Advanced Science
·
2025
·
IF 14.1
Shuaishuai Xing,Yanbing Lin,Yi Sun,Xiaoping Yue,Qigang Fan,Jisheng Nie,Zhihong Zhang,Yajing Liu,Juntang Yang,Qingzheng Kang,Yanxin Wang,Haijun Yan,Chan Tian,Ying Chang,Huidong Zhang
Lithium (Li) batteries have been used worldwide, but few are recycled, thus, the waste Li has been widely spread into the environment and finally accumulated in human body. Cuproptosis is a newly reported Cu-dependent and programmed cell death form. The unclear pathogenesis of unexplained miscarriage (UM) largely restricts its clinical treatment and global human reproduction. In this study, a UM case-control study shows that Li levels in serum or villous tissues, the levels of cuproptosis in villous tissue, and UM are positively associated. Li-exposed mouse models further confirm that Li exposure causes placental cuproptosis to induce miscarriage. Mechanistically, Li exposure up-regulates FOXO1 expression levels and thus promotes FOXO1-mediated STEAP4 transcription, up-regulating STEAP4 levels. STEAP4 up-regulates intracellular Cu + ion levels and causes cuproptosis, which further induces miscarriage. The cellular mechanisms are consistent with those in UM villous tissues and Li-exposed mouse placental tissues. Finally, treatment with TTM to suppress cuproptosis or the therapeutic down-regulation of FOXO1 or STEAP4 could efficiently suppress placental cuproptosis and alleviate mouse miscarriage in the Li-exposed mouse models. Collectively, this study not only discovers new healthy risks of Li exposure and novel pathogenesis of Li-induced unexplained miscarriage but also reveals new biological targets for treatment against miscarriage.
研究领域:
生殖医学
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毒理学
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细胞生物学
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环境卫生
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分子生物学
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DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2024
·
IF 5.9
Zhijin Zhang,Wentao Zhang,Huan Wang,Haotian Chen,Hong Wang,Yang Yu,Danjing Shen,Man Pi,Yang Wu,Ming Luo,Yanyan He,Shiyu Mao,Jiang Geng,Wei Li,Guangchun Wang,Changcheng Guo,Daqiang Yin,Xudong Yao
Epidemiological studies indicate that prostate cancer (PCa) is the second prevalent malignant tumor affecting men globally. Environmental pollution such as cigarette smoke is one of the important risk factors for the development of prostate cancer. However, as one of the main carcinogens in cigarette smoke, the role of benzo[a]pyrene (BaP) in prostate cancer is still unclear. The current study aimed to investgate the impacts of BaP exposure on the progression of PCa toward malignancy and the regulation of the immune microenvironment. We verified that BaP exposure can promote the proliferation, migration, and apoptosis of prostate cancer cells through in vitro experiments. We constructed a subcutaneous xenograft tumor model of BaP exposure mouse and found that can promote the proliferation of tumors in vivo . Organoids-driven by PCa patients showed higher growth rate under BaP exposure. Flow cytometric analysis demonstrated a remarkable decrease in CD4 + T and CD8 + T cell infiltration levels. Moreover, we identified four genes ( Mdm2, Ar, Foxo1, Crebbp ) were strongly associated with BaP exposure by combining mouse tumor RNA-seq and CTD database. Additionally, a nomogram integrating clinicopathological features was constructed to assess the prognosis of prostate cancer patients under BaP exposure. This study systematically proved that BaP exposure promotes malignant progression of PCa and suppresses the immune microenvironment, in which Mdm2, Ar, Foxo1, Crebbp may play a crucial role in inhibiting apoptosis. These findings offer novel insights into the mechanisms via which BaP exposure contributes to PCa development.
