scholarly journals An Investigation into the Impact of a Glutaminase Inhibitor, Compound 968, on Nrf2 Signaling

2021 ◽  
Vol 1 (1) ◽  
pp. 41-47
Author(s):  
Wei Lei ◽  
Valentin M. Kliebe ◽  
Xin Chen
Keyword(s):  
Molecular Docking ◽  
Pilot Study ◽  
Neurodegenerative Diseases ◽  
Heme Oxygenase ◽  
Pathological Process ◽  
Luciferase Assay ◽  
Heme Oxygenase 1 ◽  
Nrf2 Activation ◽  
Energy Synthesis ◽  
The Impact

Glutaminase is a critical enzyme that catalyzes the process of glutaminolysis for energy synthesis. Meanwhile, glutaminase also contributes to the pathological process of various diseases, such as cancer, neurodegenerative diseases, and inflammation. This leads to the discovery of glutaminase inhibitors for therapeutical uses. However, the mechanisms of the beneficial therapeutical effect of glutaminase inhibitors are still unclear. This pilot study aimed to determine the impact of a well-characterized glutaminase inhibitor, compound 968 (C968), on Nrf2 signaling. We performed molecular docking, luciferase assay, and quantitative PCR to determine the activation of Nrf2 and the expression of several Nrf2-related genes. These experiments found that C968 induced the Nrf2 activation and promoted the expression of Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H Quinone Dehydrogenase-1 (NQO-1). All findings provide evidence that Nrf2 activation could be one of the mechanisms contributing to the therapeutical activity of C968, but more studies are warranted to further confirm this mechanism.

Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases

2018 ◽  
Vol 24 (20) ◽  
pp. 2283-2302 ◽  
Author(s):  
Vivian B. Neis ◽  
Priscila B. Rosa ◽  
Morgana Moretti ◽  
Ana Lucia S. Rodrigues
Keyword(s):  
Neurodegenerative Diseases ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
Physiological Conditions ◽  
And Oxidative Stress ◽  
Defensive Mechanism

Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.

Heme oxygenase 1 and renal ischemia and reperfusion injury: The impact of immunosuppressive drug

2006 ◽  
Vol 6 (13-14) ◽  
pp. 1966-1972 ◽  
Author(s):  
Giselle Martins Gonçalves ◽  
Marcos Antônio Cenedeze ◽  
Carla Quarim Feitoza ◽  
Carolina Batista de Paula ◽  
Georgia Daniela Macusso ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Heme Oxygenase ◽  
Immunosuppressive Drug ◽  
Renal Ischemia ◽  
Heme Oxygenase 1 ◽  
Ischemia And Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
The Impact

scholarly journals KCHO-1, a Novel Antineuroinflammatory Agent, Inhibits Lipopolysaccharide-Induced Neuroinflammatory Responses through Nrf2-Mediated Heme Oxygenase-1 Expression in Mouse BV2 Microglia Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Dong-Sung Lee ◽  
Wonmin Ko ◽  
Chi-Su Yoon ◽  
Dong-Cheol Kim ◽  
Jinju Yun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Neurodegenerative Diseases ◽  
Heme Oxygenase ◽  
Nuclear Factor Kappa B ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Bv2 Microglia ◽  
Cox 2

The brain is vulnerable to oxidative stress and inflammation that can occur as a result of aging or neurodegenerative diseases. Our work has sought to identify natural products that regulate heme oxygenase (HO)-1 and to determine their mechanism of action in neurodegenerative diseases. KCHO-1 is a novel herbal therapeutic containing 30% ethanol (EtOH) extracts from nine plants. In this study, we investigated the antineuroinflammatory effects of KCHO-1 in lipopolysaccharide- (LPS-) treated mouse BV2 microglia. KCHO-1 inhibited the protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), cyclooxygenase- (COX-) 2, and COX-2-derived prostaglandin E2 (PGE2) in LPS-stimulated BV2 microglia. It also reduced tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and IL-6 production. This effect was correlated with the suppression of inhibitor of nuclear factor kappa B-α(IκB-α) phosphorylation and degradation and nuclear factor kappa B (NF-κB) translocation and DNA binding. Additionally, KCHO-1 upregulated HO-1 expression by promoting nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in mouse BV2 microglia. Tin protoporphyrin (SnPP), an HO activity inhibitor, was used to verify the inhibitory effects of KCHO-1 on proinflammatory mediators and proteins associated with HO-1 expression. Our data suggest that KCHO-1 has therapeutic potential in neurodegenerative diseases caused by neuroinflammation.

