scholarly journals ROS networks: designs, aging, Parkinson’s disease and precision therapies

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Alexey N. Kolodkin ◽  
Raju Prasad Sharma ◽  
Anna Maria Colangelo ◽  
Andrew Ignatenko ◽  
Francesca Martorana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Data Sets ◽  
Control Coefficient ◽  
Molecular Processes ◽  
Time Control ◽  
Vitro Data ◽  
In Vitro Data

Abstract How the network around ROS protects against oxidative stress and Parkinson’s disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for “life-extending interventions”: mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.

scholarly journals 3-Amidinophenylalanine-derived matriptase inhibitors can modulate hepcidin production in vitro

2019 ◽  
Vol 393 (3) ◽  
pp. 511-520
Author(s):  
Erzsébet Pászti-Gere ◽  
Gergely Szombath ◽  
Michael Gütschow ◽  
Torsten Steinmetzer ◽  
András Székács
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Cultures ◽  
Iron Homeostasis ◽  
Binding Mode ◽  
Type Ii ◽  
Transmembrane Serine Protease ◽  
Vitro Data ◽  
In Vitro Data

Abstract Matriptase-2 (MT-2) is a type II transmembrane serine protease and predominantly attached to the surface of hepatocytes. MT-2 decreases the production of hepcidin, a key regulator of iron homeostasis. In this study, the effects of four 3-amidinophenylalanine-derived combined matriptase-1/matriptase-2 (MT-1/2) inhibitors (MI-432, MI-441, MI-460, and MI-461) on hepcidin production were investigated in hepatocyte mono- and hepatocyte-Kupffer cell co-cultures. In MI-461-treated cell cultures, the extracellular hydrogen peroxide contents and the interleukin-6 and -8 (IL-6 and IL-8) levels were determined and compared to controls. Hepcidin overproduction was observed in hepatocytes upon treatment with MI-432, MI-441 and MI-461 at 50 μM. In contrast, extracellular hydrogen peroxide levels were not elevated significantly after matriptase inhibition with MI-461. Furthermore, MI-461 did not induce increases in IL-6 and IL-8 levels in these hepatic models. A model of the binding mode of inhibitor MI-461 in complex with MT-2 revealed numerous polar contacts contributing to the nanomolar potency of this compound. Based on the in vitro data on hepcidin regulation, treatment with MI-461 might be valuable in pathological states of iron metabolism without causing excessive oxidative stress.

scholarly journals Hesperetin protects SH-SY5Y cells against 6- hydroxydopamine-induced neurotoxicity via activation of NRF2/ARE signaling pathways

2020 ◽  
Vol 19 (6) ◽  
pp. 1197-1201 ◽  
Author(s):  
Jing Li ◽  
Yue Liu ◽  
Li Wang ◽  
Zhaowei Gu ◽  
Zhigang Huan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Viability ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Ldh Release ◽  
6 Hydroxydopamine

Purpose: To investigation the protective effects of hesperetin against 6-hydroxydopamine (6-OHDA)- induced neurotoxicity. Methods: SH-SY5Y cells were incubated with 6-OHDA to create an in vitro model of neurotoxicity. This model was used to test the neuroprotective effects of hesperetin. Cell viability was assessed by MTT and lactate dehydrogenase (LDH) release assays. Flow cytometry and western blot were used to quantify apoptosis. Oxidative stress was evaluated by determining intracellular glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS). Results: In SH-SY5Y cells, treatment with 6-OHDA decreased cell viability and promoted LDH release. However, exogenous hesperetin protected against 6-OHDA-mediated toxicity. Similarly, although incubation with 6-OHDA induced apoptosis and increased cleaved caspase-3 and -9 levels, treatment with hesperetin protected against these effects. Treatment with 6-OHDA also led to significant oxidative stress, as indicated by reduced GSH and SOD levels and increased MDA and ROS levels in SH-SY5Y cells. However, these changes were reversed by pre-treatment with hesperetin. Of interest, hesperetin led to changes in 6-OHDA-induced expression of NRF2, heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCL) catalytic subunit (GCLC), and GCL modulatory (GCLM). Conclusion: Hesperetin protects against cell toxicity, apoptosis, and oxidative stress via activation of NRF2 pathway in a 6-OHDA-induced model of neurotoxicity. Future studies should investigate the use of hesperetin as a potential therapeutic approach for prevention or management of Parkinson’s disease. Keywords: Hesperetin, 6-OHDA, Neurotoxicity, NRF2, Parkinson’s disease

