EXPERIMENTAL CELL RESEARCH
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2022
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IF 4.145
Wuguang Liu,Xiaolong Liu,Ying Liu,Ting Ling,Di Chen,Wuxiyar Otkur,Hailong Zhao,Ming Ma,Kexin Ma,Bing Dong,Zexuan Yang,Hai-long Piao,Rui Liang,Chengyong Dong
PLIN2 has been found to be dysregulated in several human malignancies, which influences cancer progression. However, the roles of PLIN2 in regulating hepatocellular carcinoma (HCC) progression are still unclear. Here, we revealed that PLIN2 was frequently upregulated in HCC cells and tissues, and increased PLIN2 expression was associated with poor prognosis outcomes in HCC. In HCC cells, overexpressing PLIN2 promoted cell proliferation , PLIN2-deficiency inhibited cell vitality. Mechanistically, silencing of PLIN2 expression downregulated hypoxia inducible factor 1-α (HIF1α) expression and this downregulation in turn inhibited the targeting genes of HIF1α. Furthermore, we found that PLIN2 stabilized and retarded the degradation of the HIF1α through autophagy-lysosomal pathway by inhibiting AMPK/ULK1. Collectively, we clarified the carcinogenic role of PLIN2 in HCC and suggested a prognostic biomarker for diagnosis and clinical therapy in the future.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2022
·Vol. 79
·期 7
·1-22
·
IF 9.207
Song Chang-Chun,Pantopoulos Kostas,Chen Guang-Hui,Zhong Chong-Chao,Zhao Tao,Zhang Dian-Guang,Luo Zhi
Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters ( zip14 and fpn 1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 α (HIF1α), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1α to the pparγ and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1α-PPARγ pathway are critical mediators of iron-induced lipid deposition.
研究领域:
营养学
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生物化学
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分子生物学
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细胞生理学
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DOI
PubMed
高影响因子
Advanced Science
·
2025
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IF 14.1
Hui Luo,Xiaolu She,Yubo Zhang,Bingfan Xie,Shibo Zhang,Qianqian Li,Yangyang Zhou,Shuang Guo,Shushan Zhang,Yanhui Jiang,Yingying Dong,Jianzhong He,Lijie Wang,Qianqian Zhang,Yuan Zhuang,Panxia Deng,Feng Wang,Jihong Liu,Xin Chen,Huilong Nie,Huanhuan He
A major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites-mediated abdominal metastasis obscure. Here, a single-cell transcriptomic landscape of CD45 + immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high-grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2 hi ) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as “ascites-associated macrophages (AAMs)”. AAMs are lipid-loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro-tumor functions. Finally, a PLIN2-targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer-promoting function and lipid-rich property of ascites-enriched PLIN2 hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans-coelomic metastasis of OC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症代谢
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Yu Shan,Yang Jinghui,Zhang Rui,Guo Qian,Wang Lu
Systemic inflammatory stimulus is a risk factor for the incidence of ischemic stroke and contributes to poorer clinical outcomes. Solute carrier 15A3 (SLC15A3) is a peptide/histidine transporter that is implicated in regulating inflammatory responses. However, whether SLC15A3 affects the progression of ischemic stroke associated with systemic inflammation is unclear. The transient middle cerebral artery occlusion (tMCAO) mice with LPS administration (LPS/tMCAO) were prepared as an in vivo model, and LPS-induced BV2 cells under oxygen–glucose deprivation (OGD) exposure were utilized as an in vitro model. We found that SLC15A3 was highly expressed in the ischemic penumbra of LPS/tMCAO mice, and its inhibition reduced infarct area, attenuated neurological deficit, recovered motor function, and mitigated apoptotic neurons. Knockdown of SLC15A3 suppressed the proinflammatory M1-type markers and promoted the levels of M2-associated genes. The in vitro results confirmed that SLC15A3 overexpression promoted microglia polarizing towards M1 subtypes, while SLC15A3 inhibition exerted an opposite effect. In addition, we demonstrated that the p65 signaling pathway and HIF1α were activated by LPS/OGD. Luciferase reporter assay showed that inhibiting p65 using its specific inhibitor BAY 11–7082 or silencing HIF1α using siRNAs reduced the transcriptional activity of SLC15A3 in LPS/OGD-induced BV2 cells. Results in NIH 3T3 cells also confirmed that p65 and HIF1α directly bound to the SLC15A3 promoter to activate SLC15A3 transcription. In conclusion, this work shows that SLC15A3 , transcriptionally activated by p65 and HIF1α, contributes to poor outcomes in ischemic stroke associated with systemic inflammation by promoting microglial cells polarizing towards M1 types.