研究领域:
肿瘤学
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免疫学
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环境医学
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DOI
高影响因子
JOURNAL OF ANIMAL SCIENCE
·
2026
·
IF 3.7
Zheng Jikang,Zhao Junyin,Li Minhao,Cheng Yuqin,Fang Xingqiang,Zhao Le,Zhao Yongju
Goat semen cryopreservation generates excessive reactive oxygen species (ROS), which impair post-thaw quality and physiological function. This study investigated the effects of resveratrol (RES) on cryopreserved goat sperm and the underlying signaling pathway. The results showed that supplementation with 150 μM RES significantly improved post-thaw sperm motility, plasma membrane integrity, and acrosome integrity (P < 0.05), enhanced SOD, CAT, and T-AOC activities, and reduced MDA content and sperm deformity rates (P < 0.05), while higher concentration (200 μM) showed no significant improvement compared to control, suggesting a detrimental effect of excessive RES. Furthermore, RES effectively alleviated cryo-induced ultrastructural damage to sperm. Mechanistically, RES activated AMPK signaling, increased AMPK phosphorylation, and upregulated the expression of SIRT1 and FoxO1 proteins. In contrast, the AMPK inhibitor Compound C partially blocked these beneficial effects. These findings indicate that RES improves the quality and antioxidant capacity of cryopreserved goat sperm by activating the AMPK/SIRT1/FoxO1 pathway, suggesting that RES can serve as a promising antioxidant additive for goat semen cryopreservation.
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Jingyi Ren,Longfei Li,Ziyi Wang,Siqi Zhu,Huanting Pei,Yadong Zhang,Bowen Yin,Zhenao Zhang,Xiaoya Sun,Huicai Guo,Yuxia Ma
Background Perfluorooctane sulfonate (PFOS) is a prototypical persistent organic pollutant that has been linked to liver inflammation. Sesamin (Ses), a major lignan in sesame, has been shown to exhibit health-promoting properties. However, the role and specific mechanism of Ses in PFOS-induced liver inflammation remain largely unclear. Purpose This study aimed to investigate the hepatoprotection and potential mechanism of Ses against PFOS-induced inflammation. Methods Wild-type (WT), Mincle knockout (Ko-mincle), and Hepatocyte-specific knockout Foxo1 (Hko-Foxo1) mice were intragastrically administered Ses and/or PFOS (10 mg/kg) for 4 weeks. In vitro, HepG2 cells were pretreated with Ses for 1 h, then exposed to PFOS for 24 h to establish a cell injury model. Results We revealed that Ses markedly alleviated PFOS-induced liver injury and inflammation, as evidenced by noticeable histopathological improvements, increased cell activity, and alterations in serum liver enzyme and inflammatory factor levels. Moreover, Ses pretreatment reduced the expression of Mincle and the phosphorylation of its downstream targets, SYK and p65, in macrophages. The reducing effect of Ses on liver inflammation in wild-type mice is significantly better than that in Mincle knockout mice. We also found that Ses decreased the expression of spliceosome-associated protein 130 (SAP130) and Foxo1. Further experiments revealed that SAP130 may serve as a mediator between hepatocytes and macrophages. Hepatocyte-specific knockout Foxo1 reduced the release of SAP130 from hepatocytes and inhibited Mincle/Syk signaling activation in macrophages. Conclusion This study demonstrates that Ses protects against PFOS-induced liver inflammation in mice by modulating crosstalk between hepatocytes and macrophages. Those findings support the potential of Ses as a promising natural compound for counteracting liver inflammation.
研究领域:
毒理学
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免疫学
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药理学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2026
·Vol. 63
·期 1
·650
·
IF 5.5
Guo Yaoxue,Wang Xueyan,Zhang Lixiang,Liu Xing,Lu Pu,Liang Furu,Wu Jing,Zhao Junli,Hai Yan
Alzheimer’s disease (AD) is associated with mitochondrial dysfunction and impaired energy metabolism in astrocytes. Although ghrelin is known to exert neuroprotective effects, the mechanisms through which it modulates astrocyte bioenergetics under AD-like conditions remain incompletely defined. In primary astrocytes treated with Aβ 25-35 oligomers, ghrelin attenuated mitochondrial damage, reducing ROS and enhancing mitochondrial membrane potential (ΔΨm) and respiratory complex activities. Glycolytic function was partially restored, as evidenced by upregulation of key enzymes, increased glucose uptake, lactate release, and NAD + /NADH ratio. Ghrelin inhibited autophagosome formation while enhancing mitophagy (increased LC3II/I and Parkin) and suppressed inflammation. In co-culture models, these metabolic improvements enhanced astrocytic support for neurons, reducing apoptosis and promoting neurite growth, an effect abolished by the glycolytic inhibitor 2-DG. Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation. In Aβ 25-35 -injected mice with UCP2 or FOXO1 modulation, ghrelin improved cognitive performance and reduced pathology, effects that were negated by UCP2 knockdown and partially rescued by FOXO1 knockdown. In conclusion, ghrelin ameliorates Aβ-induced astrocyte dysfunction involving the UCP2-FOXO1 pathway, partially restoring mitochondrial integrity, glycolytic metabolism, and neurotrophic support, suggesting its therapeutic potential.
