scholarly journals Glo1 inhibitors for neuropsychiatric and anti-epileptic drug development

2014 ◽  
Vol 42 (2) ◽  
pp. 461-467 ◽  
Author(s):  
Katherine M.J. McMurray ◽  
Margaret G. Distler ◽  
Preetpal S. Sidhu ◽  
James M. Cook ◽  
Leggy A. Arnold ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Partial Agonist ◽  
Neuropsychiatric Disorders ◽  
Anxiety And Depression ◽  
Glyoxalase I ◽  
Pharmacological Treatments ◽  
Delayed Onset ◽  
Anti Epileptic Drug ◽  
Novel Target ◽  
Target Effects

Many current pharmacological treatments for neuropsychiatric disorders, such as anxiety and depression, are limited by a delayed onset of therapeutic effect, adverse side effects, abuse potential or lack of efficacy in many patients. These off-target effects highlight the need to identify novel mechanisms and targets for treatment. Recently, modulation of Glo1 (glyoxalase I) activity was shown to regulate anxiety-like behaviour and seizure-susceptibility in mice. These effects are likely to be mediated through the regulation of MG (methylglyoxal) by Glo1, as MG acts as a competitive partial agonist at GABAA (γ-aminobutyric acid A) receptors. Thus modulation of MG by Glo1 represents a novel target for treatment. In the present article, we evaluate the therapeutic potential of indirectly modulating MG concentrations through Glo1 inhibitors for the treatment of neuropsychiatric disorders.

RAS in the Central Nervous System: Potential Role in Neuropsychiatric Disorders

2018 ◽  
Vol 25 (28) ◽  
pp. 3333-3352 ◽  
Author(s):  
Natalia Pessoa Rocha ◽  
Ana Cristina Simoes e Silva ◽  
Thiago Ruiz Rodrigues Prestes ◽  
Victor Feracin ◽  
Caroline Amaral Machado ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Neuropsychiatric Disorders ◽  
Extensive Literature ◽  
Ang Ii ◽  
Mas Receptor ◽  
The Central Nervous System ◽  
The Brain

Background: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. Objective: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. Method: We carried out an extensive literature search in PubMed central. Results: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Conclusion: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.

scholarly journals Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Vratko Himič ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Structural Integrity ◽  
Viral Vector ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Pharmacological Treatments ◽  
Genetic Sequencing ◽  
Reading Frame ◽  
Target Effects

AbstractDuchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.

scholarly journals BrainSeq: Neurogenomics to Drive Novel Target Discovery for Neuropsychiatric Disorders

Neuron ◽  
2015 ◽  
Vol 88 (6) ◽  
pp. 1078-1083 ◽  
Author(s):  
Christian R. Schubert ◽  
Patricio O’Donnell ◽  
Jie Quan ◽  
Jens R. Wendland ◽  
Hualin S. Xi ◽  
...  
Keyword(s):  
Neuropsychiatric Disorders ◽  
Target Discovery ◽  
Novel Target

scholarly journals Anxiety and depression in children and adolescents with obesity: a nationwide study in Sweden

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Louise Lindberg ◽  
Emilia Hagman ◽  
Pernilla Danielsson ◽  
Claude Marcus ◽  
Martina Persson
Keyword(s):  
Risk Factors ◽  
Family History ◽  
General Population ◽  
Children And Adolescents ◽  
Neuropsychiatric Disorders ◽  
Obesity Treatment ◽  
Sensitivity Analyses ◽  
Anxiety And Depression ◽  
History Of ◽  
Anxiety Depression

Abstract Background Anxiety and depression are more common in children with obesity than in children of normal weight, but it is unclear whether this association is independent of other known risk factors. Interpretation of results from previous studies is hampered by methodological limitations, including self-reported assessment of anxiety, depression, and anthropometry. The aim of this study was to investigate whether obesity increases the risk of anxiety or depression independently of other risk factors in a large cohort of children and adolescents, using robust measures with regard to exposure and outcome. Methods Children aged 6–17 years in the Swedish Childhood Obesity Treatment Register (BORIS, 2005–2015) were included (n = 12,507) and compared with a matched group (sex, year of birth, and area of residence) from the general population (n = 60,063). The main outcome was a diagnosis of anxiety or depression identified through ICD codes or dispensed prescribed medication within 3 years after the end of obesity treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox proportional models were adjusted for several known confounders. Results Obesity remained a significant risk factor for anxiety and depression in children and adolescents after adjusting for Nordic background, neuropsychiatric disorders, family history of anxiety/depression, and socioeconomic status. Girls in the obesity cohort had a 43% higher risk of anxiety and depression compared to girls in the general population (adjusted HR 1.43, 95% CI 1.31–1.57; p < 0.0001). The risk in boys with obesity was similar (adjusted HR 1.33, 95% CI 1.20–1.48; p < 0.0001). In sensitivity analyses, excluding subjects with neuropsychiatric disorders and a family history of anxiety/depression, the estimated risks in individuals with obesity were even higher compared with results from the main analyses (adjusted HR [95% CI]: girls = 1.56 [1.31–1.87], boys = 2.04 [1.64–2.54]). Conclusions Results from this study support the hypothesis that obesity per se is associated with risk of both anxiety and depression in children and adolescents.

scholarly journals Carbohydrate 3′-sialyllactose as a novel target for theranostics in pancreatic ductal adenocarcinoma