Molecular simulation studies of Alpha Pinene, an alkene in search for oxidative stress targeted therapeutic paradigms for the treatment of Parkinson’s disease: A computational approach and its in-vitro antioxidant validation

2021 ◽  
Vol 18 ◽  
Author(s):  
Rajnish Srivastava ◽  
Pratim Kumar Choudhury ◽  
Suresh Kumar Dev ◽  
Vaibhav Rathore
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Energy ◽  
Molecular Interaction ◽  
Hypochlorous Acid ◽  
Cell Degeneration ◽  
Mao B ◽  
Alpha Pinene

Aim: The present study was expected to explore the molecular interaction of five oxidative stress (OS) associated target receptors with Alpha-Pinene and its antioxidant validation for the effective treatment of Parkinson’s disease (PD). Background: Oxidative stress (OS) via multitudinous cascades is considered to be the leading attribute to dopaminergic cell degeneration in PD. Furthermore, it is also well-linked to other mechanisms involved in the neurodegeneration process, like dysfunction of mitochondria, neuroinflammation and excitotoxicity due to NO. Objective: The present investigation was to establish a molecular association of OS-associated target receptors with the bioactive compound alpha-pinene and how this molecular interaction empowers the mitigation of PD. Material and Method: Five different molecular targets namely Peroxisome Proliferator-Activated Receptor- Gamma (PPARγ), Liver-X receptor beta (LXR- β), Human Monoamine Oxidase-B (MAO-B), Human Nuclear receptor related-1 protein (Nurr1) and Human Lipoprotein-associated phospholipase A2 (Lp-PLA2) were obtained from RCSB-PDB, which has some leading association in the inhibition of the OS-induced neurodegeneration. Molecular interactions were stuffed by the simulation molecular docking software. Antioxidant activity was validated by in-vitro models as per standardized procedures against 2,2- diphenyl-1- picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline -6-sulfonic acid) (ABTS), Ferric ion (Fe3+), Hydroxyl (•OH), nitric oxide (•NO), Peroxynitrite (ONOO-) and Hypochlorous acid (HOCl). Result: Our results indicated that alpha-pinene can interact with all the five different target receptors at the active binding site of receptors. Alpha-pinene was found to show better interaction with MAO-B, Nurr1 and PPARγ with binding energy of -5.50, -4.52 and -5.25, respectively as compared to the native ligand. Furthermore, the interaction of alpha-pinene with LXR-β and Lp-PLA2 was also significant with binding energy of -5.6 and -5.12, respectively. It also capable of neutralizing all the different free radicals under consideration with significant IC50 values against HOCl and •NO. Conclusion: It might be concluded that alpha-pinene could act as a potential inhibitor and scavenger of OS which could act on the multiple target receptors under consideration.

Evaluation of Levodopa and Carbidopa Antioxidant Activity in Normal Human Lymphocytes In Vitro: Implication for Oxidative Stress in Parkinson’s Disease

2014 ◽  
Vol 27 (2) ◽  
pp. 106-117 ◽  
Author(s):  
Monica Colamartino ◽  
Massimo Santoro ◽  
Guglielmo Duranti ◽  
Stefania Sabatini ◽  
Roberta Ceci ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Antioxidant Activity ◽  
Parkinson's Disease ◽  
Human Lymphocytes ◽  
Normal Human

scholarly journals Protective Mechanisms of Flavonoids in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Kasthuri Bai Magalingam ◽  
Ammu Kutty Radhakrishnan ◽  
Nagaraja Haleagrahara
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorder ◽  
Dopaminergic Neurons ◽  
Target Therapy ◽  
Cellular Damage ◽  
Substantia Nigra Pars Compacta ◽  
Protective Mechanisms

