scholarly journals proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bangkun Yang ◽  
Lesheng Wang ◽  
Ying Nie ◽  
Wei Wei ◽  
Wenping Xiong
Keyword(s):  
Neural Plasticity ◽  
Cell Model ◽  
Neurotrophin Receptor ◽  
Control Group ◽  
P75 Neurotrophin Receptor ◽  
Post Stroke ◽  
Post Stroke Depression ◽  
Cellular Apoptosis ◽  
Related Proteins

AbstractBrain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.

scholarly journals SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhiya Deng ◽  
Maomao Sun ◽  
Jie Wu ◽  
Haihong Fang ◽  
Shumin Cai ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Cell Model ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Autophagy Induction ◽  
Promising Therapeutic Approach ◽  
Related Proteins ◽  
Caecal Ligation And Puncture

AbstractOur previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

scholarly journals Isoflurane Neurotoxicity Is Mediated by p75NTR-RhoA Activation and Actin Depolymerization

2011 ◽  
Vol 114 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Brian P. Lemkuil ◽  
Brian P. Head ◽  
Matthew L. Pearn ◽  
Hemal H. Patel ◽  
John C. Drummond ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Hippocampal Slice ◽  
Hippocampal Slices ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Actin Depolymerization ◽  
Rhoa Activation ◽  
Hippocampal Slice Cultures ◽  
Developing Neurons

Background The mechanisms by which isoflurane injured the developing brain are not clear. Recent work has demonstrated that it is mediated in part by activation of p75 neurotrophin receptor. This receptor activates RhoA, a small guanosine triphosphatase that can depolymerize actin. It is therefore conceivable that inhibition of RhoA or prevention of cytoskeletal depolymerization might attenuate isoflurane neurotoxicity. This study was conducted to test these hypotheses using primary cultured neurons and hippocampal slice cultures from neonatal mouse pups. Methods Primary neuron cultures (days in vitro, 4-7) and hippocampal slice cultures from postnatal day 4-7 mice were exposed to 1.4% isoflurane (4 h). Neurons were pretreated with TAT-Pep5, an intracellular inhibitor of p75 neurotrophin receptor, the cytoskeletal stabilizer jasplakinolide, or their corresponding vehicles. Hippocampal slice cultures were pretreated with TAT-Pep5 before isoflurane exposure. RhoA activation was evaluated by immunoblot. Cytoskeletal depolymerization and apoptosis were evaluated with immunofluorescence microscopy using drebrin and cleaved caspase-3 staining, respectively. Results RhoA activation was increased after 30 and 120 min of isoflurane exposure in neurons; TAT-Pep5 (10 μm) decreased isoflurane-mediated RhoA activation at both time intervals. Isoflurane decreased drebrin immunofluorescence and enhanced cleaved caspase-3 in neurons, effects that were attenuated by pretreatment with either jasplakinolide (1 μm) or TAT-Pep5. TAT-Pep5 attenuated the isoflurane-mediated decrease in phalloidin immunofluorescence. TAT-Pep5 significantly attenuated isoflurane-mediated loss of drebrin immunofluorescence in hippocampal slices. Conclusions Isoflurane results in RhoA activation, cytoskeletal depolymerization, and apoptosis. Inhibition of RhoA activation or prevention of downstream actin depolymerization significantly attenuated isoflurane-mediated neurotoxicity in developing neurons.

scholarly journals Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tao Yang ◽  
Kevin C. Tran ◽  
Anne Y. Zeng ◽  
Stephen M. Massa ◽  
Frank M. Longo
Keyword(s):  
Small Molecule ◽  
Intracellular Signaling ◽  
Rho Kinase ◽  
Tau Phosphorylation ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Fyn Kinase ◽  
Synapse Degeneration ◽  
Preclinical And Clinical Studies

AbstractLongitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.

scholarly journals The p75 Neurotrophin Receptor Promotes Amyloid- (1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo

2009 ◽  
Vol 29 (34) ◽  
pp. 10627-10637 ◽  
Author(s):  
J. K. Knowles ◽  
J. Rajadas ◽  
T.-V. V. Nguyen ◽  
T. Yang ◽  
M. C. LeMieux ◽  
...  
Keyword(s):  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Neuritic Dystrophy

scholarly journals TLR4 Signaling in MPP+-Induced Activation of BV-2 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Peng Zhou ◽  
Ruihui Weng ◽  
Zhaoyu Chen ◽  
Rui Wang ◽  
Jing Zou ◽  
...  
Keyword(s):  
Western Blot ◽  
Mtt Assay ◽  
Inflammatory Responses ◽  
Cell Model ◽  
Critical Role ◽  
Control Group ◽  
Immunofluorescence Technique ◽  
Rt Pcr ◽  
Sirna Interference

