Protection against cerebral infarction by Withaferin A involves inhibition of neuronal apoptosis, activation of PI3K/Akt signaling pathway, and reduced intimal hyperplasia via inhibition of VSMC migration and matrix metalloproteinases

Zhang, Qizhi; Guo, Yu‐Dong; Li, Hao-Mei; Wang, Rui-Zheng; Du, Yifeng

doi:10.1016/j.advms.2016.09.003

Cited by 30 publications

(24 citation statements)

References 51 publications

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“…Recent studies reported that apigenin has protective effects on both neuronal and glial cells during stroke 26,27 . Furthermore, Withaferin A and Carvacrol were also found to protect against cerebral infarction 1,28 .…”

Section: Discussionmentioning

confidence: 96%

“…MMP3 has been associated with vascular risk and can predict the risk of ischemic stroke and myocardial infarction 30 . In the study of Zhang et al, downregulation of MMP2 and MMP9 inhibited cell migration 1 . Chen et al reported a similar result in a rodent model of cerebral ischemia 31 .…”

Section: Discussionmentioning

confidence: 98%

“…Stroke is a major health problem, with high morbidity and mortality in developing and developed countries 1 . According to the World Health Organization, approximately 15 million people suffer from stroke per year worldwide 2 .…”

Section: Introductionmentioning

confidence: 99%

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Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway

Luo

et al. 2019

Exp Mol Med

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This study aimed to explore potential new drugs in the treatment of ischemic stroke by Connectivity Map (CMap) and to determine the role of luteolin on ischemic stroke according to its effects on matrix metalloproteinase-9 (MMP9) and PI3K/Akt signaling pathway. Based on published gene expression data, differentially expressed genes were obtained by microarray analysis. Potential compounds for ischemic stroke therapy were obtained by CMap analysis. Cytoscape and gene set enrichment analysis (GSEA) were used to discover signaling pathways connected to ischemic stroke. Cell apoptosis and viability were, respectively, evaluated by flow cytometry and an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were used to test the expression of MMP9 and the PI3K/Akt signaling pathway-related proteins in human brain microvascular endothelial cells (HBMECs) and tissues. Additionally, the infarct volume after middle cerebral artery occlusion (MCAO) was determined by a TTC (2,3,5-triphenyltetrazolium chloride) assay. The microarray and CMap analyses identified luteolin as a promising compound for future therapies for ischemic stroke. Cytoscape and GSEA showed that the PI3K/Akt signaling pathway was crucial in ischemic stroke. Cell experiments revealed that luteolin enhanced cell viability and downregulated apoptosis via inhibiting MMP9 and activating the PI3K/Akt signaling pathway. Experiments performed in vivo also demonstrated that luteolin reduced the infarct volume. These results suggest that luteolin has potential in the treatment of ischemic stroke through inhibiting MMP9 and activating PI3K/Akt signaling pathway.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

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Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway

Luo

et al. 2019

Exp Mol Med

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“…In an ischemic and hypoxic environment, muscone was found to improve ischemia-reperfusion injury by activating the PI3K/AKT pathway and promoting endothelial eNOS phosphorylation [ 42 ]. Consequently, those ingredients improve the survival rate of nerve cells and reduce the degree of brain damage [ 43 – 45 ]. In addition, well-functioning collateral circulation improves the clinical prognosis of ischemic stroke, so, angiogenesis may be a potential direction for ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Investigate the Active Compounds and Mechanisms of Musk for Ischemic Stroke

Zhang

Liao

Liu

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objectives. This study aims to study the material basis and effective mechanism of musk for ischemic stroke (IS) based on the network pharmacology approach. Methods. We collected the chemical components and target gene of musk from the BATMAN-TCM analytical platform and identified ischemic stroke-related targets from the following databases: DisGeNET, NCBI-Gene, HPO, OMIM, DrugBank, and TTD. The targets of musk and IS were uploaded to the String database to construct the protein-protein interaction (PPI) network, and then, the key targets were analyzed by topological methods. At last, the function biological process and signaling pathways of key targets were carried out by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and cluster analysis by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server and Metascape platform. Results. A total of 29 active compounds involving 1081 predicted targets were identified in musk and there were 1104 IS-related targets. And 88 key targets of musk for IS were obtained including AKT1, MAPK1/3, TP53, TNF, SRC, FOS, CASP3, JUN, NOS3, and IL1B. The GO and KEGG enrichment analysis suggested that these key targets are mainly involved in multiple pathways which participated in TNF signaling pathway, estrogen signaling pathway, prolactin signaling pathway, neurotrophin signaling pathway, T-cell receptor signaling pathway, cAMP signaling pathway, FoxO signaling pathway, and HIF1 signaling pathway. Conclusion. This study revealed that the effective mechanisms of musk against IS would be associated with the regulation of apoptosis, inflammatory response, and gene transcription.

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“…Withaferin-A treatment conferred protection in two mouse models of ALS (16,40). Furthermore, .withaferin-A treatment of a mouse model of cerebral ischemia led to amelioration of pathological changes with reduction in NF-κB-mediated in ammation (41). Despite bene cial properties of withaferin-A, this compound can induce cell death at high dose or prolonged treatment (42).…”

Section: Discussionmentioning

confidence: 99%

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

Kumar

Phaneuf

Cordeau

et al. 2020

Preprint

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Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

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Protection against cerebral infarction by Withaferin A involves inhibition of neuronal apoptosis, activation of PI3K/Akt signaling pathway, and reduced intimal hyperplasia via inhibition of VSMC migration and matrix metalloproteinases

Cited by 30 publications

References 51 publications

Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway

Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway

A Network Pharmacology Approach to Investigate the Active Compounds and Mechanisms of Musk for Ischemic Stroke

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

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