scholarly journals Unraveling the Neuroprotective Effect of Tinospora Cordifolia in Parkinsonian Mouse Model Through Proteomics Approach.

2021 ◽  
Author(s):  
Hareram Birla ◽  
Chetan Keswani ◽  
Saumitra Sen Singh ◽  
Walia Zahra ◽  
Hagera Dilnashin ◽  
...  
Keyword(s):  
Treatment Group ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Mitochondrial Gene ◽  
Tinospora Cordifolia ◽  
Therapeutic Effects ◽  
Label Free ◽  
Neuroprotective Effects ◽  
Multiple Drugs

Abstract BackgroundStress-induced dopaminergic (DAergic) neuronal death in the midbrain region is the primary cause of Parkinson’s disease (PD). Approximately 2% of the global population aged above 65 years is affected with PD. Various factors are responsible for the death of DAergic neurons, among which mitochondrial dysfunction, oxidative stress, misfolded protein aggregation and neuroinflammation are the primary factors. From the discovery of L-dopa, multiple drugs were discovered to improve lifestyle of PD patients, but they failed due to their multiple side effects. Tinospora cordifolia (Tc), a medicinal herb has been used in traditional medicines to treat neurodegenerative diseases. In our previous study, the neuroprotective role of Tc against MPTP-intoxicated Parkinsonian mice was reported. Here, we further explore the neuroprotective molecular mechanisms of Tc in Rotenone (ROT) intoxicated mouse model through proteomics approach.MethodsMice were pretreated with Tc extract by oral administration, followed by ROT-intoxication (2mg/kg body wt. for 35 days, subcutaneous). Rotarod, catalepsy, footprint and pole tests were carried out at 35th day to observe the neuroprotective effects of Tc on motor impairment caused by ROT in PD mice. Protein from nigrostriatal region of the mid brain was isolated, and label free quantification (LFQ) was carried out to identify differentially expressed protein (DEPs) in control vs. PD and PD vs. treatment group. Bioinformatics analysis of DEPs was carried out to explore the molecular pathway, cellular location, molecular function of proteins.ResultsIn this study, we report 800 DEPs in control vs. PD and 133 in PD vs. Treatment group. In silico tools clearly demonstrate significant enrichment of biochemical and molecular pathways with DEPs which are known to be important for PD progression, including, mitochondrial gene expression, hypothetical network for drug addiction, PD pathways, TGF-β signaling, Alzheimer’s disease, Odorant GPCRs and chemokine signaling pathway.ConclusionThis study provides a novel insight for the disease progression in PD mouse. More importantly, it demonstrates that Tc exerts the therapeutic effects through the regulation of multiple pathways to protect DAergic neurons.

scholarly journals Unraveling the neuroprotective effect of Tinospora cordifolia in Parkinsonian mouse model through proteomics Approach.

2021 ◽  
Author(s):  
Hareram Birla ◽  
Chetan Keswani ◽  
Saumitra Sen Singh ◽  
Walia Zahra ◽  
Hagera Dilnashin ◽  
...  
Keyword(s):  
Treatment Group ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Mitochondrial Gene ◽  
Tinospora Cordifolia ◽  
Therapeutic Effects ◽  
Proteomics Data ◽  
Proteomics Approach ◽  
Multiple Drugs

Abstract Stress-induced dopaminergic (DAergic) neuronal death in the midbrain region is the primary cause of Parkinson’s disease (PD). From the discovery of L-dopa, multiple drugs were discovered to improve lifestyle of PD patients, but they failed due to their multiple side effects. Tinospora cordifolia (Tc), a medicinal herb has been used in traditional medicines to treat neurodegenerative diseases. In our previous study, the neuroprotective role of Tc against MPTP intoxicated Parkinsonian mice was reported. Here, we further explore the neuroprotective molecular mechanisms of Tc in Rotenone (ROT) intoxicated mouse model through proteomics approach. Mice were pretreated with Tc extract by oral administration, followed by ROT-intoxication. Behavioral tests were performed to check motor functions of mice. Protein was isolated, and label free quantification (LFQ) was carried out to identify differentially expressed protein (DEPs) in control vs. PD and PD vs. treatment group. In this study, we report 800 DEPs in control vs. PD and 133 in PD vs. Treatment group. In silico tools clearly demonstrate significant enrichment of biochemical and molecular pathways with DEPs which are known to be important for PD progression including mitochondrial gene expression, PD pathways, TGF-β signaling, Alzheimer’s disease etc. This results were further validated by qRT-PCR and found that the expression of target gene were identical to the proteomics data. This study provides a novel insight for the disease progression as well new therapeutic tagets. More importantly, it demonstrates that Tc exerts the therapeutic effects through the regulation of multiple pathways to protect DAergic neurons.