scholarly journals Using ultrasound to define the time point of intrauterine growth retardation in a mouse model of heme oxygenase-1 deficiency†

2020 ◽  
Vol 103 (1) ◽  
pp. 126-134 ◽  
Author(s):  
Nicole Meyer ◽  
Stefanie Langwisch ◽  
Markus Scharm ◽  
Ana Claudia Zenclussen
Keyword(s):  
Heme Oxygenase ◽  
Fetal Growth ◽  
Molecular Mechanisms ◽  
Maternal Blood ◽  
Heme Oxygenase 1 ◽  
Intrauterine Growth ◽  
Flow Parameters ◽  
Free Heme ◽  
The Impact

Abstract The enzyme heme oxygenase-1 (HO-1), encoded by the HMOX1 gene, mediates heme catabolism by cleaving free heme. We have previously revealed the importance of HO-1 in pregnancy. Here, we determined the impact of maternal or paternal HO-1 deficiency on fetal growth and placental parameters throughout gestation. We mated Hmox1-sufficient (WT), partial (HET)-, or total (KO)-deficient BALB/c female mice with Hmox1-WT or -KO BALB/c males and performed ultrasound analysis to monitor placental and fetal growth. Doppler measurements were used to determine maternal blood flow parameters. Offspring weights and feto-placental indices (FPI) were also determined. We found a significantly increased number of underdeveloped fetuses at gd10 in HET females that were mated with WT males compared with WT × WT pairings. At the same gestational age, underdeveloped placentas could be detected in HET females mated with KO males. Many fetuses from the KO × KO combination died in utero between gd12 and gd14. At gd14, abnormal placental parameters were found in surviving fetuses, which had significant reduced weights. Moreover, only 3.11% female and 5.33% male KO pups resulted from 10 HET × HET breeding pairs over 1 year. Our results show that HO-1 from both maternal and paternal origins is important for proper placental and fetal growth. Placental growth restriction and occurrence of abortions in mice that were partially or totally deficient in HO-1 were recorded in vivo from gd10 onwards. Future studies will focus on elucidating the cellular and molecular mechanisms behind these observations.

scholarly journals Induction of heme oxygenase-1 shifts the balance from proinjury to prosurvival in the placentas of pregnant rats with reduced uterine perfusion pressure

2012 ◽  
Vol 302 (5) ◽  
pp. R620-R626 ◽  
Author(s):  
Eric M. George ◽  
Istvan Arany
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Caspase 3 ◽  
Perfusion Pressure ◽  
Atp Depletion ◽  
Heme Oxygenase 1 ◽  
Pregnant Rats ◽  
Intracellular Atp ◽  
Uterine Perfusion ◽  
The Impact

Placental hypoxia/ischemia has been implicated as a central factor in the development of preeclampsia. One particularly useful animal model to study the impact of placental ischemia is the reduced uterine perfusion pressure (RUPP) model. We have previously demonstrated that RUPP animals exhibit elevated placental oxidative stress, which plays an important role in the development of the associated maternal hypertension. Recently, we have demonstrated that cobalt protoporphyrin (CoPP)-mediated induction of heme oxygenase-1 (HO-1) attenuates RUPP-induced oxidative stress and consequent hypertension. However, signaling pathways that are involved in this process are virtually unknown. Here, we show that placentas from RUPP animals exhibit increased phosphorylation of JNK, STAT1, STAT3, and p52shc with a concomitant increase in caspase-3 activation and depletion of intracellular ATP. Treatment with CoPP decreased RUPP-induced phosphorylation of JNK and STAT1, while it increased phosphorylation of ERK and STAT3, leading to decreased caspase-3 activation and restoration of intracellular ATP content. Our data imply that RUPP induces oxidative stress and the consequent injurious state by increasing phosphorylation of mediators of injury (STAT1, JNK) and, to a lesser extent, survival (STAT3, p52shc) in placentas of pregnant rats. HO-1 induction shifts this balance to a prosurvival phenotype by augmenting phosphorylation of the prosurvival ERK and STAT3, while suppressing phosphorylation of JNK and STAT1. This attenuates the resulting injury, as indicated by caspase-3 activation and ATP depletion. These results demonstrate a novel therapeutic activity of HO-1 induction in placental cell survival during ischemia and support the HO-1 pathway as a promising therapeutic target for the management of preeclampsia.

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