scholarly journals LRP4 in Hippocampal Astrocytes Serves as A Negative Feedback Factor in Seizures

2020 ◽  
Author(s):  
Zheng Yu ◽  
Meiying Zhang ◽  
Bin Luo ◽  
Hongyang Jing ◽  
Yue Yu ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Expression Level ◽  
Regulatory Mechanisms ◽  
Potential Therapeutic Target ◽  
Typical Symptom ◽  
Feedback Factor ◽  
Local Reduction ◽  
Genetic Level ◽  
Hippocampal Astrocytes ◽  
High Level

Abstract Backgroud Epilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory. To find a better treatment, it makes sense to further explore the regulatory mechanisms of seizures at genetic level. LRP4 regionally expresses in mice hippocampus where is key to limbic epileptogenesis. It is well known that neurons release a high level of glutamate during seizures, and it has been reported that LRP4 in astrocytes down-regulates glutamate released from neurons. However, it is still unclear whether there is a relationship between LRP4 expression level and seizures, and whether LRP4 plays a role in seizures.Results We found that seizures induced by pilocarpine decreased LRP4 expression level and increased miR-351-5p expression level in mice hippocampus. Glutamate reduced LRP4 expression and enhanced miR-351-5p expression in cultured hippocampal astrocytes, and these effects can be partially attenuated by AP5. Furthermore, miR-351-5p inhibitor lessened the reduction of LRP4 expression in glutamate treated hippocampal astrocytes. Local reduction of LRP4 in hippocampus by sh Lrp4 lentivirus injection in hippocampus increased the threshold of seizures in pilocarpine or pentylenetetrazol (PTZ) injected mice. Conclutions These results indicated that high released glutamate induced by seizures down-regulated astrocytic LRP4 through increasing miR-351-5p in hippocampal astrocytes via activating astrocytic NMDA receptor, and locally reduction of LRP4 in hippocampus increased the threshold of seizures. LRP4 in hippocampal astrocytes appears to serve as a negative feedback factor in seizures. This provides a new potential therapeutic target for seizures regulation.

scholarly journals Lrp4 in hippocampal astrocytes serves as a negative feedback factor in seizures

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zheng Yu ◽  
Meiying Zhang ◽  
Bin Luo ◽  
Hongyang Jing ◽  
Yue Yu ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Expression Level ◽  
Regulatory Mechanisms ◽  
Potential Therapeutic Target ◽  
Typical Symptom ◽  
Feedback Factor ◽  
Local Reduction ◽  
Genetic Level ◽  
Hippocampal Astrocytes ◽  
High Level

Abstract Background Epilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory. To find a better treatment, it makes sense to further explore the regulatory mechanisms of seizures at genetic level. Lrp4 regionally expresses in mice hippocampus where is key to limbic epileptogenesis. It is well known that neurons release a high level of glutamate during seizures, and it has been reported that Lrp4 in astrocytes down-regulates glutamate released from neurons. However, it is still unclear whether there is a relationship between Lrp4 expression level and seizures, and whether Lrp4 plays a role in seizures. Results We found that seizures induced by pilocarpine decreased Lrp4 expression level and increased miR-351-5p expression level in mice hippocampus. Glutamate reduced Lrp4 expression and enhanced miR-351-5p expression in cultured hippocampal astrocytes, and these effects can be partially attenuated by AP5. Furthermore, miR-351-5p inhibitor lessened the reduction of Lrp4 expression in glutamate treated hippocampal astrocytes. Local reduction of Lrp4 in hippocampus by sh Lrp4 lentivirus injection in hippocampus increased the threshold of seizures in pilocarpine or pentylenetetrazol (PTZ) injected mice. Conclusions These results indicated that high released glutamate induced by seizures down-regulated astrocytic Lrp4 through increasing miR-351-5p in hippocampal astrocytes via activating astrocytic NMDA receptor, and locally reduction of Lrp4 in hippocampus increased the threshold of seizures. Lrp4 in hippocampal astrocytes appears to serve as a negative feedback factor in seizures. This provides a new potential therapeutic target for seizures regulation.