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2026
·
IF 3.9
Lu Wang,Kejian Wei,Jiahua Yan,Kun Wang,Siqi Liu,Fei Fang,Yu Jiang
As a major citrus flavonoid, hesperidin (HP) shows bone-protective potential, yet its role in calcium–phosphorus homeostasis and antioxidant mechanisms remains unclear. This study investigated the anti-osteoporotic effects of HP in retinoic acid (RA)-induced osteoporotic mice and primary bone marrow mesenchymal stem cells (BMSCs). HP promoted BMSC proliferation, migration, and osteogenic differentiation, with increased alkaline phosphatase (ALP) activity and mineralization. Network pharmacology identified antioxidant PI3K/AKT/FOXO1 pathways as key targets, with fibroblast growth factor 23 (FGF23) as a pivotal effector. In osteoporotic mice, HP normalized serum calcium, phosphorus, and 25-hydroxyvitamin D, increased bone formation and decreased resorption markers, alleviating bone loss and preserving trabecular microarchitecture and enhancing biomechanical properties. Mechanistically, PI3K/AKT/FOXO1-mediated FGF23 suppression was essential for osteoprotection, as confirmed using a PI3K inhibitor. Collectively, these findings suggest that HP ameliorates RA-induced osteoporosis by restoring calcium–phosphorus homeostasis via PI3K/AKT/FOXO1-dependent FGF23 inhibition, underscoring its potential as a functional food ingredient.
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DOI
高影响因子
Oncology Letters
·
2019
·Vol. 17
·期 5
·4505-4513
·
IF 1.871
Jian Jiang,Yaodong Chen,Tianxiu Dong,Minlu Yue,Yu Zhang,Tingting An,Jiuwei Zhang,Pengfei Liu,Xiuhua Yang
Polydatin, extracted from Polygonum cuspidatum, is known for its anti‑platelet aggregation and anti‑inflammatory effects. However, studies on the association of polydatin with cancer are limited, particularly with regards to epithelial‑mesenchymal transition (EMT)‑associated migration and invasion of cancer cells. The purpose of the present study was to reveal the potential anticancer effects of polydatin on hepatocellular carcinoma (HCC) cells, particularly its effects on EMT. MTT assay was used to determine cell viability. Migration and invasion were evaluated through wound healing and transwell assays. Colony formation efficiency assay was conducted to detect proliferation. Flow cytometric analyses of apoptosis and cell cycle progression were performed following cells staining with Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide (PI) and PI alone, respectively. Western blotting was used to investigate relevant molecular mechanisms. The results indicated that polydatin inhibited proliferation via G2/M arrest, suppressed migration and invasion of HCC cells, and promoted their apoptosis. In addition, phosphorylated (p)‑protein kinase B (AKT), p‑Janus kinase 1 and p‑signal transducer and activator of transcription 3 (STAT3) levels were decreased as polydatin concentrations increased, and forkhead box protein O1 (FOXO1) expression was upregulated. Furthermore, the expression levels of various markers of EMT were reversed following treatment with polydatin. In conclusion, the present study validated that polydatin may inhibit proliferation via G2/M arrest, and suppressed EMT‑associated migration and invasion of HCC cells. The results also suggested that polydatin may promote HCC cell apoptosis by blocking the AKT/STAT3‑FOXO1 signaling pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 11
·5269-5282
·
IF 5.31
Jian Shen,Ganglei Li,Yu Zhu,Qingsheng Xu,Hengjun Zhou,Kangli Xu,Kaiyuan Huang,Renya Zhan,Jianwei Pan
The blood-brain barrier (BBB) damage is a momentous pathological process of ischaemic stroke. NADPH oxidases 4 (NOX4) boosts BBB damage after ischaemic stroke and its expression can be influenced by microRNAs. This study aimed to probe into whether miR-92b influenced the BBB damage after ischaemic stroke by regulating NOX4 expression. Here, miR-92b expression was lessened in the ischaemic brains of rats and oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs). In middle cerebral artery occlusion (MCAo) rats, miR-92b overexpression relieved the ameliorated neurological function and protected the BBB integrity. In vitro model, miR-92b overexpression raised the viability and lessened the permeability of OGD-induced BMECs. miR-92b targeted NOX4 and regulated the viability and permeability of OGD-induced BMECs by negatively modulating NOX4 expression. The transcription factor Foxo1 bound to the miR-92b promoter and restrained its expression. Foxo1 expression was induced by OGD-induction and its knockdown abolished the effects of OGD on miR-92b and NOX4 expressions, cell viability and permeability of BMECs. In general, our findings expounded that Foxo1-induced lessening miR-92b boosted BBB damage after ischaemic stroke by raising NOX4 expression.
