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1.
J Neurosci ; 38(6): 1575-1587, 2018 02 07.
Article in English | MEDLINE | ID: mdl-29326173

ABSTRACT

Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFƟ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat-Wilson syndrome.SIGNIFICANCE STATEMENT Bergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat-Wilson syndrome.


Subject(s)
Cerebellum/cytology , Cerebellum/growth & development , Neurogenesis/genetics , Neurogenesis/physiology , Neuroglia/physiology , Zinc Finger E-box Binding Homeobox 2/genetics , Zinc Finger E-box Binding Homeobox 2/physiology , Animals , Astrocytes/physiology , Cell Count , Cerebellum/physiology , Facies , Gene Expression Profiling , Hirschsprung Disease/genetics , Intellectual Disability/genetics , Locomotion/physiology , Mice , Mice, Transgenic , Microcephaly/genetics , Neural Stem Cells/physiology , Oligodendroglia/physiology , Purkinje Cells/physiology , Transcriptome/physiology
2.
World J Clin Cases ; 12(17): 3035-3044, 2024 Jun 16.
Article in English | MEDLINE | ID: mdl-38898858

ABSTRACT

BACKGROUND: Some patients with coronary atherosclerotic heart disease experience major adverse cardiac events (MACE) and require readmission after Coronary Artery Bypass Grafting (CABG) surgery. This is often attributed to patients' unhealthy lifestyles and dietary habits, inadequate understanding of the disease, and poor disease management compliance. Thus, searching for more targeted nursing intervention models that can enhance patients' self-management abilities and reduce the risk of readmission after CABG surgery is significant. AIM: To observe the impact of specialized nursing outpatient case management on patients after CABG surgery. METHODS: A total of 103 patients who underwent CABG surgery in our hospital between April 2021 and April 2022 comprised the study sample. The patients were divided into two groups using an odd-even number grouping method. The control group received routine nursing care, while the case management group received specialized nursing outpatient case management. The differences in psychological status, adherence to medical treatment, self-care ability, knowledge mastery, quality of life scores, and the occurrence rate of MACE were compared between the two groups. RESULTS: After the intervention, the case management group had lower scores on the self-rating depression scale and self-rating anxiety scale and lower MACE rate, as well as higher scores for adherence to a healthy diet, medication adherence, good lifestyle habits, regular exercise, and timely follow-up, higher scores on the Coronary Heart Disease Self-Management Scale, higher scores for managing adverse habits, symptoms, emotional cognition, emergency response, disease knowledge, general lifestyle, and treatment adherence, higher scores for understanding coronary heart disease, recognizing the importance of medication adherence, understanding self-care points after CABG surgery, and being aware of post-CABG precautions, higher scores for physical well-being, disease condition, general health, social-psychological well-being, and work-related aspects (P < 0.05). CONCLUSION: Specialized nursing outpatient case management can enhance patient adherence to medical treatment, knowledge mastery, psychological well-being, and overall quality of life in patients after CABG surgery.

3.
Mol Cancer Ther ; 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37963566

ABSTRACT

Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more saccharide-structure-perturbing compounds, a repurposed drug screen by using a library consisting of 1530 FDA-approved drugs was performed. Interestingly, an antipsychotic drug, penfluridol, was identified as being able to decrease cell surface Wheat germ agglutinin (WGA) staining. In the presence of penfluridol, cell membrane glycoproteins PD-L1 shifted to a lower molecular weight. Further studies demonstrated that penfluridol treatment caused an accumulation of high-mannose oligosaccharides, especially Man5-7GlcNAc2 glycan structures. Mechanistically, this effect is due to direct targeting of MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation. Moreover, we found that altered glycosylation of PD-L1 caused by penfluridol disrupted interactions between PD-1 and PD-L1, resulting in activation of T-cell tumor immunity. In a mouse xenograft and glioma model, penfluridol enhanced the anti-tumor effect of the anti-PD-L1 antibody in vivo. Overall, these findings revealed an important biological activity of the antipsychotic drug penfluridol as an inhibitor of glycan processing and proposed a repurposed use of penfluridol in anti-tumor therapy through activation of T-cell immunity.

4.
Open Biol ; 12(4): 210310, 2022 04.
Article in English | MEDLINE | ID: mdl-35472288

ABSTRACT

Cigarette smoke significantly induces oxidative stress, resulting in cardiovascular disease. NRF2, a well-known antioxidative stress response factor, is generally considered to play protective roles in cardiovascular dysfunction triggered by oxidative stress. Interestingly, recent studies reported adverse effects of NRF2 on the cardiovascular system. These unfavourable pathogenic effects of NRF2 need to be further investigated. Our work shows that cigarette smoke extract (CSE)-induced oxidative stress disturbs fibronectin (FN) assembly during angiogenesis. Furthermore, this effect largely depends on hyperactive NRF2-STAT3 signalling, which consequently promotes abnormal FN deposition. Consistently, disruption of this pathway by inhibiting NRF2 or STAT3 prevents CSE-induced FN disorganization and vasculature disruption in human umbilical vein endothelial cells or zebrafish. Taken together, these findings demonstrate the cardiovascular dysfunction caused by CSE from a novel perspective that NRF2-dependent signalling engages in FN disorganization.