Evolution theory and the future of humanity

2008 ◽  
Author(s):  
Christopher Wills
Keyword(s):  
Natural Selection ◽  
Communication Skills ◽  
Evolutionary Biology ◽  
Skin Pigmentation ◽  
Homo Erectus ◽  
Skin Colour ◽  
Evolution Theory ◽  
The Future ◽  
Genetic Level ◽  
High Level

No field of science has cast more light on both the past and the future of our species than evolutionary biology. Recently, the pace of new discoveries about how we have evolved has increased (Culotta and Pennisi, 2005). It is now clear that we are less unique than we used to think. Genetic and palaeontological evidence is now accumulating that hominids with a high level of intelligence, tool-making ability, and probably communication skills have evolved independently more than once. They evolved in Africa (our own ancestors), in Europe (the ancestors of the Neanderthals) and in Southeast Asia (the remarkable ‘hobbits’, who may be miniaturized and highly acculturated Homo erectus). It is also becoming clear that the genes that contribute to the characteristics of our species can be found and that the histories of these genes can be understood. Comparisons of entire genomes have shown that genes involved in brain function have evolved more quickly in hominids than in more distantly related primates. The genetic differences among human groups can now be investigated. Characters that we tend to think of as extremely important markers enabling us to distinguish among different human groups now turn out to be understandable at the genetic level, and their genetic history can be traced. Recently a single allelic difference between Europeans and Africans has been found (Lamason et al., 2005). This functional allelic difference accounts for about a third of the differences in skin pigmentation in these groups. Skin colour differences, in spite of the great importance they have assumed in human societies, are the result of natural selection acting on a small number of genes that are likely to have no effects beyond their influence on skin colour itself. How do these and other recent findings from fields ranging from palaeontology to molecular biology fit into present-day evolution theory, and what light do they cast on how our species is likely to evolve in the future? I will introduce this question by examining briefly how evolutionary change takes place.

scholarly journals Characterization and High-Level Periplasmic Expression of Thermostable α-Carbonic Anhydrase from Thermosulfurimonas Dismutans in Escherichia Coli for CO2 Capture and Utilization

2019 ◽  
Vol 21 (1) ◽  
pp. 103 ◽  
Author(s):  
Byung Hoon Jo ◽  
In Seong Hwang
Keyword(s):  
Escherichia Coli ◽  
Carbonic Anhydrase ◽  
Co2 Capture ◽  
Industrial Applications ◽  
Expression Level ◽  
High Level Expression ◽  
Whole Cell ◽  
Operational Conditions ◽  
Periplasmic Expression ◽  
High Level

Carbonic anhydrase (CA) is a diffusion-controlled enzyme that rapidly catalyzes carbon dioxide (CO2) hydration. CA has been considered as a powerful and green catalyst for bioinspired CO2 capture and utilization (CCU). For successful industrial applications, it is necessary to expand the pool of thermostable CAs to meet the stability requirement under various operational conditions. In addition, high-level expression of thermostable CA is desirable for the economical production of the enzyme. In this study, a thermostable CA (tdCA) of Thermosulfurimonas dismutans isolated from a deep-sea hydrothermal vent was expressed in Escherichia coli and characterized in terms of expression level, solubility, activity and stability. tdCA showed higher solubility, activity, and stability compared to those of CA from Thermovibrio ammonificans, one of the most thermostable CAs, under low-salt aqueous conditions. tdCA was engineered for high-level expression by the introduction of a point mutation and periplasmic expression via the Sec-dependent pathway. The combined strategy resulted in a variant showing at least an 8.3-fold higher expression level compared to that of wild-type tdCA. The E. coli cells with the periplasmic tdCA variant were also investigated as an ultra-efficient whole-cell biocatalyst. The engineered bacterium displayed an 11.9-fold higher activity compared to that of the recently reported system with a halophilic CA. Collectively these results demonstrate that the highly expressed periplasmic tdCA variant, either in an isolated form or within a whole-cell platform, is a promising biocatalyst with high activity and stability for CCU applications.

