Paeonol reverses promoting effect of the HOTAIR/miR‐124/Notch1 axis on renal interstitial fibrosis in a rat model

Zhou, Hao; Qiu, Zhen‐Zhen; Yü, Zhihui; Gao, Lin; He, Ji‐Ming; Zhang, Zhiwei; Zheng, Jian

doi:10.1002/jcp.28137

Cited by 29 publications

(17 citation statements)

References 35 publications

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“…S7). IMR-1 evidently can inhibit Notch signaling at higher concentrations, as previously reported (30,59,60). RIN1 is another small molecule that was recently reported to modulate the Notch transcription complex (31).…”

Section: Discussionsupporting

confidence: 55%

Pharmacological disruption of the Notch transcription factor complex

Lehal

Zarić

Vigolo

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

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Section: Discussionsupporting

confidence: 55%

Pharmacological disruption of the Notch transcription factor complex

Lehal

Zarić

Vigolo

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…LncRNA HOX transcript antisense RNA (HOTAIR) has been found to promote hypoxia-induced ischaemic infarct (Yang and Lu, 2016). A previous report indicated that PAN inhibited the expression of HOTAIR (Zhou et al, 2019). Thus, PAN might affect the progression of ICH via regulation of HOTAIR.…”

Section: Introductionmentioning

confidence: 99%

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

et al. 2021

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Intracerebral haemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. It has been reported that paeonol (PAN) inhibits the progression of ICH. However, the mechanism by which paeonol mediates the progression of ICH remains unclear. To mimic ICH in vitro, neuronal cells were treated with hemin. An in vivo model of ICH was established to detect the effect of paeonol on ferroptosis in neurons during ICH. Cell viability was tested by MTT assay. Furthermore, cell injury was detected by GSH, MDA and ROS assays. Ferroptosis was examined by iron assay. RT-qPCR and western blotting were used to detect gene and protein expression, respectively. The correlation among HOTAIR, UPF1 and ACSL4 was explored by FISH, RNA pull-down and RIP assays. Paeonol significantly inhibited the ferroptosis of neurons in ICH mice. In addition, paeonol significantly reversed hemin-induced injury and ferroptosis in neurons, while this phenomenon was notably reversed by HOTAIR overexpression. Moreover, paeonol notably inhibited ferroptosis in hemin-treated neuronal cells via inhibition of ACSL4. Additionally, HOTAIR bound to UPF1, and UPF1 promoted the degradation of ACSL4 by binding to ACSL4. Furthermore, HOTAIR overexpression reversed paeonol-induced inhibition of ferroptosis by mediating the UPF1/ACSL4 axis. Paeonol inhibits the progression of ICH by mediating the HOTAIR/UPF1/ACSL4 axis. Therefore, paeonol might serve as a new agent for the treatment of ICH.

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“…The decreased DE miRNAs with the largest numbers of targets included miR-122-5p, the miR-3073 family (miR-3073a-5p, miR-3073a-3p and miR-3073b-5p), the miR-1948 family (miR-1948-5p and miR-1948-3p), miR-669c-5p and let7a-1-3p. Among these, fibrosis was reported to be regulated by the increase in expression of the miR-21 family ( 49 – 54 ), miR-124 family ( 55 , 56 ) and miR-34b-3p ( 57 , 58 ), and the decrease in miR-122-5p ( 59 – 61 ) and let7a-1-3p ( 62 ). The present study was the first to report that AAN was associated with an increase in miR-129-2-3p expression and a decrease in the expression levels of the miR-3073 family (miR-3073a-5p, miR-3073a-3p and miR-3073b-5p), miR-1948 family (miR-1948-5p and miR-1948-3p) and miR-669c-5p.…”

Section: Discussionmentioning

confidence: 99%

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Zhu

Wang

et al. 2020

Mol Med Rep

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in acute aristolochic acid nephropathy (aan), aristolochic acid (aa) induces renal injury and tubulointerstitial fibrosis. However, the roles of micrornas (mirnas/mirs) and mrnas involved in aan are not clearly understood. The aim of the present study was to examine aa-induced genome-wide differentially expressed (de) mirnas and de mrnas using deep sequencing in mouse kidneys, and to analyze their regulatory networks. in the present self-controlled study, mice were treated with 5 mg/kg/day aa for 5 days, following unilateral nephrectomy. AA-induced renal injury and tubulointerstitial fibrosis were detected using hematoxylin and eosin staining and Masson's trichrome staining in the mouse kidneys. a total of 82 DE miRNAs and 4,605 DE mRNAs were identified between the aa-treated group and the self-control group. of these de mirnas and mrnas, some were validated using reverse transcription-quantitative Pcr. expression levels of the profibrotic miR-21, miR-433 and miR-132 families were significantly increased, whereas expression levels of the anti-fibrotic miR-122-5p and let-7a-1-3p were significantly decreased. Functions and signaling pathways associated with the de mirnas and mrnas were analyzed using Gene ontology and Kyoto encyclopedia of Genes and Genomes (KeGG). a total of 767 de pairs (in opposing directions) of mirnas and their mrna targets were identified. among these, regulatory networks of mirnas and mrnas were analyzed using KeGG to identify enriched signaling pathways and extracellular matrix-associated pathways. in conclusion, the present study identified genome-wide de mirnas and mrnas in the kidneys of aa-treated mice, as well as their regulatory pairs and signaling networks. The present results may improve the understanding of the role of de mirnas and their mrna targets in the pathophysiology of acute aan.

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Paeonol reverses promoting effect of the HOTAIR/miR‐124/Notch1 axis on renal interstitial fibrosis in a rat model

Cited by 29 publications

References 35 publications

Pharmacological disruption of the Notch transcription factor complex

Pharmacological disruption of the Notch transcription factor complex

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

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