研究领域:
神经科学
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免疫学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Fake Li,Jie Luo,Huan Xu,Yang Wang,Wenbin Jiang,Kai Chang,Shaoli Deng,Ming Chen
Early secreted antigenic target 6-kDa protein (ESAT6) is an essential virulence factor of Mycobacterium tuberculosis (MTb). However, ESAT6 helped fighting MTb infection according to vaccine studies. It's unclear whether ESAT6 confers protection via enhancing the innate immunity of macrophages, which are the first-line defense against MTb. We profiled the global transcriptional changes and characterized the innate immunity of THP-1 macrophages treated with ESAT6. We found ESAT6 promoted the phagocytosis ability, enhanced reactive oxygen species (ROS) generation and accelerated glucose metabolism in macrophages. Meanwhile, ESAT6 induced a distinctive phenotype of macrophages with a concurrence of pro-inflammatory and anti-inflammatory cytokines and chemokines . ESAT6 increased the expression of HIF1α mRNA and protein. Interfering HIF1α with siRNA defected the capacity of phagocytosis and ROS generation as well as glucose metabolism. Thus, ESAT6 enhanced the protective innate immunity of macrophages partially via HIF1α. This study provided clues for developing therapies against tuberculosis by targeting ESAT6.
研究领域:
免疫学
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微生物学
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传染病学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
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IF 4.2
Maoshan Wang,Yingxue Liu,Houda Gui,Gaoqiang Ma,Binyang Li,Zhanwei Zhang,Gyeonghwi Yu,Ailin Wu,Xin Xu,Dongjiao Zhang
Eldecalcitol (ED-71), a novel active form of vitamin D, shows potential in treating osteoporosis. However, its underlying mechanisms of action remain to be determined. This study aimed to investigate the effect of ED-71 on bone regeneration and to illustrate its mode of action. The in-vitro model was developed using rat primary osteoblasts cultured under high-glucose conditions, and these cells were treated with ED-71. Additionally, an in vivo model of cranial bone defects was established in type 2 diabetic rats, and ED-71 was administered by gavage. The results demonstrated that ED-71 prevented osteoblast cell death, enhanced rat primary osteoblasts' osteogenic capacity, and attenuated the overexpression of hypoxia-inducible factor 1α (HIF1α) induced by high glucose levels. Furthermore, ED-71 increased glutathione peroxidase 4 (GPX4) levels and inhibited ferroptosis in response to hyperglycemic stimulation. Notably, interference with the HIF1α activator and ferroptosis activator Erastin significantly reduced the therapeutic effects of edetate osteolysis. These findings were further tested in vivo experiments. These results suggest that ED-71 activates the HIF1α pathway in vivo and in vitro, effectively relieving the ferroptosis induced by high glucose. Significantly, ED-71 may improve osteogenic disorders caused by diabetes.
研究领域:
药理学
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内分泌学
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骨科
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细胞生物学
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DOI
PubMed
高影响因子
Journal of the American Heart Association
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2026
·Vol. 15
·期 13
·
IF 6
Xinying Wang,Ge Zhan,Jiatian Li,Xinmiao Yang,Yuhang Wen,Yuqi Tang,Puyu Zhang,Yunlong Xia,Xiaolei Yang
BackgroundThe clinical utility of doxorubicin, a potent chemotherapeutic agent, is severely limited by its dose‐dependent cardiotoxicity. Hypoxia‐inducible factor 1α (HIF1α) is a key regulator of cardiovascular adaptation, but its role and mechanism in doxorubicin‐induced cardiotoxicity (DIC) remain unclear.MethodsUsing in vitro (AC16 cells) and in vivo (mouse) models of DIC, we used genetic (knockout, knockdown) and pharmacological (FG4592) approaches to modulate HIF1α. Cardiac function, apoptosis, endoplasmic reticulum (ER) morphology, and ER‐phagy flux were assessed. Molecular mechanisms were investigated using chromatin immunoprecipitation and promoter activity assays.ResultsHIF1α exhibited a dynamic, biphasic expression pattern during DIC progression. Stabilization of HIF1α by FG4592 alleviated doxorubicin‐induced cardiac dysfunction, atrophy, fibrosis, and apoptosis, whereas HIF1α knockout exacerbated these injuries. The protective effects of FG4592 were strictly dependent on HIF1α. Mechanistically, HIF1α transcriptionally activated the ER‐phagy receptor gene testis‐expressed protein 264 (TEX264) by directly binding to its promoter. This activation enhanced ER‐phagy, and suppressed ER stress–mediated apoptosis. Crucially, ablation of TEX264 abolished the cardioprotective effects of both HIF1α and FG4592.ConclusionsThis study identifies a novel HIF1α/TEX264/ER‐phagy axis that is suppressed in DIC and is central to cardiomyocyte survival. Targeting this pathway, particularly with the clinically available HIF1α stabilizer FG4592, represents a promising therapeutic strategy against DIC.