Heterogeneity of hypoxia-mediated decrease in IK(V) and increase in [Ca2+]cyt in pulmonary artery smooth muscle cells

2007 ◽  
Vol 293 (2) ◽  
pp. L402-L416 ◽  
Author(s):  
Oleksandr Platoshyn ◽  
Ying Yu ◽  
Eun A Ko ◽  
Carmelle V. Remillard ◽  
Jason X.-J. Yuan
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Muscle Cells ◽  
Expression Level ◽  
Kv Channels ◽  
Pulmonary Artery Smooth Muscle ◽  
High Level

Hypoxic pulmonary vasoconstriction is caused by a rise in cytosolic Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) via multiple mechanisms. PASMC consist of heterogeneous phenotypes defined by contractility, proliferation, and apoptosis as well as by differences in expression and function of various genes. In rat PASMC, hypoxia-mediated decrease in voltage-gated K+ (Kv) currents ( IK(V)) and increase in [Ca2+]cyt were not uniformly distributed in all PASMC tested. Acute hypoxia decreased IK(V) and increased [Ca2+]cyt in ∼46% and ∼53% of PASMC, respectively. Using combined techniques of single-cell RT-PCR and patch clamp, we show here that mRNA expression level of Kv1.5 in hypoxia-sensitive PASMC (in which hypoxia reduced IK(V)) was much greater than in hypoxia-insensitive cells (in which hypoxia negligibly affected IK(V)). These results demonstrate that 1) different PASMC express different Kv channel α- and β-subunits, and 2) the sensitivity of a PASMC to acute hypoxia partially depends on the expression level of Kv1.5 channels; hypoxia reduces whole-cell IK(V) only in PASMC that express high level of Kv1.5. In addition, the acute hypoxia-mediated changes in [Ca2+]cyt also vary in different PASMC. Hypoxia increases [Ca2+]cyt only in 34% of cells tested, and the different sensitivity of [Ca2+]cyt to hypoxia was not related to the resting [Ca2+]cyt. An intrinsic mechanism within each individual cell may be involved in the heterogeneity of hypoxia-mediated effect on [Ca2+]cyt in PASMC. These data suggest that the heterogeneity of PASMC may partially be related to different expression levels and functional sensitivity of Kv channels to hypoxia and to differences in intrinsic mechanisms involved in regulating [Ca2+]cyt.

scholarly journals MCOLN1 Promotes Proliferation and Predicts Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Zhan-Dong Hu ◽  
Jun Yan ◽  
Kai-Yue Cao ◽  
Zhi-Qi Yin ◽  
Wei-Wei Xin ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Expression Level ◽  
Nuclear Antigen ◽  
Ductal Adenocarcinoma ◽  
Proliferation Capacity ◽  
Late Endosomes ◽  
Tumor Tissues ◽  
High Level

Background. MCOLN1 (mucolipin subfamily, member 1) was first identified as an autophagic regulator, which was essential for efficient fusion of both autophagosomes and late endosomes with lysosomes. This study is aimed at investigating the role of MCOLN1 in the development of pancreatic ductal adenocarcinoma (PDAC). Methods. Immunohistochemistry (IHC) assay was conducted to evaluate the expression level of MCOLN1 in 82 human PDAC tumor tissues. Overall survival (OS) and recurrence-free survival (RFS) analysis was performed to assess the prognosis of patients. Colony formation and MTT assays [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] were performed to measure the proliferation capacity of tumor cells. The expression level of related genes was measured by RT-PCR (reverse transcription polymerase chain reaction) and western blot assays. The animal model was used to examine the effects of indicated protein on tumorigenesis in vivo. Results. The results of IHC showed that a high level of MCOLN1 expression was associated with the poor clinical characteristics of PDAC patients. OS and RFS were significantly worse in patients with high MCOLN1 expression. Silencing of MCOLN1 dramatically blocked the proliferation of PDAC cells. Mechanism studies confirmed that knockdown of MCOLN1 decreased the expression of Ki67 and PCNA (proliferating cell nuclear antigen), two markers of cell proliferation. In vivo, MCOILN1 depletion reduced the formation and growth of tumors in mice. Conclusion. The high level of MCOLN1 expression was associated with poor clinical outcomes of PDAC patients. MCOLN1 ablation could inhibit PDAC proliferation of both in vitro and in vivo, which provide a new insight and novel therapeutic target for the treatment of PDAC.