Tumor Biology ◽  
2020 ◽  
Vol 42 (10) ◽  
pp. 101042832096527
Author(s):  
Kiyoshi Higashi ◽  
Keiko Maeda ◽  
Kaori Miyata ◽  
Saori Yoshimura ◽  
Keita Yamada ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Ductal Adenocarcinoma ◽  
Significant Activity ◽  
Gastric Cancer Cells ◽  
Complement Dependent Cytotoxicity ◽  
Elevated Expression ◽  
Novel Target

We previously demonstrated that the carbohydrate 3′-sialyllactose is overexpressed in cancer stem-like cells such as metastatic pancreatic and poorly differentiated gastric cancer cells, and undifferentiated human embryonic stem cells. In this study, we investigated the possibility of 3′-sialyllactose as a target for theranostics in cancers using a recombinant mouse monoclonal antibody r3B1E2 that binds to 3′-sialyllactose. Immunohistochemistry analysis confirmed an elevated expression of 3′-sialyllactose in tumors of pancreas, stomach, and testis, while no expression of 3′-sialyllactose was observed in corresponding normal controls. In addition, a stage-independent expression of 3′-sialyllactose was observed, especially in pancreatic ductal adenocarcinoma (PDAC). The level of serum 3′-sialyllactose in PDAC subjects was significantly higher than that in healthy controls, providing excellent AUC of 0.88. We next explored the therapeutic potential of r3B1E2 for PDAC in vitro. Treatment of r3B1E2 with 3′-sialyllactose-bearing human PDAC cells exhibited a complement-dependent cytotoxicity, whereas no significant activity of r3B1E2 against 3′-sialyllactose-negative cells was observed. Collectively, these findings raise the possibility of 3′-sialyllactose as a novel target for theranostics in PDAC.

Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha as a Novel Target for Bipolar Disorder and Other Neuropsychiatric Disorders

2018 ◽  
Vol 83 (9) ◽  
pp. 761-769 ◽  
Author(s):  
Andrew A. Nierenberg ◽  
Sharmin A. Ghaznavi ◽  
Isadora Sande Mathias ◽  
Kristen K. Ellard ◽  
Jessica A. Janos ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Neuropsychiatric Disorders ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Novel Target

scholarly journals Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

2010 ◽  
Vol 17 (7) ◽  
pp. 1211-1220 ◽  
Author(s):  
M Takeuchi ◽  
S Kimura ◽  
J Kuroda ◽  
E Ashihara ◽  
M Kawatani ◽  
...  
Keyword(s):  
Leukemic Cells ◽  
Glyoxalase I ◽  
Hypoxic Environment ◽  
Novel Target

Platelets in Storage: Altered S-Nitrosothiol Metabolism and Decreased Responsiveness May Be Related.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1995-1995
Author(s):  
Julie Kanter ◽  
Dk McLaughlin ◽  
J Dimitry ◽  
S. Rogers ◽  
Pj Kell ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fluorescence Probe ◽  
Therapeutic Potential ◽  
Fold Increase ◽  
Storage Process ◽  
Novel Target ◽  
Storage Times ◽  
And Storage ◽  
Apheresis Platelets ◽  
Inducible Activation

Abstract Under normal physiologic conditions, platelets circulate in an inactivated state and require only minimal stimulation ensuring their immediate availability for hemostasis. Previous research has shown that during platelet pheresis and storage, platelets undergo early activation resulting in expression of the surface activation marker CD62, release of α granule contents, and a decrease in inducible activation. In addition to regulating vascular tone, nitric oxide (NO) groups in plasma may provide tonic inhibition to circulating platelets thereby preventing the inappropriate adhesion and aggregation seen in stored platelets. S-Nitrosothiols (RSNOs) may serve as a reservoir for nitric oxide (NO) in the normal circulation. We hypothesize that platelets are prematurely activated during the process of apheresis in part due to the lack of RSNOs in the microenvironment during collection and storage. Furthermore, RSNO metabolism by stored platelets is changed by the process of apheresis itself. To test this hypothesis, we monitored the activation status of platelets using CD62 flow cytometry and quantified intracellular NO content and uptake using the fluorescence probe diaminodifluorofluorescein diacetate (DAF-FM DA). Both measurements were made on freshly isolated platelets (Fl-Plts) and on apheresis platelets (A-Plts). In addition, we employed these techniques to evaluate the responsiveness of Fl-Plts and A-Plts to agonists [thrombin receptor activating peptide (TRAP), ADP, and collagen] and to NO-donating molecules after varying storage times. In preliminary studies we have found that Fl-Plts bind RSNOs and demonstrate steroselectivity in their degree of uptake. Fl-Plts incubated with L-RSNOs produce over 2-fold the fluorescence compared to Fl-Plts incubated with D-RSNOs. A-Plts lose this stereoselectivity in RSNO uptake following the collection and storage process. We have also found that A-Plts have up to a 10-fold increase in uptake of nitric oxide from RSNOs compared to Fl-Plts. This significant increase and loss of stereoselectivity in RSNO uptake in A-Plts correlates with the loss of inducible activation over storage time. These data suggest RSNO metabolism in platelets is fundamentally altered during apheresis, collection, and storage and provides a novel target with therapeutic potential for further investigation into the loss of platelet function during storage.

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