研究领域:
神经科学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF PINEAL RESEARCH
·
2026
·Vol. 78
·期 2
·e70139
·
IF 7.5
Yi Zheng,Qing-qing Chen,Hai-xiang Guo,Yu-xin Zhang,Ling-ling Qiu,Bing-bing Wang,Song Yu,Jia-rui Gao,Zhe Zhang,Jia-bao Zhang,Guo-shi Liu,Bao Yuan
Melatonin, a signaling molecule secreted by the pineal gland, is closely associated with physiological activities, such as animal growth, development, and reproduction. Multiple studies have indicated that melatonin acts on the adenohypophysis to promote the synthesis and secretion of growth hormone (GH), but the specific mechanism of melatonin remains unclear. We have previously reported that melatonin levels in bovine serum are closely correlated with GH levels. In the present study, transcriptome sequencing was performed on primary bovine adenohypophyseal cells treated with melatonin, which identified FOXO1 as a key transcription factor that is responsive to melatonin and regulates GH synthesis and secretion. Cellular experiments revealed that melatonin binds to the MTNR1A in bovine adenohypophyseal cells, activates the cAMP/PKA signaling pathway, and promotes the expression of FOXO1 protein. Dual-luciferase reporter assays verified the binding of FOXO1 to the GH1 promoter. Treatment with Luzindole, 4P-PDOT, 2′,5′-Dideoxyadenosine or H-89 elucidated the molecular mechanism through which melatonin promotes GH synthesis and secretion in adenohypophyseal cells through the cAMP/PKA/CREB/FOXO1 pathway. The present study provides critical evidence for the direct action of melatonin on adenohypophyseal cells and its targeted regulatory sites, and it offers new insights into the conserved and species-specific modes of action of melatonin across different species, providing data and theoretical support for the application of melatonin in promoting animal growth and development.
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PubMed
高影响因子
Nature Communications
·
2022
·Vol. 13
·期 1
·1-13
·
IF 17.694
Pan An,Sun Xiao-Meng,Huang Feng-Qing,Liu Jin-Feng,Cai Yuan-Yuan,Wu Xin,Alolga Raphael N.,Li Ping,Liu Bao-Lin,Liu Qun,Qi Lian-Wen
Disordered hepatic glucagon response contributes to hyperglycemia in diabetes. The regulators involved in glucagon response are less understood. This work aims to investigate the roles of mitochondrial β-oxidation enzyme HADHA and its downstream ketone bodies in hepatic glucagon response. Here we show that glucagon challenge impairs expression of HADHA. Liver-specific HADHA overexpression reversed hepatic gluconeogenesis in mice, while HADHA knockdown augmented glucagon response. Stable isotope tracing shows that HADHA promotes ketone body production via β-oxidation. The ketone body β-hydroxybutyrate (BHB) but not acetoacetate suppresses gluconeogenesis by selectively inhibiting HDAC7 activity via interaction with Glu543 site to facilitate FOXO1 nuclear exclusion. In HFD-fed mice, HADHA overexpression improved metabolic disorders, and these effects are abrogated by knockdown of BHB-producing enzyme. In conclusion, BHB is responsible for the inhibitory effect of HADHA on hepatic glucagon response, suggesting that HADHA activation or BHB elevation by pharmacological intervention hold promise in treating diabetes.
