Pharmaceuticals
·
2024
·Vol. 17
·期 11
·1416
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IF 4.3
Ziang Zhou,Yumeng Wang,Yu Xing,Shuman Pan,Wanru Wang,Jie Yang,Wenyuan Wu,Jie Zhou,Luyi Huang,Qiongdan Liang,Dongmei Zhang,Lingdong Kong
Background/Objectives: High fructose has been implicated as an important trigger of kidney inflammation in patients and experimental models. Magnolol, isolated fromMagnolia officinalis, has an anti-inflammatory effect, but its protective role in podocytes remains underexplored. This study explored the protective effects and underlying mechanism of magnolol against high fructose-induced podocyte inflammation. Methods: The effects of magnolol on high fructose-induced podocyte inflammation were assessed in male Sprague Dawley rats administered 10% (w/v) fructose water for 12 weeks and heat-sensitive human podocyte cell lines (HPCs) exposed to 5 mM fructose. Podocyte foot processes were examined using transmission electron microscopy. The expression levels of nephrin, podocin, tumor necrosis factor-α (TNF-α), Notch1 intracellular domain (NICD1), triokinase/FMN cyclase (TKFC), specificity protein 1 (Sp1) and histone deacetylase 4 (HDAC4) were determined by Western blot, immunofluorescence and real-time quantitative polymerase chain reaction (qRT-PCR). The chromatin immunoprecipitation (ChIP) assay was performed to evaluate the interaction between Sp1 and the promoter region of HDAC4. Results: Magnolol mitigated the impairment of glomerular filtration function in high fructose-fed rats. Besides, it significantly alleviated the inflammatory responses in glomeruli and HPCs, evidenced by decreased protein levels of TNF-α and NICD1. Increased protein levels of TKFC, Sp1 and HDAC4 were observed in high fructose-stimulated HPCs and rat glomeruli. TMP195, an HDAC4 inhibitor, reduced TNF-α and NICD1 protein levels in high fructose-exposed HPCs. The increased Sp1 was shown to associate with the promoter region of HDAC4, promoting HDAC4 protein expression in high fructose-exposed HPCs. The knockdown of TKFC in HPCs byTKFCsiRNA decreased Sp1, HDAC4 and NICD1 protein levels, alleviating podocyte inflammatory response. Furthermore, magnolol inhibited TKFC/Sp1/HDAC4/Notch1 activation in vivo and in vitro. Conclusions: Magnolol attenuated high fructose-induced podocyte inflammation possibly through the suppression of TKFC/Sp1/HDAC4/Notch1 activation, providing new evidence for its potential role in podocyte protection.
研究领域:
药理学
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肾病学
·
分子生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yuqian Chen,Jin Liu,Qianqian Zhang,Limin Chai,Huan Chen,Danyang Li,Yan Wang,Yuanjie Qiu,Nirui Shen,Jia Zhang,Qingting Wang,Jian Wang,Xinming Xie,Shaojun Li,Manxiang Li
Stromal derived factor 1 (SDF1) has been shown to be involved in the pathogenesis of pulmonary artery hypertension (PAH). However, the detailed molecular mechanisms remain unclear. To address this, we utilized primary cultured rat pulmonary artery smooth muscle cells (PASMCs) and monocrotaline (MCT)-induced PAH rat models to investigate the mechanisms of SDF1 driving PASMCs proliferation and pulmonary arterial remodeling. SDF1 increased runt-related transcription factor 2 (Runx2) acetylation by Calmodulin (CaM)-dependent protein kinase II (CaMKII)-dependent HDAC4 cytoplasmic translocation, elevation of Runx2 acetylation conferred its resistance to proteasome-mediated degradation. The accumulation of Runx2 further upregulated osteopontin (OPN) expression, finally leading to PASMCs proliferation. Blocking SDF1, suppression of CaMKII, inhibition the nuclear export of HDAC4 or silencing Runx2 attenuated pulmonary arterial remodeling and prevented PAH development in MCT-induced PAH rat models. Our study provides novel sights for SDF1 induction of PASMCs proliferation and suggests that targeting SDF1/CaMKII/HDAC4/Runx2 axis has potential value in the management of PAH.