Aims.This work was conducted to establish anin vitroParkinson’s disease (PD) model by exposing BV-2 cells to 1-methyl-4-phenylpyridinium (MPP+) and exploring the roles of TLR2/TLR4/TLR9 in inflammatory responses to MPP+.Methods/Results.MTT assay showed that cell viability of BV-2 cells was 84.78 ± 0.86% and 81.18 ± 0.99% of the control after incubation with 0.1 mM MPP+for 12 hours and 24 hours, respectively. Viability was not significantly different from the control group. With immunofluorescence technique, we found that MPP+incubation at 0.1 mM for 12 hours was the best condition to activate BV-2 cells. In this condition, the levels of TNF-α, IL-1β, and iNOS protein were statistically increased compared to the control according to ELISA tests. Real time RT-PCR and western blot measurements showed thatTLR4was statistically increased after 0.1 mM MPP+incubation for 12 hours. Furthermore, after siRNA interference ofTLR4mRNA, NF-κB activation and the levels of TNF-α, IL-1β, and iNOS were all statistically decreased in this cell model.Conclusion.MPP+incubation at the concentration of 0.1 mM for 12 hours is the best condition to activate BV-2 cells for mimicking PD inflammation in BV-2 cells. TLR4 signalling plays a critical role in the activation of BV-2 cells and the induction of inflammation in this cell model.

scholarly journals The Effect of “SELF-HELP Packages” on Post Stroke Depression among Ischemic Stroke Survivors

2020 ◽  
Vol 10 (3) ◽  
pp. 361-375
Author(s):  
Fitria Handayani ◽  
Setyowati Setyowati ◽  
Dwi Pudjonarko ◽  
Dian Ratna Sawitri
Keyword(s):  
Social Support ◽  
Ischemic Stroke ◽  
Intervention Group ◽  
Nursing Intervention ◽  
Control Group ◽  
Stroke Survivors ◽  
Post Stroke ◽  
Self Help ◽  
Confounding Variables ◽  
Post Stroke Depression

Background: There are several factors that contribute to Post Stroke Depression (PSD). Since a single intervention is proven ineffective to deal with PSD, an intervention which includes biological, psychological, social, and spiritual aspects (“SELF-HELP Packages”), therefore, needs to be established.Purpose: The purpose of the study was to investigate the effect of “SELF HELP Packages” intervention on PSD among ischemic stroke survivors after three months from onset and its effect after confounding variables were controlled.Methods: This study was a pre and post quasi-experiment with a control group involving 34 ischemic stroke survivors each group. The inclusion criteria were survivors after three months from ischemic stroke, no aphasia, having a good hearing, and having Mini Mental Status Examination (MMSE) score of ≥ 22. GRID-HAMD 17, Multidimensional Scale of Perceived Social Support (MSPSS), and Barthel-Index were used to measure PSD, social support, and functional status respectively. “SELF-HELP Packages” intervention was delivered in three sessions, namely information delivery, discussion and activity. Statistical analyses were conducted using McNemar test, Chi-square and logistic regression.Results: The result showed that “SELF-HELP Packages” considerably decreased PSD in the intervention group (p=0.004). There were also significant differences in PSD after the intervention between two groups (p=0.008). Logistic regression showed that ‘SELF-HELP Package” had no effect on PSD when other confounding variables were controlled (p=0.075, OR=0.288, 95% CI 0.073 – 1.135).Conclusion: SELF-HELP Packages” should be applied in providing the nursing intervention among stroke ischemic survivors in clinical setting. A longer period of time for the intervention is also recommended for the next study in order to obtain a more robust result.   

scholarly journals Effectiveness of mirror therapy on upper limb function, activities of daily living, and depression in post-stroke depression patients

2021 ◽  
Vol 67 (3) ◽  
pp. 365-369
Author(s):  
Xiang Zhang ◽  
Yi Zhang ◽  
Yu Liu ◽  
Qiujin Yao
Keyword(s):  
Occupational Therapy ◽  
Motor Function ◽  
Daily Living ◽  
Control Group ◽  
Mirror Therapy ◽  
Post Stroke ◽  
Upper Limb Function ◽  
Mirror Group ◽  
Post Stroke Depression ◽  
The Mean

Objectives: This study aims to investigate the effects of mirror therapy (MT) on upper limb function, activities of daily living (ADLs), and depression in post-stroke depression patients. Patients and methods: Between November 2018 and December 2019, a total of 60 post-stroke patients (33 males, 27 females; mean age: 58.45±11.13 years; range, 35 to 88 years) were included. The patients were randomly divided into either the cosntrol group (n=30) or the MT group (n=30). Regular occupational therapy was provided for the control group (two times per day for 30 min per session, five times per week over four weeks). Occupational therapy and MT were used to treat patients in the mirror group (one 30 min session once per day, five times per week over four weeks). Motor function (Fugl-Meyer Assessment of the Upper Extremity, FMA-UE), ADL (Modified Barthel Index, MBI) and depression (17-item Hamilton Depression Scale, HAMD-17) were used to evaluate the treatment outcomes. Results: Before treatment, the mean HAMD-17, FMA-UE, and MBI scores showed no significant difference between the two groups (p>0.05). After treatment, the mirror group exhibited more significant improvements than the control group in terms of the mean HAMD-17, FM-UE, and MBI (p<0.05). After four weeks, the mean FMA-UE and MBI scores revealed more significant improvements than the baseline scores in the control group (p<0.01). The mean HAMD-17, FMA-UE, and MBI scores showed more significant improvements than the baseline scores in the MT group (p<0.001). Conclusion: Based on these results, MT can effectively improve motor function, ADLs, and depression in post-stroke depression patients. The curative effectiveness of MT seems to be more prominent than the regular occupational therapy.

