International Journal of Oral Science
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2024
·Vol. 16
·期 1
·1-16
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IF 10.8
Chen Jiayao,Kuang Shuhong,Cen Jietao,Zhang Yong,Shen Zongshan,Qin Wei,Huang Qiting,Wang Zifeng,Gao Xianling,Huang Fang,Lin Zhengmei
The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.
研究领域:
生物学
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生物化学
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干细胞研究
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营养学
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内分泌学
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老年学
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Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-21
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IF 8.9
He Qiongyao,He Wu,Ren Yanlin,Wu Wenbin,Dong Hui,Yuan Gang,Ren Huihui,Wang Xinwei,Lu Fuer,Wang Dingkun
Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting ferroptosis of RTECs. VDR knockout exacerbates ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular ferroptosis. These findings elucidate the role of ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.
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CELLULAR SIGNALLING
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2022
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IF 4.85
Yao Ding,Qinan Wu
Background Type 2 diabetes mellitus (T2DM) is a global health problem that seriously threatens human health. Vitamin D (VD) has antidiabetic effects. However, the protective mechanism of 1,25-dihydroxyvitamin D3 (1,25D) on T2DM is still unclear. Methods A rat model of T2DM was constructed using a high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Glucose tolerance was assessed by an oral glucose tolerance test (OGTT). Insulin secretion in blood and cell supernatant was determined by ELISA. Cell viability was analysed by CCK-8 assay. The level of ROS was detected by the DCFH-DA fluorescent probe method. The iron level in pancreatic tissues and cells was detected by an iron assay kit. Immunofluorescence staining was used to detect the expression of the pancreatic β cell marker CD49a . Furthermore, the protein expression levels of ferroptosis pathway-related proteins and vitamin D receptor (VDR) were detected by western blot . Downstream VDR targets were screened by proteomic sequencing. Results The DM group had increased glucose levels and decreased insulin secretion, while 1,25D treatment decreased glucose levels and increased insulin secretion. 1,25D also suppressed DM-induced ferroptosis in pancreatic tissues in vivo. In addition, 1,25D significantly enhanced the viability of pancreatic β cells and reduced the levels of ROS and iron. 1,25D significantly upregulated the expression of VDR and the ferroptosis-related pathway protein GPX4 and downregulated the expression of ACSL4. Furthermore, knockdown of VDR reversed the effects of 1,25D on cell viability, ROS and iron levels, and ferroptosis-related protein expression in pancreatic β cells. Proteomic sequencing revealed that FOXO1 was the downstream target gene of VDR. Knockdown of FOXO1 reduced pancreatic β cell death, decreased ROS, iron and ACSL4 levels, and increased GPX4 levels. Conclusion 1,25D/VDR inhibited pancreatic β cell ferroptosis in T2DM by downregulating the expression of FOXO1. This study provides a new theoretical basis for basic research on T2DM and is expected to establish a new idea for the treatment of T2DM.
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NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
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2025
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IF 2.4
Jingjing Lu,Dongxuan Wang,Hongjin Huo,Hao Jiang,Wei Wei,Jie Sun,Fei Jiang
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high metastatic potential and limited therapeutic options. This study investigates the effects of calcitriol, an active metabolite of vitamin D, on TNBC progression by targeting the vitamin D receptor (VDR)-mediated hypoxia-inducible factor-1α (HIF-1α) axis. We established in vivo TNBC xenograft models using 4T1 cells and in vitro models with MDA-MB-231 and 4T1 cells overexpressing HIF-1α. Results showed that calcitriol inhibited lung metastasis and downregulated glycolytic activity in TNBC xenografts without affecting primary tumor growth. In vitro, calcitriol reduced cell viability, migration, and invasion by suppressing HIF-1α expression. It also decreased glucose uptake, lactate production, and ATP levels while downregulating key glycolytic regulators. VDR knockdown abolished these effects, confirming VDR as the critical mediator. Our findings suggest that calcitriol exerts anti-metastatic effects in TNBC by modulating the VDR-HIF-1α axis, inhibiting glycolysis, and suppressing the epithelial-mesenchymal transition. This study highlights the potential therapeutic role of calcitriol in TNBC treatment by targeting both metabolic reprogramming and invasive capacity. Future research should further explore the mechanisms underlying calcitriol-mediated HIF-1α suppression and its clinical application in TNBC.