研究领域:
心血管疾病
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分子生物学
·
药理学
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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Tiantian Wang,Ruihe Zheng,Song Sun
Acute lung injury (ALI) is a significant cause of morbidity and mortality worldwide. To search for a new treatment for acute lung injury, we investigated the effect of escitalopram on lipopolysaccharide (LPS)-induced ALI. Our results showed that escitalopram inhibited salt-inducible kinase 2 (SIK2) activity (IC 50 = 6.36 ± 0.93 μM) and triggered histone deacetylase 4 (HDAC4) dephosphorylation . Following its dephosphorylation, HDAC4 translocated into the nucleus, promoted deacetylation and cytoplasmic shuttling of p65, thus inhibited LPS-induced pro-inflammatory cytokine production. Moreover, escitalopram markedly ameliorated the inflammatory responses, reduced neutrophils infiltration and attenuated LPS-induced pulmonary injury in mice. Taken together, we identified a previously unexplored role for escitalopram in SIK2/HDAC4/NF-κB pathway, therefore escitalopram may be considered as a new treatment for ALI.
研究领域:
药理学
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免疫学
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肺病学
·
药物再利用
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Li Guo,Fuyang Cao,Jihao Wen,Chengyang Lu,Li Wang,Yongsheng Ma,Gaige Wu,Xiaochun Wei,Pengcui Li,Zhi Chen
A zoned osteochondral unit with scaffold zonation and cell zonation was constructed. • HDAC4 promotes osteochondral repair via improved function of SFZCs and MDZCs. • HDAC4 improves SFZCs/MDZCs function via activating oxidative phosphorylation. Achieving a physiological microenvironment in tissue engineering represents the ultimate objective. Current strategies for constructing osteochondral units focus primarily on biomimicking scaffold materials and often overlook the zonal distribution of seed cells. Studies indicate that chondrocytes, which are utilized as seed cells, are susceptible to reduced proliferation and dedifferentiation, which compromises regenerative outcomes. In this study, we biomimetically fabricated a three-layer hydrogel scaffold of zonal osteochondral units using gelatin methacryloyl and nanohydroxyapatite (GelMA/nHA), where the first and second layers were composed of superficial zone chondrocytes (SFZCs) and middle-deep zone chondrocytes (MDZCs), respectively. The lower layer contained a GelMA/nHA hydrogel loaded with bone marrow mesenchymal stem cells (BMSCs) derived from a rat osteochondral defect model. The SFZCs and MDZCs were modified with histone deacetylase 4 (HDAC4) to increase their viability. The results showed that the simultaneous zonation of cells and the scaffold effectively enhanced osteochondral defect repair. Moreover, delivering HDAC4 to chondrocytes in each layer further improved the repair outcomes. Omics and validation data suggest that HDAC4 optimizes chondrocyte function across zones by upregulating oxidative phosphorylation. This study highlights the importance of zonal cell biomimicry in engineered osteochondral constructs and defect repair. In addition, this study reveals the molecular mechanism by which HDAC4 regulates chondrocytes, providing new insights for osteochondral regeneration. Schematic illustration of the zonal osteochondral unit: fabrication, mechanism and in vivo repair. (A) Preparation of the osteochondral unit integrating scaffold and celluar zonation. (B) The role and mechanism of HDAC4 in the regulation of chondrocyte function. (C) In vivo osteochondral repair with cell and scaffold zonation. SFZ, superficial zone of cartilage; MDZ, middle–deep zone of cartilage; HDAC4, histone deacetylase 4; OXPHOS, oxidative phosphorylation; BMSCs, bone marrow mesenchymal stem cells; MF, molecular function; CC, cellular component; BP, biological process; NADH-DH, NADH dehydrogenase; IMMC, inner mitochondrial membrane protein complex. The graphical abstract was not generated by AI. Download: Download high-res image (129KB) Download: Download full-size image
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