scholarly journals Neuroprotective Effects of Tripeptides—Epigenetic Regulators in Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 14 (6) ◽  
pp. 515
Author(s):  
Vladimir Khavinson ◽  
Anastasiia Ilina ◽  
Nina Kraskovskaya ◽  
Natalia Linkova ◽  
Nina Kolchina ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Dna Sequences ◽  
Dendritic Spine ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Intraperitoneal Administration ◽  
Neuroprotective Effects ◽  
Model Of Alzheimer’S Disease

KED and EDR peptides prevent dendritic spines loss in amyloid synaptotoxicity in in vitro model of Alzheimer’s disease (AD). The objective of this paper was to study epigenetic mechanisms of EDR and KED peptides’ neuroprotective effects on neuroplasticity and dendritic spine morphology in an AD mouse model. Daily intraperitoneal administration of the KED peptide in 5xFAD mice from 2 to 4 months of age at a concentration of 400 μg/kg tended to increase neuroplasticity. KED and EDR peptides prevented dendritic spine loss in 5xFAD-M mice. Their action’s possible molecular mechanisms were investigated by molecular modeling and docking of peptides in dsDNA, containing all possible combinations of hexanucleotide sequences. Similar DNA sequences were found in the lowest-energy complexes of the studied peptides with DNA in the classical B-form. EDR peptide has binding sites in the promoter region of CASP3, NES, GAP43, APOE, SOD2, PPARA, PPARG, GDX1 genes. Protein products of these genes are involved in AD pathogenesis. The neuroprotective effect of EDR and KED peptides in AD can be defined by their ability to prevent dendritic spine elimination and neuroplasticity impairments at the molecular epigenetic level.

scholarly journals Xiangshao Granule Exerts Antidepressive Effects in a Depression Mouse Model by Ameliorating Deficits in Hippocampal BDNF and TrkB

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Yi Chen ◽  
Jie Liu ◽  
Xiaoting Wu ◽  
Edouard Collins Nice
Keyword(s):  
Treatment Group ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Open Field Test ◽  
The Body ◽  
Control Group ◽  
Therapeutic Effects ◽  
Model Group ◽  
Depression Group ◽  
Antidepressive Effects

This study explores the therapeutic effects of Xiangshao granules in a mouse depression model and examines the potential molecular mechanisms involved. After 21 consecutive days of chronic stress challenge, all mice were divided into three groups: control group, depression group, and Xiangshao granule treatment group. On the 22nd day, rats in the Xiangshao granule treatment group received Xiangshao granules via gastrogavage for 3 consecutive weeks. Depression group mice showed a significant reduction of crossings (P<0.01) but not rearings (P<0.05). Serum CRH, CORT, and ACTH levels were significantly increased in depression mice compared with control (P<0.05) and the expression levels of hippocampal BDNF and TrkB were reduced in the model group (P<0.05). However, Xiangshao granule treatment remarkably rescued the decrease in the body weight (P<0.05), increased crossings in the open field test (P<0.05), upregulated the expression of hippocampal BDNF and TrkB expression, and reduced the serum CRH, CORT, and ACTH concentrations compared with the depression group (P<0.05). Collectively, these results demonstrated that Xiangshao granule could effectively induce antidepressive effects in the depression mouse model by ameliorating the expression of hippocampal BDNF and TrkB.

