Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy

Shang, Jie; Lin, Nan; Peng, Rong; Jiang, Ning; Wu, Biao; Xing, Baizhou; Lin, Shiyuan; Xu, Xiaolong; Lu, Huading

doi:10.3390/molecules28030924

Cited by 14 publications

(14 citation statements)

References 53 publications

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“…Several known genes related to ARHL or senescence, including the forkhead gene family (comprising a diverse group of "winged-helix" proteins, e.g., Foxp1, Foxo1, Foxj1, Foxc1, and Foxg1) and the Adamts2, Arih2 (ariadne RBR E3 ubiquitin protein ligase 2), ACE2, Col13a1, and CDKN1C proteins, could be found among the genes predicted by motif-TF analysis (Fig. 3C and Table S8) [51][52][53][54][55][56]. In particular, the regulatory function of Foxg1 through the autophagy pathway during HC degeneration in presbycusis has been demonstrated in a previous study, and FOXG1 is considered a new molecular target for the treatment of age-related hearing loss [21].…”

Section: Discussionmentioning

confidence: 99%

The chromatin accessibility and transcriptomic landscape of the aging mice cochlea and the identification of potential functional super-enhancers in age-related hearing loss

Zhang,

Yang,

Luo

et al. 2024

Preprint

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Background Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Importantly, the aging process affects individuals in diverse ways and is influenced by various factors, including epigenetic factors. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on investigating alterations in chromatin-accessible regions, commonly known as peaks. Methods To accomplish this,we employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq, which provides reciprocal validation from DNA to RNA between young and aging cochleae.Integrated analysis and motif/TF(Transcription factor)-gene prediction were conducted. Additionally,the essential role of super-enhancers (SEs) in the development of ARHL were identified by comparative analysis to previous research.Meanwhile, an ARHL mouse model and an aging mimic hair cell(HC) model were established with a comprehensive identification of various senescence phenotypes to access the role of SEs in ARHL progression. Results The ATAC-seq analysis revealed that the control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL.Integrated analyses indicated that peaks found in the promoter and 5'UTR regions have a more pronounced regulatory impact on the expression of neighboring genes in ARHL compared to peaks in other genomic elements. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL.The CCCTC-binding factor (CTCF), a constituent of chromatin loops that restricts the interaction between enhancers and promoters, was identified as the transcription factor with the most abundant binding to its motif. Subsequently, we identified potential ARHL-associated SASEs(senescence associated super-enhancers), most of which exhibited significantly decreased chromatin accessibility.The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs. Importantly, the expression of genes regulated by the identified SASEs, such as Atp6v1a, Dcun1d3, Mitf1, and Sdcbp, was noticeably altered following treatment with the BRD4 inhibitor JQ1 (a commonly used SE inhibitor). Conclusion The analysis of ATAC-seq showed that the chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL.Additionally, by conjoint analysis and dual model verification,we establishes a framework for understanding epigenetic regulatory mechanisms underlying the development of ARHL in the cochlea and identifies potential SEs involved in HC senescence, which might provide a basis for future therapeutics targeting SEs in ARHL.

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Section: Discussionmentioning

confidence: 99%

The chromatin accessibility and transcriptomic landscape of the aging mice cochlea and the identification of potential functional super-enhancers in age-related hearing loss

Zhang,

Yang,

Luo

et al. 2024

Preprint

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“…Surprisingly, co‐knockdown of KLF10 and Bcl2‐interacting protein 3 (BNIP3) resulted in a decrease in COL2A1 and LC3II/I and an increase in the expression of MMP13, p62, p16 and p21, as seen in the suppression of autophagic flux. This seems to indicate that KLF10 regulates autophagy by regulating the expression of BNIP3 107 . Moreover, another study reported that KLF10 overexpression accompanied by up‐regulation of Acvr1 gene expression and down‐regulation of Inhbb gene expression resulted in a significant reduction in chondrocyte proliferation and migration, promoting OA 108 .…”

Section: Role Of Klfs In Bone Diseasesmentioning

confidence: 93%

“…A recent study found that high expression of KLF10 was detected in human OA cartilage and mouse OA cartilage. 107 Notably, KLF10 was also up‐regulated in senescent chondrocytes. Down‐regulation of KLF10 not only restored the impaired mitochondrial autophagic flux, but also attenuated tert‐butyl hydroperoxide (TBHP)‐induced chondrocyte senescence by promoting mitochondrial autophagy, facilitated cell proliferation and inhibited senescence‐associated secretory phenotypes (SASPs), including the secretion of IL‐6, CXCL10, MCP1 and MMP3.…”

