GABA

Getachew, Bruk / Csoka, Antonei B / Tizabi, Yousef

Neurotoxicity research

2022 Volume 40, Issue 3, Page(s) 892–899

Abstract: Toxicity induced by binge alcohol drinking, particularly in adolescent and young adults, is of major medical and social consequence. Recently, we reported that butyrate, a short chain fatty acid, can protect against ethanol (ETOH)-induced toxicity in an ... ...

Abstract	Toxicity induced by binge alcohol drinking, particularly in adolescent and young adults, is of major medical and social consequence. Recently, we reported that butyrate, a short chain fatty acid, can protect against ethanol (ETOH)-induced toxicity in an in vitro model. In this study, we sought to evaluate the potential effectiveness of dihydromyricetin (DHM), a natural bioactive flavonoid, alone or in combination with butyrate in the same model. Exposure of SH-SY5Y cells for 24 h to 500 mM ETOH resulted in approximately 40% reduction in cell viability, which was completely prevented by 0.1 μM DHM. Combinations of DHM and butyrate provided synergistic protection against alcohol toxicity. Whereas butyrate effect was shown to be mediated primarily through fatty acid receptor 3 activation, DHM protection appears to be mediated primarily via benzodiazepine receptor site of GABA
MeSH term(s)	Butyrates ; Cell Line, Tumor ; Ethanol/toxicity ; Flavonols/pharmacology ; Humans ; Receptors, GABA-A/metabolism
Chemical Substances	Butyrates ; Flavonols ; Receptors, GABA-A ; Ethanol (3K9958V90M) ; dihydromyricetin (KD8QND6427)
Language	English
Publishing date	2022-04-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036826-4
ISSN	1476-3524 ; 1029-8428
ISSN (online)	1476-3524
ISSN	1029-8428
DOI	10.1007/s12640-022-00503-9
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Article ; Online: Duality of Antidepressants and Neuroprotectants.

Tizabi, Yousef

Neurotoxicity research

2015 Volume 30, Issue 1, Page(s) 1–13

Abstract: The co-morbidity of neuropsychiatric disorders, particularly major depressive disorder (MDD) with neurodegenerative diseases, in particular Parkinson's disease (PD) is now well recognized. Indeed, it is suggested that depressive disorders, especially in ... ...

Abstract	The co-morbidity of neuropsychiatric disorders, particularly major depressive disorder (MDD) with neurodegenerative diseases, in particular Parkinson's disease (PD) is now well recognized. Indeed, it is suggested that depressive disorders, especially in late life, may be an indication of latent neurodegeneration. Thus, it is not unreasonable to expect that deterrents of MDD may also deter the onset and/or progression of the neurodegenerative diseases including PD. In this review, examples of neuroprotective efficacy of established as well as prospective antidepressants are provided. Conversely, mood-regulating effects of some neuroprotective drugs are also presented. Thus, in addition to currently used antidepressants, ketamine, nicotine, curcumin, and resveratrol are discussed for their dual efficacy. In addition, potential neurobiological substrates for their actions are presented. It is concluded that pharmacological developments of mood-regulating or neuroprotective drugs can have cross benefit in co-morbid conditions of neuropsychiatric and neurodegenerative disorders and that inflammatory and neurotrophic factors play important roles in both conditions.
MeSH term(s)	Animals ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Comorbidity ; Depressive Disorder, Major/drug therapy ; Depressive Disorder, Major/epidemiology ; Depressive Disorder, Major/physiopathology ; Humans ; Inflammation Mediators/physiology ; Nerve Growth Factors/physiology ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/epidemiology ; Neurodegenerative Diseases/physiopathology ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use
Chemical Substances	Antidepressive Agents ; Inflammation Mediators ; Nerve Growth Factors ; Neuroprotective Agents
Language	English
Publishing date	2015-11-27
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2036826-4
ISSN	1476-3524 ; 1029-8428
ISSN (online)	1476-3524
ISSN	1029-8428
DOI	10.1007/s12640-015-9577-1
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Article ; Online: COVID-19-associated Coagulopathy: Role of Vitamins D and K.