研究领域:
内分泌学
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代谢学
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分子生物学
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糖尿病研究
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DOI
PubMed
高影响因子
PLoS One
·
2026
·Vol. 21
·期 4
·e0348261
·
IF 2.8
Yating Lv,Yanfei Meng,Haiying Rui,Tongqin Li,Jing Zhang,Jie Liu,Xin Ma,Jiaqi Wang,Yamin Yuan,Yujing Jiang,Xiaoxi Yan,Miaobo Li,Xiaorong Dong,Bei Zhang,Li Ma
Sepsis-associated acute lung injury (SALI) is characterized by endothelial barrier dysfunction and capillary leakage. Ulinastatin (UTI), a serine protease inhibitor with recognized clinical benefits in sepsis, has been reported to protect endothelial function, but the underlying mechanisms remain incompletely defined. This study investigated the protective effects of UTI against SALI and its specific mechanism of action. We found that UTI attenuated lung injury and endothelial dysfunction in both cecal ligation and puncture (CLP)-induced septic rats and LPS-stimulated human umbilical vein endothelial cells (HUVECs). UTI treatment reduced the expression of angiopoietin-2 (Ang-2), a key mediator of vascular destabilization, and exerted similar protective effects on endothelial function as dexamethasone (DEX). Mechanistically, UTI was demonstrated to have a stable interaction and favorable binding affinity to PI3K by docking and activating the PI3K/Akt signaling pathway. This led to phosphorylation and subsequent nuclear export of the transcription factor FoxO1, thereby suppressing FoxO1-dependent Ang-2 transcription. The protective effects of UTI on capillary leakage and junctional protein integrity were abolished by the PI3K inhibitor wortmannin. In conclusion, our findings demonstrate that UTI alleviates SALI by disrupting an Ang-2-mediated vicious cycle via the PI3K/Akt/FoxO1 pathway, revealing a novel mechanistic insight into its therapeutic action against sepsis-induced vascular leakage.
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Jin Wu,Xiang Li,Hepeng Nie,Yue Shen,Zixiang Guo,Catherine Huihan Chu,Kunzhan Cai,Chunbo Tang
Diabetes-related hyperglycemia inhibits bone marrow mesenchymal stem cell (BMSC) function, thereby disrupting osteoblast capacity and bone regeneration. Dietary supplementation with phytic acid (PA), a natural inositol phosphate, has shown promise in preventing osteoporosis and diabetes-related complications. Emerging evidence has suggested that circular (circ)RNAs implicate in the regulation of bone diseases, but their specific regulatory roles in BMSC osteogenesis in hyperglycemic environments remain elucidated. In this study, in virto experiments demonstrated that PA treatment effectively improved the osteogenic capability of high glucose-mediated BMSCs. Differentially expressed circRNAs in PA-induced BMSCs were identified using circRNA microarray analysis. Here, our findings highlight an upregulation of circEIF4B expression in BMSCs stimulated with PA under a high-glucose microenvironment. Further investigations demonstrated that circEIF4B overexpression promoted high glucose-mediated BMSC osteogenesis . In contrast, circEIF4B knockdown exerted the opposite effect. Mechanistically, circEIF4B sequestered microRNA miR-186-5p and triggered osteogenesis enhancement in BMSCs by targeting FOXO1 directly. Furthermore, circEIF4B inhibited the ubiquitin-mediated degradation of IGF2BP3, thereby stabilizing ITGA5 mRNA and promoting BMSC osteogenic differentiation. In vivo experiments, circEIF4B inhibition attenuated the effectiveness of PA treatment in diabetic rats with cranial defects. Collectively, our study identifies PA as a novel positive regulator of BMSC osteogenic differentiation through the circEIF4B/miR-186-5p/FOXO1 and circEIF4B/IGF2BP3/ITGA5 axes, which offers a new strategy for treating high glucose-mediated BMSC osteogenic dysfunction and delayed bone regeneration in diabetes.
研究领域:
干细胞生物学
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分子生物学
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糖尿病研究
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骨再生
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RNA生物学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）