scholarly journals Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

2021 ◽  
Vol 13 ◽  
Author(s):  
Ni-Ni Chiang ◽  
Te-Hsien Lin ◽  
Yu-Shan Teng ◽  
Ying-Chieh Sun ◽  
Kuo-Hsuan Chang ◽  
...  
Keyword(s):  
Cellular Response ◽  
Memory Loss ◽  
Treatment Strategies ◽  
Camp Response Element Binding ◽  
Neuroprotective Effects ◽  
Downstream Signaling ◽  
Element Binding Protein ◽  
Tropomyosin Related Kinase B ◽  
New Treatment ◽  
Tau Aggregation

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.

scholarly journals Low Dose of Valproate Improves Motor Function after Traumatic Brain Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yu-Ting Tai ◽  
Wen-Yuan Lee ◽  
Fei-Peng Lee ◽  
Tien-Jen Lin ◽  
Chia-Lin Shih ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Brain Injuries ◽  
The United States ◽  
Camp Response Element Binding ◽  
Pharmacological Intervention ◽  
Neuroprotective Effects ◽  
Adult Rats ◽  
Protein Activation ◽  
Element Binding Protein ◽  
High Doses

Background.Traumatic brain injuries (TBIs) are a major health care problem worldwide. Approximately 1.5 million new TBI cases occur annually in the United States, with mortality rates ranging between 35% and 40% in severe patients. Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use. Several studies have indicated that 300 mg/kg or 400 mg/kg of valproate (VPA) exhibits neuroprotective effects in animal models. However, humans cannot tolerate high doses of VPA. This study aims to investigate whether 30 mg/kg of VPA administered to rats affects TBIs.Methods.We used a rat model to test the effects of 30 mg/kg of VPA on TBIs. Molecular identifications for histone acetylation and phosphorylation of cAMP response element-binding protein (CREB) and phosphorylated extracellular signal regulated kinase (ERK) were performed.Results.The results indicated that treating adult rats with VPA after TBIs significantly decreased the contusion volume and recovery of contusion-related skilled forelimb reaching deficits. Applying VPA also increased histone acetylation, p-ERK, and p-CREB expression in the brain. Furthermore, applying VPA reduced inflammation, glial fibrillary acidic protein activation, and apoptosis.Conclusion.This study found that 30 mg/kg of VPA assists in treating TBIs in rat models.

Intermolecular disulfide-dependent redox signalling

2014 ◽  
Vol 42 (4) ◽  
pp. 971-978 ◽  
Author(s):  
Marrit Putker ◽  
Harmjan R. Vos ◽  
Tobias B. Dansen
Keyword(s):  
Cellular Response ◽  
Redox State ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Cysteine Residue ◽  
Cysteine Oxidation ◽  
Redox Signalling ◽  
Wide Range ◽  
Element Binding Protein ◽  
Growth Factor Signalling

Until recently, ROS (reactive oxygen species) were often seen as merely damaging agents. However, small, but significant, amounts of hydrogen peroxide (H2O2) are also being produced upon, for instance, NADPH-oxidase activation in response to growth factor signalling and as a by-product of mitochondrial respiration. H2O2 perturbs the local cellular redox state and this results in specific and reversible cysteine oxidation in target proteins, thereby translating the redox state into a signal that ultimately leads to an appropriate cellular response. This phenomenon of signalling through cysteine oxidation is known as redox signalling and has recently been shown to be involved in a wide range of physiological processes. Cysteine residue oxidation can lead to a range of post-translational modifications, one of which is the formation of intermolecular disulfides. In the present mini-review we will give a number of examples of proteins regulated by intermolecular disulfides and discuss a recently developed method to screen for these interactions. The consequences of the regulation of the FOXO4 (forkhead box O4) transcription factor by formation of intermolecular disulfides with both TNPO1 (transportin 1) and p300/CBP [CREB (cAMP-response-element-binding protein)-binding protein] are discussed in more detail.

Brominated flame retardant TBPH induced oxidative damage and reduced the expression of memory-related proteins in mice, with no discernable impairment of learning and memory

2021 ◽  
pp. 096032712110588
Author(s):  
Zhang Bao ◽  
Yin Jing
Keyword(s):  
Oxidative Damage ◽  
Learning And Memory ◽  
Flame Retardants ◽  
Camp Response Element Binding ◽  
Oral Exposure ◽  
Neuroprotective Effects ◽  
Stress Markers ◽  
Neurobehavioral Function ◽  
Neurotoxic Effects ◽  
Element Binding Protein