Getachew, Bruk / Landis, Harold E / Manaye, Kebreten F / Tizabi, Yousef

Current pharmaceutical biotechnology

2022 Volume 24, Issue 3, Page(s) 401–410

Abstract: Recent reports show coagulopathy as a potential complication and poorer outcome of coronavirus disease 2019 (COVID-19), especially in those with comorbid conditions such as diabetes and hypertension as thrombosis could result in stroke and heart attacks. ...

Abstract	Recent reports show coagulopathy as a potential complication and poorer outcome of coronavirus disease 2019 (COVID-19), especially in those with comorbid conditions such as diabetes and hypertension as thrombosis could result in stroke and heart attacks. Indeed, cardiovascular complications in COVID-19 account for 40% of mortality. Although there is no standard treatment protocol or guidelines for COVID-19, it is a common practice to use anti-inflammatory corticosteroids and anti-coagulants, especially for severe COVID-19 patients. It has also been confirmed that deficiencies of vitamin D and/or vitamin K can exacerbate premorbid cardiovascular and diabetes conditions associated with COVID-19, at least partially due to a higher incidence of coagulopathy. Here, we discuss the roles of vitamins D and K in general and in COVID-19-related coagulopathy. Moreover, the suggestion for proper supplementations of these vitamins in countering COVID-19 is provided.
MeSH term(s)	Humans ; COVID-19/complications ; SARS-CoV-2 ; Vitamin A ; Vitamins/therapeutic use ; Vitamin D/therapeutic use
Chemical Substances	Vitamin A (11103-57-4) ; Vitamins ; Vitamin D (1406-16-2)
Language	English
Publishing date	2022-09-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2132197-8
ISSN	1873-4316 ; 1389-2010
ISSN (online)	1873-4316
ISSN	1389-2010
DOI	10.2174/1389201023666220527110455
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Article ; Online: Botulinum Neurotoxin, an Example of Successful Translational Research.

Segura-Aguilar, Juan / Tizabi, Yousef

Clinical pharmacology and translational medicine

2018 Volume 2, Issue 3, Page(s) 125–126

Language	English
Publishing date	2018-10-19
Publishing country	United States
Document type	Journal Article
ISSN	2572-7656
ISSN (online)	2572-7656
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Article ; Online: Interaction of Heavy Metal Lead with Gut Microbiota: Implications for Autism Spectrum Disorder.

Tizabi, Yousef / Bennani, Samia / El Kouhen, Nacer / Getachew, Bruk / Aschner, Michael

Biomolecules

2023 Volume 13, Issue 10

Abstract: Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by persistent deficits in social interaction and communication, manifests in early childhood and is followed by restricted and stereotyped behaviors, interests, or activities in ... ...

Abstract	Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by persistent deficits in social interaction and communication, manifests in early childhood and is followed by restricted and stereotyped behaviors, interests, or activities in adolescence and adulthood (DSM-V). Although genetics and environmental factors have been implicated, the exact causes of ASD have yet to be fully characterized. New evidence suggests that dysbiosis or perturbation in gut microbiota (GM) and exposure to lead (Pb) may play important roles in ASD etiology. Pb is a toxic heavy metal that has been linked to a wide range of negative health outcomes, including anemia, encephalopathy, gastroenteric diseases, and, more importantly, cognitive and behavioral problems inherent to ASD. Pb exposure can disrupt GM, which is essential for maintaining overall health. GM, consisting of trillions of microorganisms, has been shown to play a crucial role in the development of various physiological and psychological functions. GM interacts with the brain in a bidirectional manner referred to as the "Gut-Brain Axis (GBA)". In this review, following a general overview of ASD and GM, the interaction of Pb with GM in the context of ASD is emphasized. The potential exploitation of this interaction for therapeutic purposes is also touched upon.
MeSH term(s)	Adolescent ; Humans ; Child, Preschool ; Gastrointestinal Microbiome ; Lead/toxicity ; Autism Spectrum Disorder/etiology ; Brain ; Brain Diseases
Chemical Substances	Lead (2P299V784P)
Language	English
Publishing date	2023-10-19
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13101549
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