scholarly journals Cannabidiol and the Canonical WNT/β-Catenin Pathway in Glaucoma

2021 ◽  
Vol 22 (7) ◽  
pp. 3798
Author(s):  
Alexandre Vallée ◽  
Yves Lecarpentier ◽  
Jean-Noël Vallée
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disease ◽  
Therapeutic Strategy ◽  
Cannabis Sativa ◽  
Inflammatory Signaling ◽  
Down Regulation ◽  
Lower Affinity ◽  
Therapeutic Properties ◽  
Gsk 3Β ◽  
Canonical Wnt

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway.

scholarly journals Lithium: a potential therapeutic strategy in obsessive–compulsive disorder by targeting the canonical WNT/β pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexandre Vallée ◽  
Jean-Noël Vallée ◽  
Yves Lecarpentier
Keyword(s):  
Oxidative Stress ◽  
Obsessive Compulsive Disorder ◽  
Therapeutic Strategy ◽  
Behavioral Therapy ◽  
First Line ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
First Line Therapy ◽  
New Treatment ◽  
Gsk 3Β

AbstractObsessive–compulsive disorder (OCD) is a neuropsychiatric disorder characterized b–y recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and the glutamatergic pathway play key roles in the causes of OCD. However, first-line therapies include cognitive–behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for a new treatment is mandatory. This review focuses on the potential effects of lithium, as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which lithium provides its benefit properties. Lithium medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. The activation of the WNT/β-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway. Future prospective clinical trials could focus on lithium and its different and multiple interactions in OCD.

Emerging Biomarkers and Contributing Factors of Prostate Cancer.

2020 ◽  
Vol 16 ◽  
Author(s):  
Mini Dahiya ◽  
Monu Yadav ◽  
Kalpana Nagpal ◽  
Nidhi Sharma ◽  
Kajal Joshi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Prostate Cancer ◽  
Tumor Suppressor Genes ◽  
Therapeutic Strategy ◽  
Cannabinoid Receptors ◽  
Contributing Factors ◽  
Cause Of Deaths ◽  
Pharmaceutical Industries ◽  
Brca1 Brca2 ◽  
Molecular Pathophysiology

: Prostate Cancer (PC) is one the most prominent cause of deaths in males worldwide especially in western countries. The exhaustive research into prostate cancer to date has demonstrated ELAC2, RNASEL, MSR1, NBS1, CHEK2, MYC, BCL-2, c-Kit, tumor suppressor genes, BRCA1, BRCA2, PACE4, GSTP1, PTEN,CDKN1B, NKX3.1, KLF6, FOXA1, Retinoblastoma, p53, androgen receptor, kallikreins, ETS, CYP17, SRD5A2, E-cadherin, KAI1/CD82, hepsin, AMACR, PIM1, MTA-1, EZH2, EPHB2, growth factors & its receptors, cannabinoid receptors, annexins, oxidative stress and inflammation are entailed changes underlying the initiation, development, and progression of PC. Furthermore, oncology would shift from a reactive to proactive discipline so exploring these targets open new area of research. Therefore, the present review is focused on molecular pathophysiology biomarkers for the progression of PC that would encourage the researchers and pharmaceutical industries to investigate potential therapeutic strategy to overcome demerits of currently available clinically therapies.

Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition

2003 ◽  
Vol 312 (4) ◽  
pp. 1342-1348 ◽  
Author(s):  
Takanori Yokota ◽  
Kanako Sugawara ◽  
Kaoru Ito ◽  
Ryosuke Takahashi ◽  
Hiroyoshi Ariga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Er Stress ◽  
Proteasome Inhibition ◽  
Down Regulation

scholarly journals Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3437
Author(s):  
Hee Eun Kang ◽  
Yoojeong Seo ◽  
Jun Seop Yun ◽  
Sang Hyun Song ◽  
Dawool Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Therapeutic Strategy ◽  
Target Gene ◽  
Advanced Colorectal Cancer ◽  
Therapeutic Potential ◽  
Cancer Stemness ◽  
Reciprocal Regulation ◽  
Canonical Wnt

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome

2011 ◽  
Vol 7 (3) ◽  
pp. 219-227 ◽  
Author(s):  
Francesco Angelico ◽  
Lorenzo Loffredo ◽  
Pasquale Pignatelli ◽  
Teresa Augelletti ◽  
Roberto Carnevale ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Weight Loss ◽  
Endothelial Dysfunction ◽  
Down Regulation ◽  
The Metabolic Syndrome

Protective effect of GSK-3β/Nrf2 mediated by dimethyl fumarate in middle cerebral artery embolization reperfusion rat model

2021 ◽  
Vol 18 ◽  
Author(s):  
Yuan Li ◽  
Lan Chu ◽  
Chunfeng Liu ◽  
Zongyi Zha ◽  
Yuanlu Shu
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Sham Group ◽  
Infarct Volume ◽  
Dimethyl Fumarate ◽  
Control Group ◽  
Related Factor ◽  
Nissl Staining ◽  
Gsk 3Β ◽  
Nrf2 Expression

