Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Huang, Peixian; Zhang, Qiuping; Lin, Qian; Lin, Lanfen; Wang, Hong; Chen, Xuan; Jiang, Shuqi; Fu, Hui; Deng, Yuying

doi:10.1111/bpa.12798

Cited by 29 publications

(39 citation statements)

References 74 publications

(104 reference statements)

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“…Previous studies in cultured cancer cell lines suggest that DDX5 promotes oncogene expressions downstream of β-catenin [41,42]. Here, our in vivo studies revealed an unappreciated role of DDX5 in promoting the expression of complement protein C3, a potent inducer of the Wnt/β-catenin cascade that drives tumorigenesis in the colon [44].…”

Section: Discussionsupporting

confidence: 53%

DDX5 targets tissue-specific RNAs to promote intestine tumorigenesis

Abbasi

Long

et al. 2020

Preprint

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Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that an RNA binding protein DDX5 augments C3 and FABP1 expressions post-transcriptionally to promote tumorigenesis in the colon and small intestine, respectively. Mice with epithelial-specific knockout of DDX5 are protected from intestine tumorigenesis. The identification of DDX5 as the common upstream regulator of tissue-specific oncogenic molecules provides a new therapeutic target for intestine cancers.

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Section: Discussionsupporting

confidence: 53%

DDX5 targets tissue-specific RNAs to promote intestine tumorigenesis

Abbasi

Long

et al. 2020

Preprint

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“…Our study revealed that the knockdown of CLDN-1 or CLDN-3 could inhibit myelinogenesis. The expression levels of myelin proteins such as PLP and MBP are significantly reduced in the white matter, and the number of PLP-positive and MBPpositive cells markedly decrease, which result in the reduction of myelin sheath thickness, and subsequently, LA (45,46). The molecular mechanism underlying the basic promoter activity of PLP and MBP depend on AKT activation (47,48), and CLDN-1 or CLDN-3 knockdown can significantly inhibit AKT activity (41,49).…”

Section: ' Discussionmentioning

confidence: 99%

“…Therefore, the reduction of the expression levels of CLDN-1 and CLDN-3 in LA patients may attenuate MBP and PLP synthesis by downregulating AKT signaling. Besides, the increased levels of phosphorylated-AKT promotes Wnt/b-catenin/Tcf4 signal transduction; this inhibits OLIG2, SOX10, PLP, and MBP expression in OPCs (46). The differentiation or maturation of OPCs is regulated by the transcription factors OLIG1, OLIG2, NKX2.2, and SOX10 (50).…”

Section: ' Discussionmentioning

confidence: 99%

Claudin-1 and Claudin-3 as Molecular Regulators of Myelination in Leukoaraiosis Patients

Chen

Zhang

Mei

et al. 2021

Clinics

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Leukoaraiosis is described as white matter lesions that are associated with cognitive dysfunction, neurodegenerative disorders, etc. Myelin depletion is a salient pathological feature of, and the loss of oligodendrocytes is one of the most robust alterations evident in, white matter degeneration. Recent studies have revealed that claudin proteins are aberrantly expressed in leukoaraiosis and regulate oligodendrocyte activity. However, the roles of claudin-1 and claudin-3 in oligodendrocytes and leukoaraiosis are still not well-defined. METHODS: Quantitative polymerase chain reaction was used to measure the expression of claudin-1 (CLDN1), claudin-3 (CLDN3), and myelinogenesis-related genes such as myelin basic protein (MBP), proteolipid protein (PLP), oligodendrocyte transcription factor 2 (OLIG2), and SRY-box transcription factor 10 (SOX10) in leukoaraiosis patients (n=122) and healthy controls (n=122). The expression of claudin-1 and claudin-3 was either ectopically silenced or augmented in Oli-neu oligodendrocytes, and colony formation, apoptosis, and migration assays were performed. Finally, the expression of myelin proteins was evaluated by western blotting. RESULTS: Our results revealed that in addition to SOX10, the expression levels of claudin-1, claudin-3, and myelinogenesis-related proteins were prominently downregulated in leukoaraiosis patients, compared to those in healthy controls. Furthermore, the growth and migration of Oli-neu cells were downregulated upon silencing claudin-1 or claudin-3. However, the overexpression of claudin-1 or claudin-3 resulted in the reduction of the degree of apoptosis in Oli-neu cells. In addition, claudin-1 and claudin-3 promoted the expression of MBP, OLIG2, PLP, and SOX10 at the translational level. CONCLUSION: Our data has demonstrated that the abnormal expression of claudin-1 and claudin-3 regulates the pathological progression of leukoaraiosis by governing the viability and myelination of oligodendrocytes. These findings provide novel insights into the regulatory mechanisms underlying the roles of claudin-1 and claudin-3 in leukoaraiosis.

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“…NG2 is a type-1 membrane protein, which is expressed by OPCs [25]. OPCs gradually differentiated into mature oligodendrocytes labeled CNPase or PLP under the action of differentiation promoting transcription factors [26,27]. The maturation of OPCs plays an important role in the myelination of targeting axons.…”

Section: Discussionmentioning

confidence: 99%

Clemastine Improves Hypomyelination in Rats with Hypoxic–Ischemic Brain Injury by Reducing Astroglia-Derived IL-1β via Autophagy

Xie¹,

Niu²,

Gao³

et al. 2020

Preprint

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Background Cardiac arrest can lead to a poor prognosis of the nervous system. Neuroinflammation plays an important role in hypoxic ischemic brain injury (HIBI). Regulation of inflammation via autophagy might be a suitable therapeutic target in HIBI. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated astrocytes via autophagy and improving axonal hypomyelination in HIBI.Methods A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, autophagy related protein and OPCs differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of astrocytes and OPCs were used to explore the link between astrocytes activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher’s protected least significant difference test.Results Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. Expression of LC3Ⅱ/Ⅰdecreased after astrocytic activation. Co-culture of astrocytes and OPCs with oxygen glucose deprivation treatment exhibited NLRP3/1β upregulation and PLP downregulation. Clemastine could downregulate NLRP3/1β and reverse hypomyelination by promoting the autophagy.Conclusions Clemastine could improve axonal hypomyelination by inhibiting astrocytes activation via promoting the autophagy in BCCAO rats, thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.

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Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Cited by 29 publications

References 74 publications

DDX5 targets tissue-specific RNAs to promote intestine tumorigenesis

DDX5 targets tissue-specific RNAs to promote intestine tumorigenesis

Claudin-1 and Claudin-3 as Molecular Regulators of Myelination in Leukoaraiosis Patients

Clemastine Improves Hypomyelination in Rats with Hypoxic–Ischemic Brain Injury by Reducing Astroglia-Derived IL-1β via Autophagy

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