scholarly journals Puerarin attenuates locomotor and cognitive deficits as well as hippocampal neuronal injury through the PI3K/Akt1/GSK-3β signaling pathway in an in vivo model of cerebral ischemia

Oncotarget ◽  
2017 ◽  
Vol 8 (63) ◽  
pp. 106283-106295 ◽  
Author(s):  
Jinhao Tao ◽  
Yuehua Cui ◽  
Yu Duan ◽  
Nan Zhang ◽  
Congmin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Signaling Pathway ◽  
Cognitive Deficits ◽  
Neuronal Injury ◽  
In Vivo Model ◽  
Gsk 3Β

TFAP2A inhibits microRNA-126 expression at a transcriptional level to aggravate ischemic neuronal injury

2020 ◽  
Author(s):  
Zhiqiang Gao ◽  
Jiang Zhang ◽  
Yunxia Wu
Keyword(s):  
Cerebral Ischemia ◽  
Pc12 Cells ◽  
Cell Model ◽  
Pathological Condition ◽  
Neuronal Injury ◽  
Global Cerebral Ischemia ◽  
Transcriptional Level ◽  
Mechanistic Investigation ◽  
Brain Tissues

Neuronal injury induced by cerebral ischemia poses a serious risk to health worldwide, which lacks effective clinical therapies currently. This study was performed to investigate the effect of transcription factor AP-2 alpha (TFAP2A) and the underlying mechanism in oxygen-glucose deprivation (OGD) cell model and transient global cerebral ischemia (tGCI) rat model. Based on CCK-8 and Hoechst staining results, silencing of TFAP2A could enhance the viability of OGD-treated PC12 cells and decrease the apoptotic rate of cells. ChIP assay was performed to detect the binding of TFAP2A to the promoter region of microRNA (miR)-126, and we found that TFAP2A could inhibit miR-126 expression. Further mechanistic investigation showed that miR-126 targeted polo like kinase 2 (PLK2), while overexpression of PLK2 activated the IκBα/NF-κB pathway and further suppressed the growth of OGD-treated PC12 cells. As for in vivo assay, proportion of infarction area in brain tissues of rats was analyzed by TTC staining, whereas Nissl staining was applied to evaluate the number of surviving brain neurons. The pathological condition of neuronal injury in rat brain tissues was monitored using HE staining. Results suggested that TFAP2A downregulated miR-126 to upregulate PLK2 and activate IκBα/NF-κB pathway, which deteriorated neuronal injury following ischemia in vivo.

scholarly journals RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Jikui Sun ◽  
Quanfeng Ma ◽  
Banban Li ◽  
Chen Wang ◽  
Lidong Mo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Inhibitory Effect ◽  
Who Grade ◽  
Pathway Network ◽  
Mechanistic Investigation ◽  
Signaling Axis ◽  
Gsk 3Β

Abstract Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

scholarly journals Regulation of Transcription Factors and Repression of Sp1 by Prolactin Signaling Through the Short Isoform of Its Cognate Receptor

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3327-3335 ◽  
Author(s):  
Y. Sangeeta Devi ◽  
Aurora Shehu ◽  
Carlos Stocco ◽  
Julia Halperin ◽  
Jamie Le ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Short Form ◽  
Binding Activity ◽  
In Vivo Model ◽  
Regulation Of Transcription ◽  
Signaling Mechanism ◽  
Dna Binding Activity ◽  
And Function

Prolactin (PRL) affects the development and function of the reproductive system by binding to two types of receptors, which differ by the size of their intracellular domain in rodents. Whereas the signaling pathway through the long form of the receptor (PRL-RL) is well characterized, signaling through the short form (PRL-RS) remains obscure. In this investigation, we examined transcription factors regulated by PRL in the ovary and decidua of mice expressing only PRL-RS in a PRL receptor null background. These mice provide a powerful in vivo model to study the selective signaling mechanism of PRL through PRL-RS independent of PRL-RL. We also examined the regulation of transcription factors in ovarian and uterine cell lines stably transfected with PRL-RS or PRL-RL. We focused our investigation on transcription factors similarly regulated in both these tissues and clearly established that signaling through PRL-RS does not activate the JaK/Stat in vivo but leads to severe down-regulation of Sp1 expression, DNA binding activity, and nuclear localization, events that appear to involve the calmodulin-dependent protein kinase pathway. Our in vivo and in culture data demonstrate that the PRL-RS activates a signaling pathway distinct from that of the PRL-RL.

scholarly journals Mechanism of antrocytic connexin-43 autophagy degradation in oxygen-glucose deprivation and its effect on neuroinflammation

