Communications Biology
·
2025
·Vol. 8
·期 1
·1-14
·
IF 5.1
Zhou Xiaonan,Jiang Peng,Tan Huangqi,Wang Yanfang,Bai Lunhao
Osteoarthritis (OA) is a degenerative joint disease that affects the cartilage and surrounding tissues. The transcription factor Kruppel-like family factor 9 (KLF9) has been identified as a regulator of tumorigenesis. However, its role in OA is still not fully understood. Herein, this study aimed to access the potential role and molecular mechanism by which KLF9 regulates OA development. KLF9 was upregulated in cartilage tissues of OA patients and medial meniscotibial ligament (MMTL)-induced OA rats, as well as in IL-1β-treated chondrocytes. Furthermore, knockdown of KLF9 inhibited OA-related cartilage injury, as evidenced by inhibiting chondrocyte extracellular matrix (ECM) degradation, increasing chondrocyte viability, and decreasing apoptosis. Conversely, overexpression of KLF9 had the opposite effect. The downstream mechanism of KLF9 was confirmed. KLF9 mediated the transcription of G protein-coupled receptor kinase 5 (GRK5) by directly targeting the GRK5 promoter. GRK5 knockdown eliminated the effects of KLF9 overexpression on chondrocyte dysfunction. It was also found that GRK5 combined with histone deacetylase 6 (HDAC6) and promoted HDAC6 phosphorylation. The use of the HDAC6 inhibitor TubastatinA also abolished the effects of GRK5 overexpression on chondrocyte ECM degradation and apoptosis. These results demonstrate that the KLF9-GRK5-HDAC6 axis plays a crucial role in promoting the progression of OA.
研究领域:
风湿病学
·
分子生物学
·
医学遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-19
·
IF 7.5
Han Ning,Yu Na,Yu Li
Background Diabetic retinopathy (DR) is the common cause of diabetic vascular complications and it causes blindness. Until now, there are still some patients with DR who lack effective treatment. Tripartite motif containing 44 (TRIM44) has been shown to play a significant role in endothelial cells. However, the role of TRIM44 in DR remains unknown. Methods Diabetes was induced in rats through the administration of an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ). Rat retinal microvascular endothelial cells (RMECs) were subjected to stimulation under high glucose (HG) conditions. A thorough proteomic investigation and bioinformatic analysis were performed to identify the differentially expressed proteins (DEPs) in rat RMECs after blocking TRIM44. A dual luciferase reporter assay was employed to assess the luciferase activity of TRIM44. Results TRIM44 was highly expressed in the retinal tissues of rats with diabetes and HG-induced RMECs. In vivo assays suggested that TRIM44 silencing improved the pathological alterations of DR rats as demonstrated by the downregulated expression of isolectin-B4 and VEGFA, along with a decrease in acellular capillaries within the retinal tissues. Knockdown of TRIM44 markedly reduced cell viability, proliferation, migration, invasion, and angiogenesis in HG-evoked RMECs. Mechanistically, TRIM44 was demonstrated to be activated transcriptionally by KLF transcription factor 9 (KLF9), a known facilitator of angiogenesis in DR. In HG-induced cells, the loss of TRIM44 resulted in the reverse of the endothelial cell function caused by KLF9 overexpression. After the comprehensive analysis, 64 upregulated and 38 downregulated DEPs were screened out for a series of functional enrichment analyses. Conclusions Collectively, this study demonstrates that TRIM44 knockdown suppressed diabetes-induced retinal vascular dysfunction in DR.
研究领域:
分子生物学
·
糖尿病学
·
眼科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2020
·
IF 3.871
Ziwen Wei,Xiaoli Qin,Xiaojie Kang,Haixia Zhou,Shaodan Wang,Dong Wei
Background MiR-142-3p has been shown to be suppressed in obese patients , while the underlying regulatory mechanism is unclear. Methods Body shape indexes as well as peripheral blood for biochemical parameter analysis were obtained from obese and healthy subjects. When 3T3-L1 cells were induced to differentiate, miR-142-3p expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of miR-142-3p on triglyceride (TG) and adipogenic differentiation-related genes during the adipogenic differentiation of 3T3-L1 cells were detected by transfection, Oil Red O staining, and Western blot . The targeting relationship between miR-142-3p and Krueppel-like transcription factor 9 (KLF9) was verified by TargetScan and dual-luciferase experiment. The specific regulatory effects of miR-142-3p on cell adipogenic differentiation and autophagy were analyzed by rescue experiments. In vivo experiments further validated the results of in vitro experiments through obese mouse models. Results Obesity-marked biochemical indicators increased whereas high density lipoprotein and miR-142-3p decreased in obese patients. The content of miR-142-3p gradually decreased with cell lipid differentiation. Overexpression of miR-142-3p reduced TG deposition in cells by down-regulating lipid formation and fatty acid synthesis genes and up-regulating fatty acid oxidation genes. KLF9 targeting miR-142-3p was suppressed by miR-142-3p. KLF9 overexpression partially reversed the inhibitory effect of miR-142-3p mimic on adipogenic differentiation and the expressions of autophagy related-genes in 3T3-L1 cells. MiR-142-3p overexpression also inhibited fat cell differentiation and autophagy in obese mice . Conclusion Overexpressed miR-142-3p inhibited adipogenic differentiation and autophagy through targeting KLF9.
