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Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea

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《医学前沿（英文）》 2016年第10卷第3期页码 237-249 doi: 10.1007/s11684-016-0464-9

摘要：

Sensory hair cells in the inner ear are responsible for sound recognition. Damage to hair cells in adult mammals causes permanent hearing impairment because these cells cannot regenerate. By contrast, newborn mammals possess limited regenerative capacity because of the active participation of various signaling pathways, including Wnt and Notch signaling. The Wnt and Notch pathways are highly sophisticated and conserved signaling pathways that control multiple cellular events necessary for the formation of sensory hair cells. Both signaling pathways allow resident supporting cells to regenerate hair cells in the neonatal cochlea. In this regard, Wnt and Notch signaling has gained increased research attention in hair cell regeneration. This review presents the current understanding of the Wnt and Notch signaling pathways in the auditory portion of the inner ear and discusses the possibilities of controlling these pathways with the hair cell fate determiner Atoh1 to regulate hair cell regeneration in the mammalian cochlea.

关键词： inner ear cochlea hair cell regeneration Wnt Notch signaling pathways

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Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling

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《医学前沿（英文）》 2015年第9卷第4期页码 444-456 doi: 10.1007/s11684-015-0421-z

摘要：

Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg⁻¹·d⁻¹); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L⁻¹) was treated with the human equivalent of low (10 or 100 µmol·L⁻¹) and high (1000 µmol·L⁻¹) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.

关键词： aspirin Akt cardiac hypertrophy GSK-3β Wnt/β-catenin

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ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/-catenin signaling

《医学前沿（英文）》 2023年第17卷第4期页码 685-698 doi: 10.1007/s11684-022-0942-1

摘要： Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.

关键词： acute myeloid leukemia acyl-CoA synthetase long chain family member 5 Wnt3a palmitoylation ABT-199

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Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5

Hui Jiang, Shan Zeng, Wenli Ni, Yan Chen, Wenyan Li

《医学前沿（英文）》 2019年第13卷第6期页码 705-712 doi: 10.1007/s11684-019-0703-y

摘要： Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells (HCs) and supporting cells during mouse inner ear development; however, the relationship between the two signaling pathways in the mouse cochlea remains largely unknown. Here, we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5 progenitors during different cochlear development stages. We found that the downregulation of Notch1 in Lgr5 cells from embryonic day (E) 14.5 to E18.5 can drive the quiescent Lgr5 cells to re-enter the cell cycle and differentiate into extra HCs, whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells. No effect was observed on the upregulation or downregulation of Notch1 in Lgr5 cells from E10.5 to E14.5. We concluded that the roles of Notch1 in Wnt-responsive Lgr5 cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5 progenitor activation during cochlear differentiation. Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.

关键词： inner ear cochlear Wnt Notch Lgr5 auditory system

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Wnt/β-catenin signaling pathway and its role in hepatocellular carcinoma

ZHANG Xufeng, YU Liang, LU Yi

《医学前沿（英文）》 2008年第2卷第3期页码 216-228 doi: 10.1007/s11684-008-0042-x

摘要： Wnt/?-catenin signaling pathway has been identified as a key cellular pathway in embryogenesis and disease, including cancers. In recent years, more and more interacting components have been observed and their exact functions approached, thus ensuring the most complicated understanding of this pathway in normal organism development and disorders. In hepatocellular carcinoma (HCC), with a deeply understanding of this pathway, more and more genes which contribute to aberrant activation of Wnt/?-catenin signaling pathway has recently been identified and their exact roles in HCC pursued. In this review, we will focus on a mostly updated understanding of this pathway and its observed role in HCC by emphasizing the gene defects identified to promote tumorigenesis and development.