scholarly journals Ganglioside GM1 Targets Astrocytes to Stimulate Cerebral Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Charles Finsterwald ◽  
Sara Dias ◽  
Pierre J. Magistretti ◽  
Sylvain Lengacher
Keyword(s):  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Brain Diseases ◽  
Mitochondrial Activity ◽  
Ganglioside Gm1 ◽  
Neuroprotective Effects ◽  
Wide Range ◽  
Cord Injury ◽  
Clinical Benefits ◽  
The Brain

Gangliosides are major constituents of the plasma membrane and are known to promote a number of physiological actions in the brain, including synaptic plasticity and neuroprotection. In particular, the ganglioside GM1 was found to have a wide range of preclinical and clinical benefits in brain diseases such as spinal cord injury, Huntington’s disease and Parkinson’s disease. However, little is known about the underlying cellular and molecular mechanisms of GM1 in the brain. In the present study, we show that GM1 exerts its actions through the promotion of glycolysis in astrocytes, which leads to glucose uptake and lactate release by these cells. In astrocytes, GM1 stimulates the expression of several genes involved in the regulation of glucose metabolism. GM1 also enhances neuronal mitochondrial activity and triggers the expression of neuroprotection genes when neurons are cultured in the presence of astrocytes. Finally, GM1 leads to a neuroprotective effect in astrocyte-neuron co-culture. Together, these data identify a previously unrecognized mechanism mediated by astrocytes by which GM1 exerts its metabolic and neuroprotective effects.

scholarly journals Ultra-Performance Liquid Chromatography/Mass Spectrometry-Based Metabolomics for Discovering Potential Biomarkers and Metabolic Pathways of Colorectal Cancer in Mouse Model (ApcMin/+) and Revealing the Effect of Honokiol

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin Chen ◽  
Bo-lun Shi ◽  
Run-zhi Qi ◽  
Xing Chang ◽  
Hong-gang Zheng
Keyword(s):  
Colorectal Cancer ◽  
Mouse Model ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Ultra Performance Liquid Chromatography ◽  
Therapeutic Effects ◽  
Anticancer Activities ◽  
Metabolic Disturbances ◽  
Endogenous Metabolites

Endogenous metabolites are a class of molecules playing diverse and significant roles in many metabolic pathways for disease. Honokiol (HNK), an active poly-phenolic compound, has shown potent anticancer activities. However, the detailed crucial mechanism regulated by HNK in colorectal cancer remains unclear. In the present study, we investigated the therapeutic effects and the underlying molecular mechanisms of HNK on colorectal cancer in a mouse model (ApcMin/+) by analyzing the urine metabolic profile based on metabolomics, which is a powerful tool for characterizing metabolic disturbances. We found that potential urine biomarkers were involved in the metabolism of compounds such as purines, tyrosines, tryptophans, etc. Moreover, we showed that a total of 27 metabolites were the most contribution biomarkers for intestinal tumors, and we found that the citrate cycle (TCA cycle) was regulated by HNK. In addition, it was suggested that the efficacy of HNK was achieved by affecting the multi-pathway system via influencing relevant metabolic pathways and regulating metabolic function. Our work also showed that high-throughput metabolomics can characterize the regulation of metabolic disorders as a therapeutic strategy to prevent colorectal cancer.

scholarly journals Nimodipine-Dependent Protection of Schwann Cells, Astrocytes and Neuronal Cells from Osmotic, Oxidative and Heat Stress Is Associated with the Activation of AKT and CREB

2019 ◽  
Vol 20 (18) ◽  
pp. 4578 ◽  
Author(s):  
Sandra Leisz ◽  
Sebastian Simmermacher ◽  
Julian Prell ◽  
Christian Strauss ◽  
Christian Scheller
Keyword(s):  
Heat Stress ◽  
Schwann Cells ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Neuronal Cells ◽  
Cell Types ◽  
Stress Conditions ◽  
Cell Culture Supernatant ◽  
Neuroprotective Effects ◽  
Stress Dependent

