scholarly journals Attenuation of inhibitory PAS domain protein-induced cell death by synthetic peptides derived from Mcl-1 transmenbrane domain

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuya Kasai ◽  
Ken-ichi Yasumoto ◽  
Kazuhiro Sogawa
Keyword(s):  
Cell Death ◽  
Synthetic Peptides ◽  
Specific Binding ◽  
Neuronal Cell ◽  
Chimeric Protein ◽  
Substantia Nigra Pars Compacta ◽  
Pas Domain ◽  
Domain Protein ◽  
Tm Domain ◽  
Apoptotic Activity

AbstractExpression of Inhibitory PAS domain protein (IPAS) induces apoptosis by inhibiting the anti-apoptotic activity of mitochondrial pro-survival proteins including Bcl-xL and Mcl-1 through direct binding. Analysis to examine the IPAS-binding region in Bcl-xL demonstrated that the C-terminal transmembrane (TM) domain is indispensable for the specific binding. A chimeric protein composed of the TM domain of Mcl-1 fused to the C-terminus of Citrine also exhibited a binding affinity to IPAS, and markedly attenuated apoptosis caused by the overexpression of Cerulean-IPAS in SH-SY5Y cells. HIV-1 TAT cell-penetrating peptide-conjugated synthetic peptides that cover whole or parts of the Mcl-1 TM domain showed anti-apoptotic activity in the CoCl2-induced cell death in PC12 cells. Administration of these highly effective anti-apoptotic peptides to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that produces a reliable mouse model of Parkinson’s disease (PD) decreased neuronal cell loss in the substantia nigra pars compacta. Therefore, the peptides may be considered promising therapeutic agents for neurodegenerative disorders such as PD and stroke.

scholarly journals Modulating the Pro-apoptotic Activity of Cytochrome c at a Biomimetic Electrified Interface

2021 ◽  
Author(s):  
Alonso Gamero-Quijano ◽  
Shayon Bhattacharya ◽  
Pierre-André Cazade ◽  
Andrés F. Molina-Osorio ◽  
Cillian Beecher ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Inner Mitochondrial Membrane ◽  
Foetal Development ◽  
Drug Molecules ◽  
Electrified Interface ◽  
Conformational Plasticity ◽  
Apoptotic Activity

<p>Programmed cell death <i>via</i> apoptosis is a natural defence against excessive cell division, crucial at all stages of life from foetal development to maintenance of homeostasis and elimination of precancerous and senescent cells. Here we demonstrate an electrified liquid bio-interface that replicates the molecular machinery of the inner mitochondrial membrane at the onset of apoptosis. By mimicking <i>in vivo</i> cytochrome <i>c</i> (Cyt <i>c</i>) interactions with cell membranes, our platform allows us to modulate the conformational plasticity of the protein by simply varying the electrochemical environment at an aqueous|organic interface. As proof-of-concept, we use our electrified liquid bio-interface to identify drug molecules that can potentially downregulate Cyt <i>c</i> and protect against uncontrolled neuronal cell death in Alzheimer’s disease and other neurodegenerative disorders.</p>

scholarly journals Comparison of the Neuroapoptotic Properties of Equipotent Anesthetic Concentrations of Desflurane, Isoflurane, or Sevoflurane in Neonatal Mice

2011 ◽  
Vol 114 (3) ◽  
pp. 578-587 ◽  
Author(s):  
George K. Istaphanous ◽  
Jennifer Howard ◽  
Xinyu Nan ◽  
Elizabeth A. Hughes ◽  
John C. McCann ◽  
...  
Keyword(s):  
Cell Death ◽  
Prolonged Exposure ◽  
Minimum Alveolar Concentration ◽  
Neuronal Cell Death ◽  
Pediatric Anesthesia ◽  
Neuronal Cell ◽  
Newborn Mice ◽  
Neonatal Mice ◽  
Apoptotic Activity ◽  
To Receive

