scholarly journals Methionine Restriction Alleviates Aging-related Cognitive Dysfunction via Stimulating FGF21-driven Mitochondrial Biogenesis (P14-026-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Bo Ren ◽  
Luanfeng Wang ◽  
Zhigang Liu ◽  
Xuebo Liu
Keyword(s):  
Amino Acid ◽  
Cognitive Function ◽  
Signaling Pathway ◽  
Mitochondrial Biogenesis ◽  
Metabolic Phenotype ◽  
Fibroblast Growth Factor 21 ◽  
Behavioral Tests ◽  
Mice Model ◽  
Neuroprotective Effects ◽  
Methionine Restriction

Abstract Objectives Moderate dietary methionine restriction (MR) extends life span in various animal models and delays the onset of aging-associated pathologies. However, the neuroprotective effects and underlying mechanism of MR on age and age-related diseases still remain to be investigated. Notably, fibroblast growth factor-21 (FGF21), a MR responding hormone mostly generated from liver, plays a critical role in neuronal mitochondrial function. Here, we aimed to reveal the neuroprotective effects of MR and the mediating role of FGF21 in aging mice model. Methods Male C57BL/6 mice (2-, 12-, and 15- month-old) were treated with control methionine diet (0.86% methionine) and methionine restriction diet (0.17% methionine) for 3 months. Adeno-associated virus was employed to build FGF21 knockdown mice model. Behavioral tests, synapse ultrastructure detection, and amino acid metabolomics were performed to evaluate cognitive function, neuron damage and signaling pathway activation. Results In behavioral tests, we found that MR significantly improved aging-induced decreased in spatial memory and cognitive function. Meanwhile, MR ameliorated neuronal damage and synapses structure damages in aging mice hippocampus. Moreover, MR significantly improved the mRNA expression of mitochondrial biogenesis and dynamics related genes such as COX2/fis1/pink1/binp1/drp1 in aging mice brain. MR also altered plasma amino acid metabolic phenotype-related glutathione synthesis, energy metabolism, and nervous system function. Furthermore, we found that MR could significant increase FGF21 level in both liver and serum of aging mice. Knockdown of FGF21 dramatically diminished the benefits of MR on cognitive impairments. Conclusions These results showed that MR mitigated aging-induced memory impairment and synapses structure damages via activating FGF21 signaling pathway. The study suggest that this dietary restriction might be plausible therapeutic intervention for aging and other neurodegenerative diseases such AD and PD. Funding Sources This work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China. Supporting Tables, Images and/or Graphs

scholarly journals Exercise-Linked Irisin Prevents Mortality and Enhances Cognition in a Mice Model of Cerebral Ischemia by Regulating Klotho Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Zhao Jin ◽  
Zongze Zhang ◽  
Jianjuan Ke ◽  
Yanlin Wang ◽  
Huisheng Wu
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Cerebral Ischemia ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ros Generation ◽  
Mice Model ◽  
Stroke Patients ◽  
Neuroprotective Effects ◽  
Protein Expressions ◽  
The Impact

Irisin, which can be released in the hippocampus after physical exercise, is demonstrated to have beneficial effects on neurovascular diseases. This study investigated the impact of exercise linked-irisin on mortality and cognition in a mice model of cerebral ischemia and further explored its underlying mechanism. The cerebrospinal concentrations of irisin and klotho from ischemic stroke patients were measured with an enzyme-linked immunosorbent assay (ELISA). The cognitive function of mice was evaluated by a series of behavioural experiments. The expressions of klotho, MnSOD, and FOXO3a in the hippocampus of mice were detected by Western blot. Superoxide production in the brain tissue of mice was evaluated with the dihydroethidium (DHE) dying. The results demonstrated that stroke patients showed a positive correlation between their CSF irisin concentration and klotho concentration. In addition, when mice subjected to cerebral ischemia, their cognitive function was impaired, the protein expressions of klotho, MnSOD, and FOXO3a downregulated, and the production of reactive oxygen species (ROS) increased compared with the sham group. After pretreatment with exogenous irisin, improved cognitive impairment, upregulated protein expressions of klotho, MnSOD, and FOXO3a, and reduced ROS generation were observed in mice with MCAO. However, the neuroprotective effects of irisin compromised with the evidence of severe cognitive impairment, decreased protein expressions of MnSOD and FOXO3a, and increased ROS production in klotho knockout mice. Thus, our results indicated that exercise-linked irisin could prevent mortality and improve cognitive impairment after cerebral ischemia by regulating klotho expression.