Overexpression of an optimized Aspergillus sulphureus β-mannanase gene in Pichia pastoris

Biologia ◽  
2009 ◽  
Vol 64 (2) ◽  
Author(s):  
Xiaoling Chen ◽  
Jiaoyun Qiao ◽  
Haifeng Yu ◽  
Yunhe Cao
Keyword(s):  
Pichia Pastoris ◽  
Expression Level ◽  
Wild Type ◽  
Feed Supplement ◽  
Bias Effect ◽  
Key Enzyme ◽  
Aspergillus Sulphureus ◽  
Code Bias ◽  
High Level ◽  
High Expression Level

Abstractβ-Mannanase (EC 3.2.1.78) is a key enzyme to hydrolyze the β-mannosidic linkages in mannan and heteromannan. The expression of a wild type β-mannanase (manWT) of Aspergillus sulphureus in Pichia pastoris is not high enough for its application in feed supplement. To earn a high expression level, the manWT gene was firstly optimized to manM according to the code bias of P. pastoris, which was then inserted into pPICzαA and transformed into P. pastoris strain X-33. In the induction by methanol, β-mannanase was expressed in high level with 32% increase in comparison with the manWT gene expressed in P. pastoris in shaken flask. In a 10-L fermenter, the manM was expressed in 9-fold higher level than that in shaken flask, which yielded the enzyme activity of 1100 U/mL. This is the first study on codon bias effect on the β-mannanase gene expression level, which helps to achieve high β-mannanase yield and enzymatic activity in P. pastoris.

scholarly journals Circular RNA circFAT1(e2) Promotes Osteosarcoma Progression and Metastasis by Sponging miR-181b and Regulating HK2 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Huijie Gu ◽  
Xiangyang Cheng ◽  
Jun Xu ◽  
Kaifeng Zhou ◽  
Chong Bian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Critical Role ◽  
Noncoding Rnas ◽  
Circular Rna ◽  
Expression Level ◽  
Circular Rnas ◽  
Competing Endogenous Rna ◽  
Potential Therapeutic Target

As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. Nevertheless, how circRNAs participate in osteosarcoma (OS) development and progression are not well understood. In the present study, we identified a circRNA circFAT1(e2) with an upregulated expression level in OS tissues. By functional experiments, we found that circFAT1(e2) depletion significantly suppressed the proliferation and reduced migration in OS. In terms of mechanism, we found that circFAT1(e2) inhibited miR-181b, while miR-181b targeted HK2. By releasing the inhibition of miR-181b on HK2 expression, leading to attenuated OS progression. Mechanistic investigations suggested that circFAT1(e2) served as a competing endogenous RNA (ceRNA) of miR-181b to enhance HK2 expression. On the whole, our study indicated that circFAT1(e2) exerted oncogenic roles in OS and suggested the circFAT1(e2)/miR-181b/HK2 axis might be a potential therapeutic target.

State of the adaptive-compensatory mechanisms in children with type 1 diabetes mellitus and its changes after sanatorium-resort treatment

10.12737/7236 ◽  
2014 ◽  
Vol 8 (1) ◽  
pp. 0-0
Author(s):  
Лагунова ◽  
N. Lagunova ◽  
Голубова ◽  
T. Golubova ◽  
Поленок ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Emotional State ◽  
Regulatory Mechanisms ◽  
Compensatory Mechanisms ◽  
Adrenal System ◽  
Compensatory Reactions ◽  
High Level

The changes of adaptive-compensatory reactions, pronounced stress of regulatory mechanisms, the imbalance between the autonomic nerve system and sympatho-adrenal system are one of the reasons of type 1 diabetes mellitus course lability. The purpose of this study was to examine the adaptive-compensatory reactions, the condition of autonomic nervous system, sympatho-adrenal system, emotional state and changes of the studied parameters under the sanatorium stage of rehabilitation effects in children with type 1 diabetes mellitus. The research and analysis of the obtained results allowed to determine significant changes of various organs and systems in the majority of children (65,0%) with diabetes. These changes are manifested in the polymorphic somatoneurological symptoms and were as consequences of the high level of regulatory systems tension, violation of adaptive-compensatory reactions, changes in emotional state, increased activity of sympatho-adrenal system. Sanatorium-resort treatment had the positive effects on the major body life defining systems functioning of observed children. Adaptive-compensatory mechanisms of the functioning of the autonomic and sympatho-adrenal systems were improved (after treatment functional rearrangements were determined by increasing the activity of humoral and vagal effects, decreased sympathetic activity, reflecting the favorable orientation of the regulatory mechanisms of the autonomic nervous system), there were positive changes in psychological terms (decreased high level of anxiety, increased extraversion and interpersonal contacts in children).

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