关键词： interacting complicated understanding embryogenesis activation organism development

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Regeneration of hair cells in the mammalian vestibular system

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《医学前沿（英文）》 2016年第10卷第2期页码 143-151 doi: 10.1007/s11684-016-0451-1

摘要：

Hair cells regenerate throughout the lifetime of non-mammalian vertebrates, allowing these animals to recover from hearing and balance deficits. Such regeneration does not occur efficiently in humans and other mammals. Thus, balance deficits become permanent and is a common sensory disorder all over the world. Since Forge and Warchol discovered the limited spontaneous regeneration of vestibular hair cells after gentamicin-induced damage in mature mammals, significant efforts have been exerted to trace the origin of the limited vestibular regeneration in mammals after hair cell loss. Moreover, recently many strategies have been developed to promote the hair cell regeneration and subsequent functional recovery of the vestibular system, including manipulating the Wnt, Notch and Atoh1. This article provides an overview of the recent advances in hair cell regeneration in mammalian vestibular epithelia. Furthermore, this review highlights the current limitations of hair cell regeneration and provides the possible solutions to regenerate functional hair cells and to partially restore vestibular function.

关键词： utricle hair cell regeneration Atoh1 Notch Wnt

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MicroRNA-148b promotes proliferation of hair follicle cells by targeting

Wanbao YANG,Qinqun LI,Bo SU,Mei YU

《农业科学与工程前沿（英文）》 2016年第3卷第1期页码 72-80 doi: 10.15302/J-FASE-2016089

摘要： MicroRNAs (miRNAs), small non-coding RNAs, are involved in many aspects of biological processes. Previous studies have indicated that miRNAs are important for hair follicle development and growth. In our study, we found by qRT-PCR that miR-148b was significantly upregulated in sheep wool follicle bulbs in anagen phase compared with the telogen phase of the hair follicle cycle. Overexpression of miR-148b promoted proliferation of both HHDPC and HHGMC. By using the TOPFlash system we demonstrated that miR-148b could activate Wnt/β-catenin pathway and , , and were consistently upregulated accordingly. Furthermore, transcript factor nuclear factor of activated T cells type 5 ( ) and were predicted to be the target of miR-148b and this was substantiated using a Dual-Luciferase reporter system. Subsequently was further identified as the target of miR-148b using western blotting. These results were considered to indicate that miR-148b could activate the Wnt/β-catenin signal pathway by targeting to promote the proliferation of human hair follicle cells.

关键词： miR-148b hair follicle proliferation NFAT5 Wnt10b

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Intestinal Epithelial Axin1 Deficiency Protects Against Colitis via Altered Gut Microbiota

Shari Garrett,Yongguo Zhang,Yinglin Xia,Jun Sun,

《工程（英文）》 doi: 10.1016/j.eng.2023.06.007

摘要： Intestinal homeostasis is maintained by specialized host cells and the gut microbiota. Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis, and its dysregulation has been implicated in inflammation and colorectal cancer. Axin1 negatively regulates activated Wnt/β-catenin signaling, but little is known regarding its role in regulating host–microbial interactions in health and disease. Here, we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation. Axin1 expression was analyzed in human inflammatory bowel disease datasets. To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis, we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell (IEC; Axin1^Δ^IEC) and Paneth cell (PC; Axin1^Δ^PC) to compare with control (Axin1^LoxP; LoxP: locus of X-over, P1) mice. We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease (IBD). Axin1^Δ^IEC mice exhibited altered goblet cell spatial distribution, PC morphology, reduced lysozyme expression, and enriched Akkermansia muciniphila (A. muciniphila). The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium-induced colitis in vivo. Axin1^Δ^IEC and Axin1^Δ^PC mice became more susceptible to dextran sulfate sodium (DSS)-colitis after cohousing with control mice. Treatment with A. muciniphila reduced DSS-colitis severity. Antibiotic treatment did not change the IEC proliferation in the Axin1^Loxp mice. However, the intestinal proliferative cells in Axin1^Δ^IEC mice with antibiotic treatment were reduced compared with those in Axin1^Δ^IEC mice without treatment. These data suggest non-colitogenic effects driven by the gut microbiome. In conclusion, we found that the loss of intestinal Axin1 protects against colitis, likely driven by epithelial Axin1 and Axin1-associated A. muciniphila. Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota. Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.

关键词： Axin1 Bacteria Microbiome inflammation Inflammatory bowel disease Immunity Microbiome Paneth cells Akkermansia muciniphila Wnt