scholarly journals Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21

Aging Cell ◽  
2014 ◽  
Vol 13 (5) ◽  
pp. 817-827 ◽  
Author(s):  
Emma K. Lees ◽  
Elżbieta Król ◽  
Louise Grant ◽  
Kirsty Shearer ◽  
Cathy Wyse ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Metabolic Phenotype ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Adult Mice ◽  
Methionine Restriction

Outcomes of Perilla Seed Oil as an Additional Neuroprotective Therapy in Patients with Mild to Moderate Dementia: A Randomized Control Trial

2019 ◽  
Vol 16 (2) ◽  
pp. 146-155
Author(s):  
Chuntida Kamalashiran ◽  
Kusuma Sriyakul ◽  
Junya Pattaraarchachai ◽  
Sombat Muengtaweepongsa
Keyword(s):  
Cognitive Function ◽  
Randomized Control Trial ◽  
Seed Oil ◽  
Ldl Cholesterol ◽  
Neuroprotective Effects ◽  
Moderate Dementia ◽  
Neuroprotective Therapy ◽  
Randomized Control ◽  
Experimental Group ◽  
Perilla Seed

Background: Dementia is a common medical disorder in the elderly. Oxidative stress plays a major role in the process of cognitive decline in dementia. Perilla seed oil demonstrates its neuroprotective effects via anti-oxidative mechanisms against dementia. We investigate neuroprotective effects of perilla seed oil as an additional treatment in patients with mild to moderate dementia. </P><P> Method: A double-blind, randomized-control trial (perilla seed oil versus placebo) in patients with mild to moderate dementia was conducted. Perilla seed oil or placebo was added on with standard treatment for six months. Cognitive function was compared at nine months after enrollment. </P><P> Result: 182 patients, with 94 in the experimental group and 88 in the placebo group, were able to complete the study. Cognitive function is not significantly different compared between groups. However, the total cholesterol and LDL cholesterol were significantly lower in the experimental group. Perilla seed oil had no adverse effect to kidney, liver, blood components or glucose metabolism. Conclusion: Perilla seed oil as additional neuroprotective therapy in patients with mild to moderate dementia does not improve cognitive function. Perilla seed oil significantly reduced total cholesterol and LDL cholesterol. A clinical trial is needed to prove the benefit of cholesterol-lowering effects with perilla seed oil in human.

Exploring the Potential of Capsaicin Against Cancer Metastasis Based on TGF-β Signaling Modulation Through Module-based Network Pharmacology Approach

2020 ◽  
Vol 17 (5) ◽  
pp. 647-660 ◽  
Author(s):  
Shivananda Kandagalla ◽  
Sharath Belenahalli Shekarappa ◽  
Gollapalli Pavan ◽  
Umme Hani ◽  
Manjunatha Hanumanthappa
Keyword(s):  
Amino Acid ◽  
Amino Acid Composition ◽  
Signaling Pathway ◽  
Acid Composition ◽  
Protein Interaction ◽  
Cancer Metastasis ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Mode Analysis ◽  
Network Pharmacology