Clinical and experimental data assumed a neuroprotective effect of the calcium channel blocker nimodipine. However, it has not been proven which neuronal or glial cell types are affected by nimodipine and which mechanisms underlie these neuroprotective effects. Therefore, the aim of this study was to investigate the influence of nimodipine treatment on the in vitro neurotoxicity of different cell types in various stress models and to identify the associated molecular mechanisms. Therefore, cell lines from Schwann cells, neuronal cells and astrocytes were pretreated for 24 h with nimodipine and incubated under stress conditions such as osmotic, oxidative and heat stress. The cytotoxicity was measured via the lactate dehydrogenase (LDH) activity of cell culture supernatant. As a result, the nimodipine treatment led to a statistically significantly reduced cytotoxicity in Schwann cells and neurons during osmotic (p ≤ 0.01), oxidative (p ≤ 0.001) and heat stress (p ≤ 0.05), when compared to the vehicle. The cytotoxicity of astrocytes was nimodipine-dependently reduced during osmotic (p ≤ 0.01), oxidative (p ≤ 0.001) and heat stress (not significant). Moreover, a decreased caspase activity as well as an increased proteinkinase B (AKT) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation could be observed after the nimodipine treatment under different stress conditions. These results demonstrate a cell type-independent neuroprotective effect of the prophylactic nimodipine treatment, which is associated with the prevention of stress-dependent apoptosis through the activation of CREB and AKT signaling pathways and the reduction of caspase 3 activity.

Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer’s Disease

2017 ◽  
Vol 59 (4) ◽  
pp. 1415-1426 ◽  
Author(s):  
Michail B. Evgen’ev ◽  
George S. Krasnov ◽  
Inna V. Nesterova ◽  
David G. Garbuz ◽  
Vadim L. Karpov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Intranasal Administration ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Model Of Alzheimer’S Disease ◽  
Human Hsp70

scholarly journals New mouse model of pulmonary hypertension induced by respiratory syncytial virus bronchiolitis

2018 ◽  
Vol 315 (3) ◽  
pp. H581-H589
Author(s):  
Dai Kimura ◽  
Jordy Saravia ◽  
Sridhar Jaligama ◽  
Isabella McNamara ◽  
Luan D. Vu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Respiratory Syncytial Virus ◽  
Mouse Model ◽  
Pulmonary Artery ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Disease Etiology ◽  
Acceleration Time ◽  
Respiratory Syncytial Virus Bronchiolitis ◽  
Syncytial Virus

Pulmonary hypertension (PH) has been observed in up to 75% of infants with moderate to severe respiratory syncytial virus (RSV) bronchiolitis and is associated with significant morbidity and mortality in infants with congenital heart disease. The purpose of the present study was to establish a mouse model of PH secondary to RSV bronchiolitis that mimics the disease etiology as it occurs in infants. Neonatal mice were infected with RSV at 5 days of age and then reinfected 4 wk later. Serum-free medium was administered to age-matched mice as a control. Echocardiography and right ventricular systolic pressure (RVSP) measurements via right jugular vein catheterization were conducted 5 and 6 days after the second infection, respectively. Peripheral capillary oxygen saturation monitoring did not indicate hypoxia at 2–4 days post-RSV infection, before reinfection, and at 2–7 days after reinfection. RSV-infected mice had significantly higher RVSP than control mice. Pulsed-wave Doppler recording of the pulmonary blood flow by echocardiogram demonstrated a significantly shortened pulmonary artery acceleration time and decreased pulmonary artery acceleration time-to-ejection time ratio in RSV-infected mice. Morphometry showed that RSV-infected mice exhibited a significantly higher pulmonary artery medial wall thickness and had an increased number of muscularized pulmonary arteries compared with control mice. These findings, confirmed by RVSP measurements, demonstrate the development of PH in the lungs of mice infected with RSV as neonates. This animal model can be used to study the pathogenesis of PH secondary to RSV bronchiolitis and to assess the effect of treatment interventions. NEW & NOTEWORTHY This is the first mouse model of respiratory syncytial virus-induced pulmonary hypertension, to our knowledge. This model will allow us to decipher molecular mechanisms responsible for the pathogenesis of pulmonary hypertension secondary to respiratory syncytial virus bronchiolitis with the use of knockout and/or transgenic animals and to monitor therapeutic effects with echocardiography.