2019 ◽  
Author(s):  
Xinyu Wang ◽  
Liangshu Feng ◽  
Meiying Xin ◽  
Yulei Hao ◽  
Xu Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Connexin 43 ◽  
Cell Communication ◽  
Glucose Deprivation ◽  
In Vivo Model ◽  
Oxygen Glucose Deprivation ◽  
Cx43 Protein ◽  
Protein Levels

Abstract Background : Connexin 43 (Cx43) are the most widely distributed gap junction proteins in the nervous system. Cx43 enables cell-to-cell communication and plays an important role in ion transport, substrate exchange and delivery of information , which have been implicated in cerebral ischemia injury. Our previous work revealed the relationships between Cx43 and glia-mediated neuroinflammation through the release of ATP in oxygen-glucose deprivation (OGD), which means degradation of Cx43 may improve neuroinflammatory damage during OGD injury . However, the roles of Cx43 degradation and neuroinflammation caused by OGD remain unclear. Methods: We used primary cultured astrocytes treated with OGD as an in vitro model of cerebral ischemia injury and we used middle cerebral artery occlusion (MCAO) model as an in vivo model of cerebral ischemia. HeLa cells were used in overexpression experiments. Cx43 protein levels were determined by western blotting. The interaction between Cx43 and related autophagy receptors was determined by co-immunoprecipitation and immunofluorescence. The gene knockdown (KD) of ATG5, OPTN, NDP52, PINK1 and Cx43 was applied by siRNA transfection. Related cytokines were detected by cytometric bead assay. Results: We found that Cx43 protein levels increased after ischemia in gene KD of ATG5, OPTN, NDP52 and PINK1 primary astrocytes. The interaction of Cx43 with OPTN, NDP52 and PINK1 was increased after cerebral ischemia injury in vitro and vivo. While the interaction was weakened after point mutation of Cx43 at Ser368, Tyr265 and Tyr247. Meanwhile, IL-10 upregulated during OGD after KD of ATG5, OPTN, NDP52 and PINK1 in astrocytes , while TNF downregulated during OGD after KD of ATG5, OPTN, NDP52 and PINK1 in astrocytes. Conclusions: Our results suggest that degradation of Cx43 is caused by selective autophagy during ischemia injury and the autophagy degradation of Cx43 plays important roles in neuroinflammation mediated by OGD injury. Treatment targeting Cx43 degradation pathway can improve neuroinflammation responses induced by OGD injury , which provide novel therapeutic strategies and crosstalk between autophagy and neuroinflammation.

scholarly journals Reduced H3K27me3 Suppresses Wnt/β-catenin Signaling by S-adenosylmethionine Deficiency in Neural Tube Development

2021 ◽  
Author(s):  
Li Zhang ◽  
Xiuwei Wang ◽  
Rui Cao ◽  
Dandan Li ◽  
Yufei Wang ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Signaling Pathway ◽  
Neural Tube ◽  
Underlying Mechanism ◽  
Enzyme Linked Immunosorbent Assay ◽  
The Novel ◽  
Marker Proteins ◽  
Neural Tube Development ◽  
Gsk 3Β

Abstract Background: S-adenosylmethionine as a major methyl donor play a key role in methylation modification in vivo, and its disorder was closely related to neural tube defects. However, the underlying mechanism between SAM deficiency and NTDs remained unclear.Methods: we investigated the association between histone methylation modification and Wnt/β-catenin signaling pathway in NTDs induced by SAM deficiency. The levels of SAM and SAH were determined by enzyme linked immunosorbent assay. The expressions of H3K27me3 and Wnt/β-catenin signaling pathway specific markers were demonstrated by western blotting, reverse transcription, and quantitative PCR and immunofluorescence in ethionine induced E11.5 mouse NTDs and NSCs models. Results: we found that the incidence rate of NTDs induced by ethionine were 46.2%, post treatment of ethionine combined with SAM, the incidence rate of NTDs was reduced to 26.2%. The level of SAM was significantly decreased (P<0.05) and a reduction in the SAM/SAH ratio was observed. The SAM depletion caused the reduction of both H3K27me3 modifications and UTX activity, and inhibited the marker proteins (β-catenin, TCF-4, Axin-2, p-GSK-3β, CyclinD1, and C-myc) in Wnt/β-catenin signaling pathway (P<0.05). The differentiations of neural stem cells into neurons and oligodendrocytes were inhibited under SAM deficiency (P<0.05).Conclusions: These results indicated that the depletion of SAM led to reduced H3K27me3 modifications, prevented the activation of Wnt/β-catenin signaling pathway and NSCs differentiation, which provided an understanding of the novel function of epigenetic regulation in NTDs.