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is one of the new brominated flame retardants with adverse neurobehavioral potential. These flame retardants are often added to household furnishings where children would come into contact with them. This study explores whether oral exposure to TBPH for 28 days would impair neurobehavioral function in mice and the role of curcumin (CUR) in this process. CUR is a natural antioxidant and is thought to be of use in the treatment of neurological toxicity due to its neuroprotective effects. Learning and memory of mice exposed to TBPH was investigated using the Morris water maze. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined to assess oxidative damage. Western blot was used to detect the expression of glucose-regulated protein 78-kDa (GRP78), PKR-like ER kinase (PERK), and C/EBP homologous protein (CHOP) in the hippocampus. End-point effects were evaluated through observing post-synaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB). Although TBPH exposure alone does not impair learning and memory, oxidative stress markers and endoplasmic reticulum stress–associated proteins were adversely affected in exposed mice. TBPH could significantly decrease the levels of BDNF, p-CREB, and PSD-95 in the hippocampus, and these TBPH-induced neurotoxic effects were attenuated by CUR. These findings provide further understanding of the neurotoxic effects of TBPH and the protective effect of CUR on TBPH exposure.

scholarly journals An Update in the Use of Antibodies to Treat Glioblastoma Multiforme

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Norma Y. Hernández-Pedro ◽  
Edgar Rangel-López ◽  
Gustavo Vargas Félix ◽  
Benjamín Pineda ◽  
Julio Sotelo
Keyword(s):  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Cell Surface Receptor ◽  
Angiogenic Growth Factors ◽  
Modest Improvement ◽  
Innovative Strategy ◽  
Downstream Signaling ◽  
Surface Receptor ◽  
New Treatment ◽  
Improvement In Survival

Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies.

scholarly journals The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer’s Disease: A Preclinical Study in APP/PS1 Transgenic Mice

2020 ◽  
Vol 23 (10) ◽  
pp. 700-711 ◽  
Author(s):  
Hao Wang ◽  
Fang-fang Zhang ◽  
Yong Xu ◽  
Hua-rong Fu ◽  
Xiao-dan Wang ◽  
...  
Keyword(s):  
Forced Swimming Test ◽  
Memory Loss ◽  
Tail Suspension Test ◽  
Camp Response Element Binding ◽  
Novel Object Recognition ◽  
The Novel ◽  
Camp Response Element ◽  
Phosphodiesterase 4 ◽  
Element Binding Protein ◽  
Swimming Test

Abstract Background Depression is highly related to Alzheimer’s disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis. Methods Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays. Results In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin–eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice. Conclusions Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.

scholarly journals Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3095
Author(s):  
Ching-Chia Huang ◽  
Kuo-Hsuan Chang ◽  
Ya-Jen Chiu ◽  
Yi-Ru Chen ◽  
Tsai-Hui Lung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
B Cell Lymphoma ◽  
Camp Response Element Binding ◽  
Coumarin Derivatives ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
High Affinity Receptor ◽  
Tropomyosin Related Kinase B

Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.

scholarly journals Future Therapeutic Strategies in the Glaucoma Management

2020 ◽  
pp. 40-49
Author(s):  
Waleed K. Abdulsahib
Keyword(s):  
Intraocular Pressure ◽  
Treatment Strategies ◽  
Retinal Ganglion ◽  
Cellular Mechanisms ◽  
Neuroprotective Effects ◽  
Additional Risk ◽  
Genetic Components ◽  
Glaucoma Treatment ◽  
Specific Tissue ◽  
New Treatment

Glaucoma is a group of eye diseases in which progressive damage to the ocular nerves may cause retinal ganglion cell (RGC) death. Worldwide glaucoma is a leading cause of avoidable blindness. Intraocular pressure (IOP) is considering to be the main identified cause of danger so far, and lowering intraocular pressure is the only recognized technique for inhibiting disease progression. Furthermore, blood vessels and genetic components of glaucoma are considered additional risk factors. In order to realize the potential progress of glaucoma treatment, new treatment strategies and ambitious goals are constantly being developing. These treatments will provide specific tissue goals to reduce IOP and ensure neuroprotective effects on RGCs. Consequently, physicians can shortly have an expanded range of medical choices to choose from, coupled with therapies that are more successful. Therefore, this study has reviewed the recent studies that were conducted on cellular mechanisms of glaucoma treatment.

scholarly journals Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways

2020 ◽  
Author(s):  
Ayman E El-Sahar ◽  
Nesma A Shiha ◽  
Nesrine S El Sayed ◽  
Lamiaa A Ahmed
Keyword(s):  
Nuclear Factor Κb ◽  
Camp Response Element Binding ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Camp Response Element ◽  
Toll Like Receptor 4 ◽  
Neuroprotective Effects ◽  
Element Binding Protein

Abstract Background Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer’s disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. Methods Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL). Results Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain. Conclusion The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.

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