Background: Capsaicin is an active alkaloid /principal component of red pepper responsible for the pungency of chili pepper. Capsaicin by changing the intracellular redox homeostasis regulate a variety of signaling pathways ultimately producing a divergent cellular outcome. Several reports showed the potential of capsaicin against cancer metastasis, however unexplored molecular mechanism is still an active part of the research. Several growth factors have a critical role during cancer metastasis among them TGF- β signaling play a vital role. Methods: The present study aimed at analyzing capsaicin modulation of TGF-β signaling using network pharmacology approach. The chemical and protein interaction data of capsaicin was curated and abstracted using STITCH4.0, PubChem and ChEMBL database. Further, the compiled data set was subjected to the pathway and functional enrichment analysis using Protein Analysis THrough Evolutionary Relationship (PANTHER) and, Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Meanwhile, the pattern of amino acid composition across the capsaicin targets was analyzed using the EMBOSS Pepstat tool. Capsaicin targets involved in TGF- β were identified and their Protein-Protein Interaction (PPI) network constructed using STRING v10 and Cytoscape (v 3.2.1). From the above-constructed network, the clusters were mined using the MCODE clustering algorithm and finally binding affinity of capsaicin with its targets involved in TGF-β signaling pathway was analyzed using Autodock Vina. Results: The analysis explored capsaicin targets and, their associated functional and pathway annotations. Besides, the analysis also provides a detailed distinct pattern of amino acid composition across the capsaicin targets. The capsaicin targets described as MAPK14, JUN, SMAD3, MAPK3, MAPK1 and MYC involved in TGF-β signaling pathway through pathway enrichment analysis. The binding mode analysis of capsaicin with its targets has shown high affinity with MAPK3, MAPK1, JUN and MYC. Conclusion: The study explores the potential of capsaicin as a potent modulator of TGF-β signaling pathway during cancer metastasis and proposes new methodology and mechanism of action of capsaicin against TGF- β signaling pathway.

scholarly journals Bv8-Like Toxin from the Frog Venom of Amolops jingdongensis Promotes Wound Healing via the Interleukin-1 Signaling Pathway

Toxins ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 15 ◽  
Author(s):  
Jiajia Chang ◽  
Xiaoqin He ◽  
Jingmei Hu ◽  
Peter Muiruri Kamau ◽  
Ren Lai ◽  
...  
Keyword(s):  
Wound Healing ◽  
Signaling Pathway ◽  
Wide Spectrum ◽  
Interleukin 1 ◽  
Full Thickness ◽  
Mice Model ◽  
Small Peptides ◽  
Newborn Mice ◽  
Proliferative Effect ◽  
Inflammatory Phase

Prokineticins are highly conserved small peptides family expressed in all vertebrates, which contain a wide spectrum of functions. In this study, a prokineticin homolog (Bv8-AJ) isolated from the venom of frog Amolops jingdongensis was fully characterized. Bv8-AJ accelerated full-thickness wounds healing of mice model by promoting the initiation and the termination of inflammatory phase. Moreover, Bv8-AJ exerted strong proliferative effect on fibroblasts and keratinocytes isolated from newborn mice by activating interleukin (IL)-1 production. Our findings indicate that Bv8 is a potent wound healing regulator and may reveal the mechanism of rapid wound-healing in amphibian skins.

scholarly journals TAMI-38. CYSTEINE-PROMOTING COMPOUNDS INDUCE MITOCHONDRIAL TOXICITY IN GLIOBLASTOMA THROUGH ALTERED PYRUVATE AND SERINE METABOLISM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii221-ii221
Author(s):  
Evan Noch ◽  
Laura Palma ◽  
Isaiah Yim ◽  
Bhavneet Binder ◽  
Elisa Benedetti ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Glucose Deprivation ◽  
Tumor Metabolism ◽  
Metabolic Phenotype ◽  
Low Grade ◽  
Mitochondrial Toxicity ◽  
Human Cancers ◽  
Pathway Gene

Abstract Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the metabolic alterations that are specific to GBM and that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through System Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Metabolic tracing experiments with 13C6-glucose demonstrate that L-serine is rapidly depleted in GBM cells upon treatment with NAC and CTX, and exogenous serine rescues NAC- and CTX-mediated cell growth inhibition. In addition, these compounds reduce GBM mitochondrial pyruvate transport. We show that cysteine-promoting compounds reduce cell growth and induce mitochondrial toxicity in GBM, which may be due to rapid serine depletion and reduced mitochondrial pyruvate transport. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.

Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer’s Disease

2021 ◽  
pp. 1-5
Author(s):  
Hesam Khodadadi ◽  
Évila Lopes Salles ◽  
Abbas Jarrahi ◽  
Vincenzo Costigliola ◽  
MB Khan ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Decline ◽  
Murine Model ◽  
Early Onset ◽  
Behavioral Tests ◽  
Translational Model ◽  
Therapeutic Modalities ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
Motor Outcomes

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

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