Attenuation of Myeloid-Specific TGFβ Signaling Induces Inflammatory Cerebrovascular Disease and Stroke

Hollander, M. Christine; Latour, Lawrence L.; Yang, Dan; Ishii, Hiroki; Xiao, Zhiguang; Min, Yongfen; Ray-Choudhury, Abhik; Munasinghe, Jeeva; Merchant, Anand S.; Lin, Ping Chang; Hallenbeck, John M.; Boehm, Manfred; Yang, Li

doi:10.1161/circresaha.116.310349

Cited by 18 publications

(12 citation statements)

References 47 publications

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“…The H-modules 1 and 2 constitute a comprehensive targeting set to regulate this pathway. This pathway was suggested to play a role in cerebral ischemia and impaired functional cortical plasticity and to be a primary process of releasing of inflammatory cytokines (Liguz-Lecznar et al, 2015; McCoy and Tansey, 2015; Liu, et al, 2016; Hollander et al, 2017; Wang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Intermodule Coupling Analysis of Huang-Lian-Jie-Du Decoction on Stroke

Wang

Zhou

et al. 2019

Front. Pharmacol.

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Huang-Lian-Jie-Du Decoction (HLJDD) is a "Fangji" made up of well-designed Chinese herb array and widely used to treat ischemic stroke. Here we aimed to investigate pharmacological mechanism by introducing an inter-module analysis to identify an overarching view of target profile and action mode of HLJDD. Stroke-related genes were obtained from OMIM (Online Mendelian Inheritance in Man). And the potential target proteins of HLJDD were identified according to TCMsp (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform). The two sets of molecules related to stroke and HLJDD were respectively imported into STRING database to construct the stroke network and HLJDD network, which were dissected into modules through MCODE, respectively. We analyzed the inter-module connectivity by quantify "coupling score" (CS) between HLJDD-modules (H-modules) and stroke-modules (S-module) to explore the pharmacological acting pattern of HLJDD on stroke. A total of 267 stroke-related proteins and 15 S-modules, 335 HLJDD putative targeting proteins, and 13 H-modules were identified, respectively. HLJDD directly targeted 28 proteins in stroke network, majority (16, 57.14%) of which were in S-modules 1 and 4. According to the modular map based on inter-module CS analysis, H-modules 1, 2, and 8 densely connected with S-modules 1, 3, and 4 to constitute a module-to-module bridgeness, and the enriched pathways of this bridgeness with top significance were TNF signaling pathway, HIF signaling pathway, and PI3K-Akt signaling pathway. Furthermore, through this bridgeness, H-modules 2 and 4 cooperatively work together to regulate mitochondrial apoptosis against the ischemia injury. Finally, the core protein in H-module 4 account for mitochondrial apoptosis was validated by an in vivo experiment. This study has developed an integrative approach by inter-modular analysis for elucidating the "shotgun-like" pharmacological mechanism of HLJDD for stroke.

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Section: Discussionmentioning

confidence: 99%

Intermodule Coupling Analysis of Huang-Lian-Jie-Du Decoction on Stroke

Wang

Zhou

et al. 2019

Front. Pharmacol.

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“…TGF-beta acted as an anti-inflammatory factor. Myeloid TGFβ signaling has been suggested to be utilized for interference with stroke etiology-associated inflammation or vascular diseases [36]. The central intracellular mediator of TGF-beta signaling, namely, SMAD4, has been implicated in maintaining cerebrovascular integrity [37].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke

Guo

Yang

Liang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long non-coding RNAs (lncRNAs) are potential biomarkers of tumors, cardiac disease, and cerebral disease because of their interaction with coding RNAs. This work focused on ischemic stroke (IS) and aimed to identify novel lncRNA biomarkers and construct lncRNA-related networks in IS. Methods: Differentially expressed lncRNAs were identified using Arraystar Human LncRNA Microarray v4.0, and validated with qRT-PCR. A lncRNA–mRNA co-expression network and a lncRNA–miRNA–mRNA regulatory network were constructed. Functional and pathway analyses were then performed. Results: In total, 560 up-regulated and 690 down-regulated differentially expressed lncRNAs were found (P < 0.05, false discovery rate < 0.05, absolute fold change ≥ 2). qRT-PCR results confirmed that lncRNA-ENST00000568297, lncRNA-ENST00000568243, and lncRNA-NR_046084 exhibited significant differential expression between IS and controls (all P < 0.05). Areas under the curves (AUCs) for these lncRNAs were 0.733, 0.743, and 0.690, respectively, and the combined AUC was 0.843. A coding–noncoding co-expression (CNC) network was constructed based on Pearson’s correlation coefficient. A specific lncRNA–miRNA–mRNA regulatory network of ENST00000568297, ENST00000568243, and NR_046084 was also constructed. Functional annotation of the up- and down-regulated mRNAs was performed. Pathway analysis enriched IS-related pathways with mRNAs in the lncRNA–miRNA–mRNA regulatory network. Conclusion: LncRNA and mRNA expression profiles in human peripheral blood were altered after IS. ENST00000568297, ENST00000568243, and NR_046084 were identified as novel potential diagnostic biomarkers of IS. Analysis of the CNC network and lncRNA–miRNA–mRNA regulatory network suggested that lncRNAs may participate in IS pathophysiology by regulating pivotal miRNAs, mRNAs, or IS-related pathways.

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“…VEGF is involved in angiogenic growth and blood‐brain barrier (BBB) permeability . Similarly, TGFβ is a major regulator of neuroinflammation and vascular homeostasis, with critical roles at the BBB junction, including astrocytic activation and induction of important changes to neuronal extracellular matrix and hyperexcitability …”

Section: Introductionmentioning

confidence: 99%

Plasma biomarkers of astrocytic and neuronal dysfunction in early‐ and late‐onset Alzheimer's disease

Elahi

Casaletto

Joie

et al. 2020

Alzheimer's & Dementia

160

131

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Introduction We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early‐onset versus late‐onset Alzheimer's disease (EOAD and LOAD). Methods Plasma was analyzed using ultra‐sensitive immuno‐based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL‐6, IP‐10, IL‐10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

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Attenuation of Myeloid-Specific TGFβ Signaling Induces Inflammatory Cerebrovascular Disease and Stroke

Cited by 18 publications

References 47 publications

Intermodule Coupling Analysis of Huang-Lian-Jie-Du Decoction on Stroke

Intermodule Coupling Analysis of Huang-Lian-Jie-Du Decoction on Stroke

Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke

Plasma biomarkers of astrocytic and neuronal dysfunction in early‐ and late‐onset Alzheimer's disease

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