The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target

2021 ◽  
Vol 19 ◽  
Author(s):  
Yu Cheng ◽  
Wuqiong Zhang ◽  
Yue Li ◽  
Ting Jiang ◽  
Buhajar Mamat ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Brain Diseases ◽  
Mammalian Brain ◽  
Acid Sensing Ion Channels ◽  
Promising Therapeutic Target ◽  
Pathological Mechanism ◽  
Tissue Acidosis ◽  
Epileptogenic Foci

Background: Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. This said, its roles in epileptogenesis remain unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis. Methods: Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: "Acid-sensing ion channels 1a" or "ASIC1a" and "epilepsy" or "seizure". Results: The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy. Conclusion:This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to further elucidate the role of ASIC1a in epilepsy.

Molecular Interactions of α-Synuclein, Mitochondria, and Cellular Degradation Pathways in Parkinson's Disease

2020 ◽  
pp. 212-234
Author(s):  
Mansi Verma ◽  
Sujata Basu ◽  
Manisha Singh ◽  
Rachana R. ◽  
Simrat Kaur ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Interactions ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Degradation Pathways ◽  
Functional Changes ◽  
The World ◽  
Novel Therapeutic

Parkinson's disease (PD) has been reported to be the most common neurodegenerative diseases all over the world. Several proteins are associated and responsible for causing PD. One such protein is α-synuclein. This chapter discusses the role of α-synuclein in PD. Various genetic and epigenetic factors, which cause structural and functional changes for α-synuclein, have been described. Several molecular mechanisms, which are involved in regulating mitochondrial and lysosomal related pathways and are linked to α-synuclein, have been discussed in detail. The knowledge gathered is further discussed in terms of using α-synuclein as a diagnostic marker for PD and as a novel therapeutic target for the same.

scholarly journals Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy

2016 ◽  
Vol 371 (1700) ◽  
pp. 20150431 ◽  
Author(s):  
O. Ievglevskyi ◽  
D. Isaev ◽  
O. Netsyk ◽  
A. Romanov ◽  
M. Fedoriuk ◽  
...  
Keyword(s):  
Ion Channels ◽  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Strong Increase ◽  
Life And Death ◽  
Acid Sensing Ion Channels

Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca 2+ -permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg 2+ model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo . Our results reveal a significant novel role for ASICs. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

scholarly journals The Role of F11R in Pancreatic Cancer Malignancy and Its Clinical Implication as a Therapeutic Target

2019 ◽  
Author(s):  
Haidi zhang ◽  
Chunyan Zhao ◽  
Xianhua Hu ◽  
Shuai He ◽  
Jinchuan Yu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Target ◽  
Immunoglobulin Superfamily ◽  
Experimental Conditions ◽  
Cycle Arrest ◽  
Pancreatic Cancer Cells ◽  
Promising Therapeutic Target ◽  
Cell Invasiveness

Abstract Abstract Background The F11 receptor belongs to the immunoglobulin superfamily and is expressed in epithelial and endothelial cells. F11R mediates the formation of tight junctions between the epithelium and endothelium, and participates in the invasion and metastasis of tumor cells. We have previously shown that the F11R gene is closely related to KRas (P= 0.76), a known therapeutic target for pancreatic cancer (PCa). In recent years, it has been found that F11R is expressed in different tumors and has biological effects.However, according to different tumor cases, different cell lines and experimental conditions, the regulatory results and mechanisms of F11R on tumor are different, even contradictory,and the expression, clinical significance and biological mechanism of F11R in tumor tissues have not been reported in detail. Results To investigate the role of F11R in carcinogenesis of PCa and the potential of F11R as a therapies target for PCa, we silenced F11R (-/-) in the PCa cell line PANC-1 (known to express high levels of KRas) using lentiviral approaches.We found that F11R silencing led to decreased cell proliferation, a loss of cell invasiveness, reduced colony forming ability, cell cycle arrest in G1 phase, cells apoptosis enhanced, and ros enhanced. In vitro data showed that inhibition of F11R decreased proliferation and invasiveness of cancer cells.The present results suggest that F11R may be a promising therapeutic target for PCa. Conclusions This study used bioinformatics combined with gene chip data to find the gene F11R, which is closely related to KRAS gene, and we used lentivirus to package shRNA plasmid to interfere with the gene F11R in pancreatic cancer panc-1 cells. A series of biobehavioral studies indicated the biobehavioral function and malignancy of panc-1 in pancreatic cancer cells with negative regulation of F11R gene.Based on this, we need to continue to clarify the expression of F11R gene in clinical case samples to determine whether F11R gene can be a new therapeutic target for pancreatic cancer.

scholarly journals Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

2021 ◽  
Author(s):  
Sebastian Curti ◽  
Federico Davoine ◽  
Antonella Dapino
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Electrical Transmission ◽  
Electrical Synapses ◽  
Electrophysiological Properties ◽  
Voltage Dependent ◽  
Theoretical Evidence ◽  
Circuit Function

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals are mostly composed of the protein connexin (Cx)36. Circuits of electrically coupled neurons are widespread in these animals, plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations like lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on gap junction conductance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage dependent channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

scholarly journals Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Samuel Teo ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Model Systems ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Wnt Ligands