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Chinese Medicine
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2025
·Vol. 20
·期 1
·1-17
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IF 5.7
Zhu Mengyao,Ren Lu,Xiao Wenlong,Wang Longjian,Hu Zhiming,Wang Nani
Hepatic stellate cells (HSCs) activation represents a central pathological mechanism in liver fibrosis, with emerging evidence implicating fatty acid metabolic reprogramming as a critical regulator of this process. Our study established the vitamin D receptor (VDR) as a key transcriptional coordinator of fatty acid metabolism during HSC activation. Genetic VDR deletion in mice exacerbated liver fibrosis progression, which was associated with elevated TGF-β1 levels and increased Smad3 phosphorylation. Mechanistically, VDR deficiency disrupted lipid homeostasis through the upregulation of lipogenic enzymes (fatty acid synthase, acetyl-CoA carboxylase 1, ATP citrate lyase) and desaturases (stearoyl-CoA desaturase-1, fatty acid desaturases 1/2) and the suppression of the β-oxidation gatekeeper carnitine palmitoyltransferase 1A (CPT1A). Pathological VDR downregulation was observed in both TGF-β1-activated HSCs and fibrotic liver tissues, suggesting a disease-associated regulatory circuit. Calcitriol-mediated VDR activation reversed TGF-β1-induced Smad3 phosphorylation and normalized metabolic enzyme expression, effectively reducing lipid accumulation and collagen deposition. We further identified senkyunolide I as a novel natural VDR agonist that rebalances fatty acid metabolism by simultaneously downregulating lipogenesis/desaturation machinery and upregulating CPT1A. The complete abolition of anti-fibrotic effects of senkyunolide I following VDR knockdown confirmed its strict receptor dependency. These findings identify VDR as a master regulator of metabolic reprogramming in HSC activation and validate pharmacological VDR activation as a promising therapeutic strategy for liver fibrosis. The dual metabolic regulatory capacity of senkyunolide I through VDR signaling highlights its potential for targeted antifibrotic intervention.
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FREE RADICAL BIOLOGY AND MEDICINE
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2022
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IF 8.101
Pingcui Xu,Bingfeng Lin,Xuehui Deng,Kai Huang,Yan Zhang,Nani Wang
Ferroptosis plays an essential role in the pathology of osteoporosis . This study investigated whether vitamin D receptor (VDR) activation could protect against age-related osteoporosis through an anti-ferroptosis mechanism. d -galactose (D-gal)-induced mice and VDR-knockout mice were used in the in-vivo study. The VDR activator (1,25(OH) 2 D 3 ) attenuated senescence and ferroptosis in the D-gal-induced bone, as illustrated by downregulated senescence-associated secretory phenotype genes, improved mitochondrial morphology, elevated glutathione , and decreased lipid peroxidation markers (malondialdehyde and 4-hydroxynonenal). The pre-osteoblast MC3T3-E1 cells and primary rat osteoblasts were applied in the in-vitro studies. 1,25(OH) 2 D 3 or ferroptosis inhibitor (ferrostatin-1) treatment downregulated the cellular senescence markers in D-gal-induced osteoblasts. Mechanistically, 1,25(OH) 2 D 3 activated the VDR and its downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway , resulting in the downregulation of lipid peroxidation. Nrf2 knockdown or addition of GPX4 inhibitor (RSL-3) blocked the protective effect of 1,25(OH) 2 D 3 against D-gal-induced ferroptosis and senescence. VDR knockdown impeded the 1,25(OH) 2 D 3 -induced activation of Nrf2/GPX4 pathway in osteoblasts. Proteomics and immunofluorescence analysis confirmed that ferroptosis and suppression of the Nrf2/GPX4 pathway occurred in VDR-knockout mice. Our data demonstrated that ferroptosis played an essential role in age-related osteoporosis. The VDR activation attenuated osteoblast ferroptosis via stimulating the Nrf2/GPX4 signaling pathway.