Aim: This study investigated the protective effect of dimethyl fumarate (DMF) in rats by mediating GSK3-β/Nrf2 using the middle cerebral artery embolization reperfusion (MCAO/R) rat model. Background: After an acute ischemic stroke (AIS), oxidative stress occurs. Dimethyl fumarate (DMF), a nuclear factor-E2-related factor 2 (Nrf2) activator, approved by the US Food and Drug Administration (FDA), was observed to regulate the Nrf2 pathway by acting as an anti-oxidative stress agent; however, whether this agent is involved in inhibiting GSK-3β remains to be established. Methods: DMF model was used to explore the effects of GSK-3β on Nrf2 expression level, Nrf2-ARE binding activity and Nrf2/ARE downstream expression level of anti-oxidant stress protein in Cerebral ischemia-reperfusion injury (CIRI). 60 rats were randomly divided into Sham group, MCAO/R group, solvent control group (DMSO group) and DMF treatment group, with 15 rats in each group. The MCAO/R, DMSO and DMF groups were considered in the MCAO/R model using the modified thread embolization method. In contrast, the Sham group was only anaesthetized and disinfected, and tissue muscle was dissected without inserting suture emboli. DMF group was gavaged with 45mg/kg per day of DMF, DMSO control group was gavaged with DMSO of equal volume, while MCAO/R group was only modeled without any intragastric treatment. The rats were treated seven days after the operation, and a neurological function Longa score was estimated. The rats were sacrificed seven days later, and the infarct volume was assessed by TTC staining. Hematoxylin-eosin (HE) staining was used to observe the pathological changes in rat brain tissue. Nissl staining was used to observe the expression of neurons in the infarcted cortex. Western blotting (WB) was used to observe the protein expression levels of glycogen synthase kinase 3β(GSK-3β), nuclear factor E2-related factor 2 (Nrf2), downstream heme oxygenase 1 (HO1) and NADPH quinone oxidoreductase 1 (NQO1) in four groups. The expression levels of GSK-3β and Nrf2 in the four groups were observed by immunohistochemistry and immunofluorescence. Results: (1) The Longa score of the MCAO/R, DMSO and DMF groups was found to be higher compared to the Sham group, indicating successful operation. The Longa score of the DMF group was lower than that of the other three groups 4-7 days after surgery (P<0.05). (2) HE and Nissl staining showed that the DMF group had lower neuron necrosis and higher gliosis compared to the control groups. (3) TTC staining results showed that the infarct volume of the DMF group was significantly smaller than the MCAO/R and DMSO groups. (4) Protein results showed that the GSK-3β expression in the DMF group was lower than that in all groups, while the expression of Nrf2, HO1 and NQO1 was higher compared to other groups. Conclusion: DMF can reduce neurological deficits and infarct size in the MCAO/R model. The protective effect may be related to decreased GSK-3β expression and increased Nrf2 expression, which may play a role in anti-oxidative stress.

Abstract 561: Dysregulation of miR-155 in Acute Oscillatory Shear Stress (OSS)-mediated Oxidative Stress, Inflammation and Endothelial Dysfunction

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Islam Mohamed ◽  
Sheena Thomas ◽  
Kimberly Rooney ◽  
Roy Sutliff ◽  
Nick Willett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Shear Stress ◽  
Barrier Function ◽  
Oscillatory Shear ◽  
Blue Dye ◽  
Down Regulation ◽  
Inflammatory Stress ◽  
Cytoskeleton Organization ◽  
Oscillatory Shear Stress

Introduction: Shear stress forces play an integral role in dictating the endothelial cell (EC) response to changes in blood flow, pro-inflammatory response and hence development of atherosclerosis. Previously, our group has identified EC microRNA-155 (miR-155) as one of the key signature dysregulated miRNAs in areas of chronic low magnitude oscillatory shear stress (OSS) in vasculature and OSS models of in-vitro. Hypothesis: we hypothesized that acute induction of OSS mediates EC oxidative stress, inflammation and dysfunction, via dysregulation of EC miR-155. Methods: 12-week old C57B/6J mice were subjected to abdominal aortic coarctation (AAC), a unique model of acute induction of OSS, for 3 days and downstream segments of acute OSS were compared to upstream unidirectional shear stress (USS) segments of the thoracic aorta. Results: Acute OSS resulted in down regulation of EC miR-155 expression and inverse upregulation of EC RhoA and Myosin light chain kinase (MYLK), known targets of miR-155-mediated EC cytoskeleton organization, in OSS segments compared with USS. This was associated with impaired EC dependent relaxation, differential contractile response to phenylephrine, and loss of EC barrier function as evaluated by extravasation of Evans-blue dye assay. In parallel, En-face immunohistochemical staining also showed increased expression of EC nitric oxide synthase (eNOS) along with increased levels of reactive oxygen species (ROS) and nitrotyrosine (NY) formation in OSS segments compared with USS. Conclusions: Together, our studies shed light on the early changes in EC response to acute induction of OSS and resulting down-regulation of EC mir-155, including; oxidative/inflammatory stress, EC dysfunction, loss of barrier function and cytoskeletal changes. Despite the early upregulation of eNOS, it could also potentially synergize with the activation of the RhoA-MYLK pathway in EC oxidative (ROS/NY)/inflammatory stress and associated EC dysfunction. Further studies are in progress to dissect the interplay between these different pathways and their causal relationships as downstream targets of EC miR-155.

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