scholarly journals Morinda officinalis oligosaccharides alleviate depressive-like behaviors in post-stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation

2021 ◽  
Author(s):  
Zhifang Li ◽  
Hexiang Xu ◽  
Yi Xu ◽  
Guanfeng Lu ◽  
Qiwei Peng ◽  
...  
Keyword(s):  
Western Blot ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Inflammation Response ◽  
Post Stroke ◽  
Pyrin Domain ◽  
Bv2 Cells ◽  
Post Stroke Depression ◽  
Depressive Episodes

Abstract Background: Morinda officinalis oligosaccharides (MOOs) is a traditional Chinese medicine extracted from plant Morinda officinalis roots. It has been used to treat mild and moderate depressive episodes. In the present study, we investigated whether MOOs can ameliorate depressive-like behaviors in post-stroke depression (PSD) rats and further discussed its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation.Methods: Behaviors tests were performed to evaluate the effect of MOOs on depressive-like behaviors in PSD rats. The effects of MOOs on the expression of IL-18, IL-1β and nucleotide-binding domain leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS)+adenosine triphosphate (ATP) stimulated BV2 cells by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence and Western blot analysis. Adeno-associated virus (AAV) were injected into hippocampus to downregulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence.Results: MOOs can alleviate depressive-like behaviors in PSD rats. PSD rats showed increased expression of IL-18, IL-1β and NLRP3 inflammasome in the ischemic hippocampus, while MOOs compromised the elevation. NLRP3 downregulation ameliorated depressive-like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 is mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL-18, IL-1β and NLRP3 inflammasome in LPS+ ATP treated BV2 cells. We further showed that modulation of NLRP3 inflammasome by MOOs was associated with IκB/NF‐κB p65 signaling pathway.Conclusion: Overall, our study revealed the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.

MicroRNA-126-5p Regulates Proliferation and Apoptosis of IL-22-Stimulated Human Keratinocytes Through Regulating Caspase 1

2021 ◽  
Vol 11 (5) ◽  
pp. 1010-1016
Author(s):  
Weifeng Zha ◽  
Bo Guo ◽  
Shuyue Chen ◽  
Junwei Lu ◽  
Yunyun Shan
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Luciferase Reporter ◽  
Control Group ◽  
Hacat Cells ◽  
Luciferase Reporter Gene ◽  
Proliferation And Apoptosis

Objective: The study was aimed to explore the roles of miR-126-5p in psoriasis and the underlying molecular mechanisms. Methods: In vitro cell model of psoriasis was established by IL-22 induction. CASP1, the target gene of miR-126-5p, was predicted by TargetScan and verified through the dual luciferase reporter gene system. qRT-PCR was used to measure the mRNA expression of miR-126-5p and CASP1 in IL-22 stimulated HaCaT cells. The protein expression of CASP1, cleaved-caspase3 and caspase3 were measured by Western blot analysis. MTT assay and flow cytometry analysis were performed to detect the cell proliferation and apoptosis. A Caspase3 Activity Assay kit was used to detect the activity of Caspase3. Results: miR-126-5p was high expressed in IL-22 stimulated HaCaT cells compared with normal HaCaT cells. We predicted and verified that CASP1 was a direct target of miR-126-5p, and the mRNA and protein expression of CASP1 were reduced in IL-22 stimulated HaCaT cells compared with the normal HaCaT cells. miR-126-5p inhibitor and CASP1-siRNA significantly decreased the expression of miR-126-5p and CASP1 in HaCaT cells respectively. miR-126-5p inhibitor up-regulated the expression of CASP1 in HaCaT cells, and the effect was reversed by the transfection with CASP1-siRNA. In comparison with the control group, miR-126-5p inhibitor decreased the cell proliferation, induced apoptosis, and improved the activity of Caspase3, enhanced cleaved-caspase3/caspase3 ratio in IL-22 stimulated HaCaT cells, and all the effects were reversed by down-regulating CASP1. Conclusion: We demonstrated that miR-126-5p inhibitor played a protective role in psoriasis by targeting CASP1, evidenced by inhibiting IL-22-induced HaCaT cell proliferation and inducing apoptosis.

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