Parkinson’s disease is a chronic, debilitating neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in thesubstantia nigra pars compactaregion in human midbrain. To date, oxidative stress is the well accepted concept in the etiology and progression of Parkinson’s disease. Hence, the therapeutic agent is targeted against suppressing and alleviating the oxidative stress-induced cellular damage. Within the past decades, an explosion of research discoveries has reported on the protective mechanisms of flavonoids, which are plant-based polyphenols, in the treatment of neurodegenerative disease using bothin vitroandin vivomodels. In this paper, we have reviewed the literature on the neuroprotective mechanisms of flavonoids in protecting the dopaminergic neurons hence reducing the symptoms of this movement disorder. The mechanism reviewed includes effect of flavonoids in activation of endogenous antioxidant enzymes, suppressing the lipid peroxidation, inhibition of inflammatory mediators, flavonoids as a mitochondrial target therapy, and modulation of gene expression in neuronal cells.

scholarly journals Norfluoxetine Prevents Degeneration of Dopamine Neurons by Inhibiting Microglia-Derived Oxidative Stress in an MPTP Mouse Model of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Kyung In Kim ◽  
Young Cheul Chung ◽  
Byung Kwan Jin
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Microglial Activation ◽  
Dopamine Neurons ◽  
Activated Microglia ◽  
Nigrostriatal Dopamine Neurons

Neuroinflammation is the neuropathological feature of Parkinson’s disease (PD) and causes microglial activation and activated microglia-derived oxidative stress in the PD patients and PD animal models, resulting in neurodegeneration. The present study examined whether norfluoxetine (a metabolite of fluoxetine) could regulate neuroinflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD and rescue dopamine neurons. Analysis by tyrosine hydroxylase (TH) immunohistochemistry demonstrated that norfluoxetine prevents degeneration of nigrostriatal dopamine neurons in vivo in MPTP-lesioned mice compared to vehicle-treated MPTP-lesioned control mice. MAC-1 immunostaining and hydroethidine histochemical staining showed that norfluoxetine neuroprotection is accompanied by inhibiting MPTP-induced microglial activation and activated microglia-derived reactive oxygen species production in vivo, respectively. In the separate experiments, treatment with norfluoxetine inhibited NADPH oxidase activation and nitrate production in LPS-treated cortical microglial cultures in vitro. Collectively, these in vivo and in vitro results suggest that norfluoxetine could be employed as a novel therapeutic agent for treating PD, which is associated with neuroinflammation and microglia-derived oxidative stress.

scholarly journals Automatic detection of morphodynamic profile of human embryos in vitro data sets preparation

2020 ◽  
Vol 176 ◽  
pp. 1736-1744
Author(s):  
G.B. Nemkovskiy ◽  
O.V. Shurygina ◽  
A.A. Bayzarova ◽  
D.Yu. Rusakov ◽  
A.B. Kuznetsov ◽  
...  
Keyword(s):  
Automatic Detection ◽  
Human Embryos ◽  
Data Sets ◽  
Vitro Data ◽  
In Vitro Data

Framework for Multivariate Selectivity Analysis, Part II: Experimental Applications

2005 ◽  
Vol 59 (6) ◽  
pp. 804-815 ◽  
Author(s):  
Trent D. Ridder ◽  
Christopher D. Brown ◽  
Benjamin J. Ver Steeg
Keyword(s):  
Method Development ◽  
Near Infrared ◽  
Calibration Model ◽  
Data Sets ◽  
Validation Data ◽  
Calibration Models ◽  
Vitro Data ◽  
In Vitro Data

In Part I of this paper, a framework for multivariate selectivity was introduced that is both calculable from first principles and experimentally tractable. In this part, we employ the proposed selectivity framework for analyzing both in vitro and in vivo near-infrared experimental data. Two in vitro data sets are used to compare different methods for estimating selectivity and to demonstrate the benefits obtained from validation data with expanded interferant concentration ranges. The in vitro data also demonstrate that the experimentally estimated selectivities provide insights into the properties of the calibration models that are difficult or impossible to infer by other means. The merits of the proposed selectivity function are further demonstrated using a complex in vivo application: the noninvasive measurement of ethanol in humans. Results indicate that in vivo calibration model sensitivity, selectivity, and concentration correlations can be systematically interrogated using the proposed selectivity framework and judicious use of experimental measurements. These analyses not only provide selectivity and sensitivity information, but also the variance components of the total MSEP, which is invaluable information for both method development and analytical method characterization.

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