scholarly journals The C. elegans miR-235 regulates the toxicity of graphene oxide via targeting the nuclear hormone receptor DAF-12 in the intestine

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tiantian Guo ◽  
Lu Cheng ◽  
Huimin Zhao ◽  
Yingying Liu ◽  
Yunhan Yang ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Signaling Pathway ◽  
Hormone Receptor ◽  
Molecular Basis ◽  
Mapk Signaling ◽  
Nuclear Hormone Receptor ◽  
In Vivo Model ◽  
Protective Mechanism ◽  
C Elegans

Abstract The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. However, the detailed mechanisms of the dysregulation of miRNA underlying GO toxicity are still largely elusive. In this study, we employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. After low concentration GO exposure, mir-235 (n4504) mutant nematodes were sensitive to GO toxicity, implying that mir-235 mediates a protection mechanism against GO toxicity. Tissue-specific assays suggested that mir-235 expressed in intestine is required for suppressing the GO toxicity in C. elegans. daf-12, a gene encoding a member of the steroid hormone receptor superfamily, acts as a target gene of mir-235 in the nematode intestine in response to GO treatment, and RNAi knockdown of daf-12 suppressed the sensitivity of mir-235(n4503) to GO toxicity. Further genetic analysis showed that DAF-12 acted in the upstream of DAF-16 in insulin/IGF-1 signaling pathway and PMK-1 in p38 MAPK signaling pathway in parallel to regulate GO toxicity. Altogether, our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12-PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level.

Regeneration of Dental Pulp by Stem Cells

2011 ◽  
Vol 23 (3) ◽  
pp. 313-319 ◽  
Author(s):  
M. Nakashima ◽  
K. Iohara
Keyword(s):  
Cerebral Ischemia ◽  
Dental Pulp ◽  
Side Population ◽  
Autologous Transplantation ◽  
In Vivo Model ◽  
Pulp Tissue ◽  
Motor Disability ◽  
Stromal Cell Derived Factor ◽  
Complete Regeneration

Angiogenesis/vasculogenesis and neurogenesis are essential for pulp regeneration. Two subfractions of side-population (SP) cells, CD31-/CD146- SP cells and CD105+ cells with angiogenic and neurogenic potential, were isolated by flow cytometry from canine dental pulp. In an experimental model of mouse hindlimb ischemia, transplantation of these cell populations resulted in an increase in blood flow, including high-density capillary formation. In a model of rat cerebral ischemia, stem cell transplantations enhanced neuronal regeneration and recovery from motor disability. Autologous transplantation of the CD31-/CD146- SP cells into an in vivo model of amputated pulp resulted in complete regeneration of pulp tissue with vascular and neuronal processes within 14 days. The transplanted cells expressed pro-angiogenic factors, implying trophic action on endothelial cells. Autologous transplantation of CD31-/CD146- SP cells or CD105+ cells with stromal-cell-derived factor-1 (SDF-1) into root canals after whole pulp removal of mature teeth resulted in complete regeneration of pulp replete with nerves and vasculature by day 14, followed by dentin formation along the dentinal wall by day 35. Therefore, the potential utility of fractionated SP cells and CD105+ cells in angiogenesis and neurogenesis was demonstrated by treatment of limb and cerebral ischemia following pulpotomy and pulpectomy.

scholarly journals CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage

Stroke ◽  
2021 ◽  
Author(s):  
Yueyang Liu ◽  
Xiaohang Che ◽  
Haotian Zhang ◽  
Xiaoxiao Fu ◽  
Yang Yao ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Kinase Inhibitor ◽  
Neuronal Damage ◽  
Neuronal Cell ◽  
In Vivo Model ◽  
Autophagic Flux ◽  
Autophagosome Formation

Background and Purpose: CAPN1 (calpain1)—an intracellular Ca 2+ -regulated cysteine protease—can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined. Methods: In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose–deprived primary neuron in vitro model. Results: CAPN1 was activated in the cortex of permanent middle cerebral occlusion–operated rats and oxygen-glucose deprivation–exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage. Conclusions: The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia–mediated autophagy-lysosomal pathway defects and neuronal damage.

Opuntia ficus-indica attenuates neuronal injury in in vitro and in vivo models of cerebral ischemia

2006 ◽  
Vol 104 (1-2) ◽  
pp. 257-262 ◽  
Author(s):  
Jung-Hoon Kim ◽  
Shin-Mi Park ◽  
Hyun-Joo Ha ◽  
Chang-Jong Moon ◽  
Tae-Kyun Shin ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Injury ◽  
Opuntia Ficus Indica ◽  
In Vivo Models
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