研究领域:
分子生物学
·
细胞生物学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Feng Yue-yao,Hao Jing-ran,Zhang Yu-jie,Qiu Tong-tong,Zhang Meng-lin,Qiao Wei,Wu Jin-jin,Qiu Ping,Xu Chao-fan,Zhang Yin-liang,Du Chun-yuan,Pan Zhe,Chang Yong-sheng
The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer’s disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9 −/− ) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9 −/− mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9 −/− mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.
研究领域:
神经生物学
·
分子生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DIABETES
·
2023
·Vol. 72
·期 8
·1083-1094
·
IF 7.7
Xie Renxiang,Yan Sujun,Zhou Xiaoling,Gao Yunyi,Qian Yu,Hou Jingyu,Chen Zhanghui,Lai Kairan,Gao Xiangwei,Wei Saisai
The induction of beige adipocytes in white adipose tissue (WAT), also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m 6 A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of the Mettl3 gene undermines WAT beiging and impairs the metabolic capability of mice fed with a high-fat diet. Mechanistically, METTL3-catalyzed m 6 A installation on thermogenic mRNAs, including Krüppel-like factor 9 ( Klf9 ), prevents their degradation. Activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate promotes WAT beiging, reduces body weight, and corrects metabolic disorders in diet-induced obese mice. These findings uncover a novel epitranscriptional mechanism in WAT beiging and identify METTL3 as a potential therapeutic target for obesity-associated diseases. Article Highlights METTL3, the methyltransferase of N6-methyladenosine (m 6 A) mRNA modification, is induced during WAT beiging. Depletion of Mettl3 undermines WAT beiging and impairs thermogenesis. METTL3-mediated m 6 A installation promotes the stability of Krüppel-like factor 9 ( Klf9 ). KLF9 rescues impaired beiging elicited by Mettl3 depletion. Pharmaceutical activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate induces WAT beiging. Methyl piperidine-3-carboxylate corrects obesity-associated disorders. The METTL3-KLF9 pathway may serve as a potential therapeutic target for obesity-associated diseases.
研究领域:
分子生物学
·
代谢
·
肥胖研究
·
表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOTECHNOLOGY
·
2022
·Vol. 65
·期 4
·612-623
·
IF 2.86
Han Ning,Zhang Lihong,Guo Mi,Yu Li
Advanced proliferative diabetic retinopathy (PDR) characterized by aberrant retinal angiogenesis is a leading cause of retinal detachment and blindness. Krüppel-like factor 9 (KLF9), a member of the zinc-finger family of transcription factors, participates in the development of diabetic nephropathy and the promotion of angiogenesis of human umbilical vein endothelial cells. Therefore, we speculate that KLF9 may exert a crucial role in PDR. The current study revealed that KLF9 was highly expressed in the high glucose (HG)-treated human retinal microvascular endothelial cells (HRMECs) and the retinas of oxygen-induced retinopathy (OIR) rats. Knockdown of KLF9 inhibited the proliferation, migratory capability, invasiveness and tube formation of HG-treated HRMECs. Besides, knockdown of KLF9 decreased the expression of yes-associated protein 1 (YAP1) in HG-treated HRMECs. Dual-luciferase reporter assays confirmed that KLF9 transcriptionally upregulated YAP1 expression. Overexpression of YAP1 reversed the KLF9 silencing-induced repression of HRMEC proliferation and tube formation. Further in vivo evidence demonstrated that knockdown of KLF9 reduced the expression of Ki67, CD31 and vascular endothelial growth factor A (VEGFA) in the retinas of OIR rats. Collectively, KLF9 silencing might mitigate the progression of PDR by inhibiting angiogenesis via blocking YAP1 transcription.
研究领域:
糖尿病
·
视网膜
·
分子生物学
·
细胞生物学
·
转录因子
·
血管生成
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）