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RESEARCH IN VETERINARY SCIENCE
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2023
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IF 2.4
Dongliu Luo,Yiming Lu,Qiaohan Liu,Hang Yin,Xiaodan Huang,Shu Li
Cadmium (Cd) is toxic non-essential heavy metal that precipitates adverse health effects in humans and animals, but the effect of Cd on lymph node toxicity of piglets is still unclear. In order to explore the possible molecular mechanism of Cd toxicity to lymph nodes of piglets, ten 6-week-old male weaned piglets were randomly divided into two groups, C group and Cd group. Group C was fed with basal diet, while group Cd was fed with basal diet supplemented with CdCl 2 (20 mg/kg) for 40 days, the pigs were euthanized and the mesenteric, inguinal and submandibular lymph nodes (MLN, ILN, SLN) were collected. The results indicated that Cd could induce the inflammatory cell infiltration , microvascular hemorrhage, microthrombosis and cell necrosis in MLN, ILN and SLN of piglets, induced Cytochrome P450 proteins (CYP1A1、CYP2E1、CYP2A1 and CYP3A2) mRNA levels and the protein levels of Vitamin D receptor (VDR) and cAMP response element binding protein 1 (CREB1). In addition, Cd exposure upregulated the mRNA and protein levels of dynamin-related protein 1 (DRP1), receptor-interacting protein kinase 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), and increased tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), interleukin-2 (IL-2), interleukin-4 (IL-4), cyclooxygenase 2 (COX-2) protein levels, and the damage degree of three kinds of lymph nodes was similar after Cd exposure. In general, these results manifest that Cd exposure regulates VDR/CREB1 pathway, activates CYP450s , induces necroptosis of lymph nodes, and leads to inflammation.
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JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
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2025
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IF 3.5
Liang Yongchao,Huo Hongjin,Wei Wei,Wang Dongxuan,Lu Jingjing,Yi Wenjie,Jiang Fei
Purpose Perfluorooctane sulfonic acid (PFOS) is a representative persistent organic pollutant that has been shown to impair male reproductive function. Epidemiological studies and animal models suggest that vitamin D may modify male reproductive function. However, whether 1α,25(OH) 2 D 3 could mitigate the PFOS-induced damage of Sertoli cells, and the underlying mechanisms remain poorly defined. Methods Mouse Sertoli cell line TM4 were pretreated with or without 10 nM or 100 nM 1α,25(OH) 2 D 3 for 6 h, followed by 100 µM or 200 µM PFOS for 24 h. Cell viability was assessed using the CCK8 assay. Reactive oxygen species (ROS) were detected by fluorescent staining, while malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were measured using commercial kits. siRNA transfection, quantitative real-time PCR (qRT‒PCR), and Western blotting were performed to elucidate the underlying mechanisms. Molecular docking studies were conducted to explore the potential binding of PFOS to Keap1. Results PFOS increased MDA contents, decreased GSH levels, and induced cytotoxicity in mouse Sertoli cells. Mechanistically, PFOS might directly bind to Keap1, facilitating its degradation, leading to persistent activation of the Nrf2-ARE pathway. Conversely, 1α,25(OH) 2 D 3 attenuated PFOS-induced cytotoxicity by alleviating the Nrf2-ARE pathway, a protective effect which was abolished by vitamin D receptor (VDR) knockdown. Conclusion PFOS induces cytotoxicity in Sertoli cells by binding to Keap1 and persistently activating the Nrf2-ARE pathway. 1α,25(OH) 2 D 3 emerges as a promising candidate for mitigating PFOS-induced testicular dysfunction. Graphical abstract
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