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DOI
高影响因子
Advanced Science
·
2026
·
IF 14.1
Lili Lian,Zhenmin Le,Xuanqiao Ye,Zimo Wang,Jiuxiao Li,Chenyu Dong,Yetao Shen,Jiazheng Li,Yueping Ren,Xiaoyin Ma,Wei Chen,Qinxiang Zheng
Hyperosmotic stress induced by tear film instability significantly exacerbates oxidative damage in corneal epithelial cells, contributing to the pathogenesis of dry eye disease (DED). Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been identified as a critical downstream mechanism of oxidative damage in DED. However, its precise regulatory mechanisms remain unclear. In this study, we demonstrate that hyperosmotic stress promotes ferroptosis in corneal epithelial cells by downregulating the NAD-dependent deacetylase sirtuin 1 (SIRT1). SIRT1 positively regulates GPX4, a pivotal mediator of ferroptosis. Pharmacological activation of SIRT1 using SRT1720 alleviated oxidative damage and suppressed ferroptosis in corneal epithelial cells both in vitro and in vivo. Mechanistically, we further observed that SIRT1 deacetylates the HIF1α, stabilizing it via the ubiquitin-proteasome pathway. The SIRT1–HIF1α axis positively regulates GPX4 levels, thereby inhibiting ferroptosis activation. These results reveal a previously unrecognized pathway of ferroptosis regulation in DED and suggest a potential therapeutic strategy for reducing oxidative damage in corneal epithelium.
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产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2026
·Vol. 18
·期 3
·2489
·
IF 1.8
Yuqing Bi,Yanchun Chen,Jimei Jiang,Wangqi Mao,Xiao Zhang,Jiayi Liu,Xin Zhao,Yueqiu Dong,Yueqing Cai,Mei Li,Xiang Li,Yunpeng Luan,Liyun Jiang
Objective: Jiangfu Fuwei granules (JFFW) are a widely used clinical prescription for the treatment of chronic atrophic gastritis (CAG), but the underlying molecular mechanism remains to be explored. This study aimed to elucidate the therapeutic mechanism of JFFW in alleviating CAG. Methods: A CAG mouse model was established using a combined approach, and the mice were treated with JFFW for six weeks. Network pharmacology was used to screen for active ingredients and signaling pathways. Subsequently, in vivo experiments were conducted to verify the predicted mechanisms, including histologic evaluation, enzyme-linked immunosorbent assay, and immunohistochemical analysis. Furthermore, molecular docking was used to simulate the interaction between key active compounds and core protein targets. Results: In vivo experimental results demonstrated that JFFW effectively reversed gastric mucosal thinning and glandular loss in CAG mice. This treatment significantly restored serum pepsinogen levels and downregulated the expression of inflammatory cytokines, specifically interleukin-6, interleukin-1β, and tumor necrosis factor-α. Network pharmacology analysis identified 224 bioactive compounds and predicted the phosphoinositol 3-kinase (PI3K)-protein kinase B (AKT)-hypoxia-inducible factor 1-α (HIF1α) signaling pathway as a key target. Immunohistochemical results confirmed that JFFW treatment significantly inhibited the protein expression of phosphorylated AKT and HIF1α. Furthermore, reduced CD31 staining occurred consistent with a decrease in microvessel density. Molecular docking analysis further confirmed that the main components of JFFW had a good binding affinity to PI3K protein. Conclusion: The therapeutic effect of JFFW on CAG is mainly achieved by inhibiting the PI3K-AKT-HIF1α signaling pathway, thereby suppressing abnormal angiogenesis and gastric inflammation.