Section: Role Of Klfs In Bone Diseasesmentioning

confidence: 97%

“…A recent study found that high expression of KLF10 was detected in human OA cartilage and mouse OA cartilage 107 . Notably, KLF10 was also up‐regulated in senescent chondrocytes.…”

Section: Role Of Klfs In Bone Diseasesmentioning

confidence: 97%

“…A recent study found that high expression of KLF10 was detected in human OA cartilage and mouse OA cartilage. 107 promoting OA. 108 Although less progress has been reported on the involvement of KLFs in the regulation of OA through autophagy, this offers a direction for future research.…”

Section: Klfs and Autophagymentioning

confidence: 99%

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KLF transcription factors in bone diseases

Wang,

Han,

Dmitrii

et al. 2024

J Cellular Molecular Medi

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Krüppel‐like factors (KLFs) are crucial in the development of bone disease. They are a family of zinc finger transcription factors that are unusual in containing three highly conserved zinc finger structural domains interacting with DNA. It has been discovered that it engages in various cell functions, including proliferation, apoptosis, autophagy, stemness, invasion and migration, and is crucial for the development of human tissues. In recent years, the role of KLFs in bone physiology and pathology has received adequate attention. In addition to regulating the normal growth and development of the musculoskeletal system, KLFs participate in the pathological process of the bones and joints and are intimately linked to several skeletal illnesses, such as osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP) and osteosarcoma (OS). Consequently, targeting KLFs has emerged as a promising therapeutic approach for an array of bone disorders. In this review, we summarize the current literature on the importance of KLFs in the emergence and regulation of bone illnesses, with a particular emphasis on the pertinent mechanisms by which KLFs regulate skeletal diseases. We also discuss the need for KLFs‐based medication‐targeted treatment. These endeavours offer new perspectives on the use of KLFs in bone disorders and provide prognostic biomarkers, therapeutic targets and possible drug candidates for bone diseases.

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Limonoids isolated from Chisocheton ceramicus Miq. and the antiadipogenic mechanism of action of ceramicine B

Bailly

2024

Archiv der Pharmazie

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Different types of limonoids have been isolated from plants of the Chisocheton genus, notably from the species Chisocheton ceramicus Miq. which is largely distributed in the Indonesian archipelago and Malaysia region. A variety of natural products have been found in the bark of the tree and characterized as antimicrobial and/or antiproliferative agents. The isolated limonoids include chisomicines A–E, proceranolide, and a few other compounds. A focus is made on a large series of limonoids designated ceramicines A to Z including derivatives with antiparasitic activities, antioxidant, antimelanogenic, and antiproliferative effects and/or acting as regulators of lipogenesis. The lead compound in the series is ceramicine B functioning as a potent inhibitor of lipid droplet accumulation (LDA). Extracts from Chisocheton ceramicus and ceramicines have shown anti‐LDA effects, with little or no cytotoxic effects. Ceramicine B is the most active compound functioning as a regulator of lipid storage in cells and tissues. Ceramicine B is a transcriptional repressor of peroxisome proliferator‐activated receptor γ (PPARγ) and an inhibitor of phosphorylation of the transcription factor FoxO1, acting via an upstream molecular target. Targeting of glycogen synthase kinase‐3β is proposed, based on the analogy with structurally related limonoids known to target this enzyme, and supported by a molecular docking analysis. The target and pathway implicated in ceramicine B activity are discussed. The analysis shed light on ceramicine B as a natural product precursor for the design of novel compounds capable of reducing LDA in cells and of potential interest for the treatment of obesity, liver diseases, and other pathologies.

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Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy

Cited by 14 publications

References 53 publications

The chromatin accessibility and transcriptomic landscape of the aging mice cochlea and the identification of potential functional super-enhancers in age-related hearing loss

The chromatin accessibility and transcriptomic landscape of the aging mice cochlea and the identification of potential functional super-enhancers in age-related hearing loss

KLF transcription factors in bone diseases

Limonoids isolated from Chisocheton ceramicus Miq. and the antiadipogenic mechanism of action of ceramicine B

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