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.

scholarly journals The Neurobiology of Selenium: Looking Back and to the Future

2021 ◽  
Vol 15 ◽  
Author(s):  
Ulrich Schweizer ◽  
Simon Bohleber ◽  
Wenchao Zhao ◽  
Noelia Fradejas-Villar
Keyword(s):  
Cell Biology ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Epileptic Seizures ◽  
Cell Types ◽  
Mammalian Brain ◽  
The Individual ◽  
The Brain ◽  
Looking Back

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

scholarly journals The Anti-Neuroinflammatory Role of Anthocyanins and Their Metabolites for the Prevention and Treatment of Brain Disorders

2020 ◽  
Vol 21 (22) ◽  
pp. 8653
Author(s):  
Joana F. Henriques ◽  
Diana Serra ◽  
Teresa C. P. Dinis ◽  
Leonor M. Almeida
Keyword(s):  
Neurological Disorders ◽  
Fruits And Vegetables ◽  
Molecular Mechanisms ◽  
Brain Inflammation ◽  
Brain Diseases ◽  
Naturally Occurring ◽  
Pathological Conditions ◽  
Promising Strategy ◽  
Prevention And Treatment

Anthocyanins are naturally occurring polyphenols commonly found in fruits and vegetables. Numerous studies have described that anthocyanin-rich foods may play a crucial role in the prevention and treatment of different pathological conditions, which have encouraged their consumption around the world. Anthocyanins exhibit a significant neuroprotective role, mainly due to their well-recognized antioxidant and anti-inflammatory properties. Neuroinflammation is an intricate process relevant in both homeostatic and pathological circumstances. Since the progression of several neurological disorders relies on neuroinflammatory process, targeting brain inflammation has been considered a promising strategy in those conditions. Recent data have shown the anti-neuroinflammatory abilities of many anthocyanins and of their metabolites in the onset and development of several neurological disorders. In this review, it will be discussed the importance and the applicability of these polyphenolic compounds as neuroprotective agents and it will be also scrutinized the molecular mechanisms underlying the modulation of neuroinflammation by these natural compounds in the context of several brain diseases.

scholarly journals Autophagy as a therapeutic target in pancreatic cancer

2020 ◽  
Author(s):  
Max Piffoux ◽  
Erwan Eriau ◽  
Philippe A. Cassier
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Mitogen Activated Protein ◽  
Cellular Components

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.

Vitamin D/VDR in acute kidney injury: a potential therapeutic target

2020 ◽  
Vol 27 ◽  
Author(s):  
Siqing Jiang ◽  
Lihua Huang ◽  
Wei Zhang ◽  
Hao Zhang
Keyword(s):  
Vitamin D ◽  
Acute Kidney Injury ◽  
Therapeutic Target ◽  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Kidney Injury ◽  
Potential Therapeutic Target ◽  
Promising Therapeutic Target ◽  
Incidence And Mortality

: Despite many strategies and parameters used in clinical practice, the incidence and mortality of acute kidney injury (AKI) are still high with poor prognosis. With the development of molecular biology, the role of vitamin D and vitamin D receptor (VDR) in AKI is drawing increasing attention. Accumulated researches have suggested that Vitamin D deficiency is a risk factor of both clinical and experimental AKI, and vitamin D/VDR could be a promising therapeutic target against AKI. However, more qualitative clinical researches are needed to provide stronger evidence for clinical application of vitamin D and VDR agonists in the future. Issues like the route and dosage of administration also await more attention. The present review aims to summarize the current works on the role of vitamin D/VDR in AKI and try to provide some new insight of its therapeutic potential.

The regulatory role of Rho GTPases and their substrates in osteoclastogenesis

2020 ◽  
Vol 21 ◽  
Author(s):  
Lin Gao ◽  
Lingbo Kong ◽  
Yuanting Zhao
Keyword(s):  
Bone Loss ◽  
Therapeutic Target ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Special Role ◽  
Cellular Functions ◽  
Potential Therapeutic Target ◽  
Cytoskeletal Organization ◽  
Osteoclastic Differentiation

: Pathological bone loss diseases (osteolysis, Paget’s diseases) are commonly caused by the over differentiation and activity of osteoclasts. The Rho GTPases family members Rac1/2 (Rac1 and Rac2) have been reported for their special role in exerting multiple cellular functions during osteoclastic differentiation, which including the most prominent function on dynamic actin cytoskeleton rearranging. Besides that, the increasing studies demonstrated the regulating effects of Rac1/2 on osteoclastic cytoskeletal organization is through the GEFs member Dock5. Although the amount of relevant studies on this topic still limited, there are several excellent studies have been reported for extensively explored the molecular mechanisms involved in Rac1/2 and Dock5 during the osteoclastogenesis regulation, as well as their role as the therapeutic target in bone loss disesases. Herein in this review, we aim to focus on recent advances studies for extensively understanding the role of Rho GTPases Rac1/2 and Dock5 in osteoclastogenesis, as well as their role as a potential therapeutic target in regulating osteoclastogenesis.

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