Background Volatile anesthetics facilitate surgical procedures and imaging studies in millions of children every year. Neuronal cell death after prolonged exposure to isoflurane in developing animals has raised serious concerns regarding its safe use in children. Although sevoflurane and desflurane are becoming more popular for pediatric anesthesia, their cytotoxic effects have not been compared with those of isoflurane. Accordingly, using newborn mice, the current study established the respective potencies of desflurane, isoflurane, and sevoflurane and then compared equipotent doses of these anesthetics regarding their effects on cortical neuroapoptosis. Methods Minimum alveolar concentrations were determined in littermates (aged 7-8 days, n = 42) using tail-clamp stimulation in a bracketing study design. By using equipotent doses of approximately 0.6 minimum alveolar concentration, another group of littermates was randomly assigned to receive desflurane, isoflurane, or sevoflurane or to fast in room air for 6 h. After exposure, animals (n = 47) were euthanized, neocortical apoptotic neuronal cell death was quantified, and caspase 3 activity was compared between the four groups. Results The minimum alveolar concentration was determined to be 12.2% for desflurane, 2.7% for isoflurane, and 5.4% for sevoflurane. After a 6-h exposure to approximately 0.6 minimum alveolar concentration of desflurane, isoflurane, or sevoflurane, neuronal cell death and apoptotic activity were significantly increased, irrespective of the specific anesthetic used. Conclusions In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents.

scholarly journals Modulating the Pro-apoptotic Activity of Cytochrome c at a Biomimetic Electrified Interface

2021 ◽  
Author(s):  
Alonso Gamero-Quijano ◽  
Shayon Bhattacharya ◽  
Pierre-André Cazade ◽  
Andrés F. Molina-Osorio ◽  
Cillian Beecher ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Inner Mitochondrial Membrane ◽  
Foetal Development ◽  
Drug Molecules ◽  
Electrified Interface ◽  
Conformational Plasticity ◽  
Apoptotic Activity

<p>Programmed cell death <i>via</i> apoptosis is a natural defence against excessive cell division, crucial at all stages of life from foetal development to maintenance of homeostasis and elimination of precancerous and senescent cells. Here we demonstrate an electrified liquid bio-interface that replicates the molecular machinery of the inner mitochondrial membrane at the onset of apoptosis. By mimicking <i>in vivo</i> cytochrome <i>c</i> (Cyt <i>c</i>) interactions with cell membranes, our platform allows us to modulate the conformational plasticity of the protein by simply varying the electrochemical environment at an aqueous|organic interface. As proof-of-concept, we use our electrified liquid bio-interface to identify drug molecules that can potentially downregulate Cyt <i>c</i> and protect against uncontrolled neuronal cell death in Alzheimer’s disease and other neurodegenerative disorders.</p>

scholarly journals Pilose Antler Extracts (PAEs) Protect against Neurodegeneration in 6-OHDA-Induced Parkinson’s Disease Rat Models

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Chaohua Li ◽  
Yanan Sun ◽  
Weifeng Yang ◽  
Shuhua Ma ◽  
Lili Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Neuronal Cell Death ◽  
Amino Acid Level ◽  
Neuronal Cell ◽  
Motor Dysfunction ◽  
Substantia Nigra Pars Compacta ◽  
Intragastric Administration ◽  
Rat Models

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide. Although dopamine replacement therapy mitigates motor dysfunction in PD patients, there are no therapeutics that are currently available to reverse neuronal cell death in the substantia nigra pars compacta (SNc), which is the main region for dopamine loss in PD patients. The protein concentration of the Pilose antler extracts (PAEs) was estimated using the Bradford Protein Assay Kit. Hematoxylin and eosin (HE) staining was used to evaluate the protective effect of PAEs on 6-OHDA induced cell death in PD model rats. Immunohistochemistry (IHC) was used to detect the tyrosine hydroxylase (TH) positive neuronal cell in SNc. HPLC-MS was used to detect dopamine (DA), 3,4-Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and glutamate (Glu) levels in the striatum and cerebrospinal fluid (CSF). The amino acid level in the striatum and CSF was measured by HPLC-FLD. Protein expression of growth associated protein-43 (GAP-43) and neurofilament heavy polypeptide (NF-H) was measured using western blotting. The components of PAEs through blood vessels were detected by HPLC/MS/MS. In this study, PAEs with proteins ranging from 10 kDa to 250 kDa molecular weight was administered to 6-OHDA-induced PD rats. We found that PAEs inhibited 6-OHDA-induced neuronal cell death and TH-positive neuronal loss in SNc. PAEs administration also increased the levels of DA, DOPAC, and 5-HT, in addition to DOPAC/DA and HVA/DA indexes in the CSF and Striatum of 6-OHDA induced rats. Conversely, PAEs decreased the levels of Glu and GABA. Treatment with PAEs and Madopar increased GAP-43 and NF-H expression in the SNc and striatum. Proteomic analysis using LC/MS/MS indicated that 11 components of PAEs may have neuropharmacological effects. These results demonstrate that PAEs protects against 6-OHDA induced toxic effects in the PD rat models. Intragastric administration of PAEs may be a novel therapeutic strategy for neurodegenerative disorders like PD.

Sign in / Sign up

Export Citation Format

Share Document