Subject(s)
Cigarette Smoking , NF-E2-Related Factor 2 , Animals , Endothelial Cells/metabolism , Fibronectins/metabolism , Fibronectins/pharmacology , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Nicotiana , Zebrafish/metabolism
5.
Curr Top Med Chem ; 18(28): 2420-2428, 2018.
Article in English | MEDLINE | ID: mdl-30526462

ABSTRACT

Histone deacetylases (HDACs), as epigenetic modifiers, are essential for gene transcriptional activities. The alternation of HDACs expression, mutation and/or inappropriate recruitments has been discovered in a broad range of tumors contributing to the tumorigenesis through a serial of biological pathways. HDACs, therefore, are characterized as promising cancer therapeutic targets, and their inhibitors are under rapid development. Here, we discuss HDAC inhibitors in terms of their functional mechanism establishing the anti-tumor effects and potential clinical applications including the synergistic effects in combinational treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Carcinogenesis , Epigenesis, Genetic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Humans , Immunotherapy , Neoplasms/genetics , Neoplasms/therapy
6.
Bio Protoc ; 7(14): e2404, 2017 Jul 20.
Article in English | MEDLINE | ID: mdl-34541135

ABSTRACT

Glioblastoma (GBM) is the most common primary brain cancer in adults and has a poor prognosis. It is characterized by a high degree of cellular infiltration that leads to tumor recurrence, atypical hyperplasia, necrosis, and angiogenesis. Despite aggressive treatment modalities, current therapies are ineffective for GBM. Mouse GBM models not only provide a better understanding in the mechanisms of gliomagenesis, but also facilitate the drug discovery for treating this deadly cancer. A retroviral vector system that expresses PDGFBB (Platelet-derived growth factor BB) and inactivates PTEN (Phosphatase and tensin homolog) and P53 tumor suppressors provides a rapid and efficient induction of glioma in mice with full penetrance. In this protocol, we describe a simple and practical method for inducing GBM formation by retrovirus injection in the murine brain. This system gives a spatial and temporal control over the induction of glioma and allows the assessment of therapeutic effects with a bioluminescent reporter.

7.
Cell Cycle ; 16(18): 1654-1660, 2017 Sep 17.
Article in English | MEDLINE | ID: mdl-28806136

ABSTRACT

Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.


Subject(s)
Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Carcinogenesis/metabolism , Carcinogenesis/pathology , Glioma/metabolism , Glioma/pathology , Oligodendrocyte Transcription Factor 2/metabolism , Animals , Brain Neoplasms/therapy , Disease Models, Animal , Glioma/therapy , Humans , Signal Transduction
8.
Dev Cell ; 40(6): 566-582.e5, 2017 03 27.
Article in English | MEDLINE | ID: mdl-28350989

ABSTRACT

A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.


Subject(s)
Central Nervous System/metabolism , Central Nervous System/pathology , MicroRNAs/metabolism , Myelin Sheath/metabolism , Myelin Sheath/pathology , Nerve Regeneration , Wound Healing , Animals , Cell Differentiation/drug effects , Cell Lineage/drug effects , Central Nervous System/drug effects , Demyelinating Diseases/genetics , Demyelinating Diseases/pathology , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Deletion , Lecithins/pharmacology , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , Multiple Sclerosis/genetics , Multiple Sclerosis/pathology , Multiple Sclerosis/therapy , Myelin Sheath/drug effects , Nerve Regeneration/drug effects , Nerve Regeneration/genetics , Nerve Tissue Proteins/metabolism , Oligodendroglia/drug effects , Oligodendroglia/metabolism , Optic Nerve/pathology , Optic Nerve/ultrastructure , Phenotype , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/pathology , Wound Healing/drug effects , Wound Healing/genetics
9.
Cancer Cell ; 29(5): 669-683, 2016 05 09.
Article in English | MEDLINE | ID: mdl-27165742

ABSTRACT

Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Proliferation/genetics , ErbB Receptors/genetics , Glioma/genetics , Nerve Tissue Proteins/genetics , Receptors, Platelet-Derived Growth Factor/genetics , Animals , Astrocytes/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , ErbB Receptors/metabolism , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Glioma/metabolism , Glioma/pathology , Humans , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Oligodendroglia/metabolism , Phenotype , Receptors, Platelet-Derived Growth Factor/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Spheroids, Cellular/metabolism , Survival Analysis
10.
Nat Med ; 20(9): 1035-42, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25150496

ABSTRACT

Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.


Subject(s)
Brain Neoplasms/metabolism , GTP-Binding Protein alpha Subunits, Gs/metabolism , Medulloblastoma/metabolism , Cyclic AMP/metabolism , GTP-Binding Protein alpha Subunits, Gs/genetics , Hedgehog Proteins/metabolism , Humans , Neural Stem Cells/metabolism , Signal Transduction
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