scholarly journals UBA2 Activates Wnt/ β-catenin Signaling Pathway during Protection of R28 Retinal Precursor Cells from Hypoxia by Extracellular Vesicles derived from Placental Mesenchymal Stem Cells

2020 ◽  
Author(s):  
Kyungmin Koh ◽  
Mira Park ◽  
Eun Soo Bae ◽  
Van-An Duong ◽  
Jong-Moon Park ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Treatment Group ◽  
Signaling Pathway ◽  
Precursor Cells ◽  
Therapeutic Effects ◽  
Label Free ◽  
Related Factors ◽  
Cell Therapies ◽  
Placental Mesenchymal Stem Cells

Abstract Background: Stem cell transplantation has been proposed as an alternative treatment for intractable optic nerve disorders characterized by irrecoverable loss of cells. Mesenchymal stem cells, with varying tissue regeneration and recovery capabilities, are being considered for potential cell therapies. To overcome the limitations of cell therapy, we isolated exosomes from human placenta–derived mesenchymal stem cells (hPMSCs), and investigated their therapeutic effects in R28 cells (retinal precursor cells) exposed to CoCl2. Method: After nine hours of exposure to CoCl2, the hypoxic damaged R28 cells were divided into non treatment group (CoCl2+R28 cells) and treatment group (CoCl2+R28 cells treated with exosome). Immunoblot analysis was performed for Pcna, Hif-1α, Vegf, Vimentin, Thy-1, Gap43, Ermn, Neuroflament, Wnt3a, β-catenin, phospo-GSK3β, Lef-1, UBA2, Skp1, βTrcp, and ubiquitin. The proteomes of each group were analyzed by liquid chromatography/tandem mass (LC-MS/MS) spectrometry. Differentially expressed proteins (DEPs) were detected by label-free quantification and the interactions of the proteins were examined through signal transduction pathway and gene ontology analysis. Result: We observed that Exosome could significantly recover proliferation damaged by CoCl2 treatment. In addition, treatment group presented the decreased expression of Hif-1α protein (P < 0.05) and increased expression of proliferation marker, Pcna, and nerve regeneration–related factors such as Vimentin, Thy-1 and Neuroflament (P < 0.05) compared with non-treatment group. In total, 200 DEPs were identified in non-treatment group and treatment group (fold change ≥ 2, p < 0.05). Catenin and ubiquitin systems (UBA2, UBE2E3, UBE2I) were found in both the DEP lists of downregulated proteins from non-treatment group and upregulated proteins from treatment group. The mRNA expressions of ubiquitin systems were significantly decreased under hypoxic condition. Moreover, UBA2 and Wnt/β-catenin protein were associated with rescue of the hypoxic damaged R28 cells. Using a siRNA system, we could find it out that hPMSC exosoms could not repair altered expressions of target proteins by CoCl2 in lacking UBA2 R28 cells. Conclusion: This study reported that hypoxic damaged expression of regeneration markers in R28 cells were significantly recovered by hPMSC exosomes. We could also demonstrate that UBA2 played a key role in activating the Wnt/β-catenin signaling pathway during protection of hypoxic damaged R28 cells, induced by hPMSC exosomes.

Cordycepin Exerts Neuroprotective Effects via an Anti-Apoptotic Mechanism based on the Mitochondrial Pathway in a Rotenone-Induced Parkinsonism Rat Model

2019 ◽  
Vol 18 (8) ◽  
pp. 609-620 ◽  
Author(s):  
Xin Jiang ◽  
Pei-Chen Tang ◽  
Qin Chen ◽  
Xin Zhang ◽  
Yi-Yun Fan ◽  
...  
Keyword(s):  
Rat Model ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Effects ◽  
Cyt C

Background: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown. Aim: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson’s Disease (PD) rat model and to delineate the possible associated molecular mechanisms. Methods: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting. Results: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group. Conclusion: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.

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