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DOI
PubMed
高影响因子
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
·
2025
·
IF 3.7
Chenmei Peng,Pan Lei,Hongying Qi,Qianjun Zhu,Chushun Huang,Ju Fu,Chengyu Zhao
Diabetes is the third most common chronic disorder worldwide. Diabetic wounds are a severe complication that is costly and often results in non-traumatic lower limb amputation. Recent investigations have demonstrated that the gut microbiota as a “virtual organ” can regulate metabolic diseases like diabetes. Fecal microbiota transplantation (FMT) is an innovative therapeutic approach for promoting wound healing, but its function remains incompletely defined. A diabetes model was established by supplying mice with a high-fat diet and performing an intraperitoneal injection of streptozotocin. Diabetic wounds were then created, followed by bacterial transplantation. The relevant indexes of wound healing were evaluated to verify the promoting effect of FMT on the diabetic wounds. Human skin keratinocytes were also cultured, and cell scratch experiments were conducted to further investigate the underlying mechanism. The FMT regulated the levels of specific bacteria in the diabetic mice and helped restore the balance of intestinal microbes. This transplantation also enhanced wound healing in the diabetic mice by augmenting the closure rate, accelerating re-epithelialization, and boosting collagen deposition in skin wounds. Furthermore, FMT promoted the production of IL-17A, which significantly enhanced the growth and movement of human keratinocytes. Inhibiting molecules related to the IL-17A–mTOR–HIF1α signaling axis were shown to hinder wound re-epithelialization.This study clarifies the function of the IL-17A–mTOR–HIF1α signaling axis in the utilization of FMT in diabetic wound healing, providing a new therapeutic method and target for promoting the healing of diabetic wounds.
研究领域:
医学
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免疫学
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微生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 17
·8935
·
IF 13.3
Jingyi Li,Liang Feng,Lei Zhang,Weiguo Zhang,Yanting Zhang,Xiaoqin Liu,Qianqian Cai,Weiming Zhao,Gang Huang,Changlian Lu
Background: Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, exhibits poor prognosis due to radiotherapy resistance. However, the underlying mechanisms and effective therapeutic agents remain elusive. Methods: We employed lactate/oxamate to assess DNA damage/repair in irradiated TNBC cell lines. Lentiviral vectors for MRE11/HDAC5 constructs and shRNA were used to explore lactylation via Western blot/Co-IP. TCGA data mining, tissue microarrays, proteomics-MS, and gene expression profiling were used to dissect Saikosaponin D (SSD)'s radiosensitizing mechanisms. Promoter luciferase assays and ChIP-qPCR were performed to map SSD-induced HIF1α binding sites on the HDAC5 promoter. Results: Elevated endogenous lactate in radioresistant TNBC cells promoted DNA repair via MRE11 Lys 673 lactylation, a critical modification conferring radioresistance. HDAC5 was identified as the key delactylase for MRE11 Lys 673, validated by HADDOCK docking (hydrogen bond between MRE11 Lys 673 and HDAC5 Ser 18 ) and Co-IP (HDAC5 overexpression reduced K 673 lactylation). TCGA and clinical tissue microarrays confirmed HDAC5 downregulation in TNBC. SSD inhibits the malignant phenotype of TNBC and enhances radiotherapy efficacy by inhibition on MRE11 lactylation via upregulating HDAC5. Mechanistically, SSD upregulated HIF1α to bind the HDAC5 promoter (-342bp to -20bp region) to activate its expression. Conclusion: Lactate-driven MRE11 Lys 673 lactylation mediates radioresistance, while SSD reverses this via HIF1α/HDAC5 axis activation. Our findings identify SSD as a radiosensitizer and HDAC5/MRE11 as potential therapeutic targets for TNBC.
研究领域:
肿瘤学
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分子生物学
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放射生物学
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药理学
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癌症治疗学
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产品关联
DOI
PubMed
高影响因子
iScience
·
2023
·
IF 5.8
Zhijie Zhang,Jiangzhou Shi,Qifang Wu,Zijian Zhang,Xiaoyan Liu,Anqi Ren,Guanlin Zhao,Ge Dong,Han Wu,Jiaxuan Zhao,Yuan Zhao,Jia Hu,Hui Li,Tongcun Zhang,Fuling Zhou,Haichuan Zhu
Dexamethasone (Dex) plays a critical role in T-ALL treatment, but the mechanisms of Dex resistance are poorly understood. Here, we demonstrated that the expression of JUN was regulated in Dex-resistant T-ALL cell lines and patient samples. JUN knockdown increased the sensitivity to Dex. Moreover, the survival data showed that high expression of JUN related to poor prognosis of T-ALL patients. Then, we generated dexamethasone-resistant clones and conducted RNA-seq and ATAC-seq. We demonstrated that the upregulation of JUN was most significant and regulated by JNK pathway in Dex-resistant cells. High-throughput screening showed that HIF1α inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1α in Dex resistance cells. These results reveal a new mechanism of Dex resistance in T-ALL and provide experimental evidence for the potential therapeutic benefit of targeting the JNK-JUN-HIF1α axis for T-ALL treatment.
研究领域:
肿瘤学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
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