FASEB JOURNAL
·
2025
·Vol. 39
·期 11
·e70681
·
IF 4.2
Yao Chen,Heqi Dai,Fei Mao,Yangbai Li,Ruizhi Feng,Yun Qian
Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in women of reproductive age. However, the underlying molecular mechanism remains unclear. In this study, we employed RNA sequencing analysis to identify differentially expressed protein‐coding genes and long noncoding RNA (lncRNA) expression profiles in granulosa cells from women with and without PCOS. It was established that the level of NONHSAT233728.1 was diminished in women with PCOS. The present study demonstrated the role of NONHSAT233728.1 in granulosa cells from patients with PCOS and further investigated the potential mechanism of NONHSAT233728.1 in the KGN cell line. Additionally, the knockdown of NONHSAT233728.1 has been observed to promote cell apoptosis, inhibit cell proliferation, promote mitochondrial dysfunction, and inflammation. Western blot analyses confirmed that phospho‐extracellular regulated protein kinases (ERK)1/2 were decreased following lnc‐NONHSAT233728.1 knockdown. Consequently, we propose that ROS accumulation activates the endogenous mitochondrial apoptosis pathway, leading to granulosa cell apoptosis via the MEK/ERK1/2 pathway, which contributes to follicular atresia. We observed a negative correlation between NONHSAT233728.1 and both LH levels and the LH/FSH ratio. These findings indicate that lncRNA NONHSAT233728.1 is linked to the pathogenesis of PCOS and offer new insights into its underlying mechanisms. Through isolation and transcriptomic profiling of granulosa cells, we identified the functional significance of lncRNA NONHSAT233728.1 in polycystic ovary syndrome (PCOS) pathogenesis. Knockdown of lncRNA NONHSAT233728.1 in granulosa cells elevated ROS levels, reduced the Bcl2/Bax ratio, downregulated phospho‐ERK1/2, and increased IL‐8 secretion. These results demonstrate ROS‐mediated mitochondrial apoptosis via MEK/ERK1/2 suppression, alongside inhibited proliferation and enhanced inflammation, consistent with follicular atresia in PCOS. Negative correlations between NONHSAT233728.1 and LH/FSH ratios further support its pathogenic role.
研究领域:
生殖医学
·
分子生物学
·
内分泌学
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DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Da Xingwen,Li Ziyan,Huang Xiaofan,He Zuhan,Yu Yubing,Tian Tongtong,Xu Chengqi,Yao Yufeng,Wang Qing K.
Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1 +/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1 smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1 +/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.
研究领域:
心血管疾病
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
DIABETES OBESITY & METABOLISM
·
2024
·
IF 5.4
Ting Zheng,Ruhao Yang,Xin Li,Zhe Dai,Hongyu Xiang
Background Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD), but its mechanism has not been clearly studied. We utilized integrative transcriptome analysis to explore the pathogenesis of DN. Methods We conducted an analysis by combining bulk dataset and single-cell transcriptome dataset. Through this approach, we identified that Serpine2 may regulate the ‘collagen-containing extracellular matrix’ pathway involved in DN. Subsequently, we established DN animal and cell models using db/db mice and mesangial cells (MCs) to validate the role of Serpine2 in DN. In the animal model, we detected the expression level of Serpine2 in DN using western blotting (WB) and immunofluorescence (IF) assays. To further clarify the molecular mechanism of Serpine2 in DN, we knocked down Serpine2 and observed its effects on MCs proliferation and extracellular matrix (ECM) accumulation. Results Our single-cell analysis of DN models highlighted a pivotal role for MCs in the disease's initiation. Next, through Cytoscape analysis of differentially expressed genes (DEGs) in MCs, we identified the following 10 hub genes: Acta2, Angpt2, Ccn1, Col4a1, Col4a2, Col8a1, Kdr, Thbs1, Tpm4 and Serpine2. Subsequently, we identified that Serpine2 and Kdr were also significantly DEGs in the bulk analysis of glomeruli. Additionally, our integrated gene set enrichment analysis of bulk dataset and single-cell RNA dataset revealed that the ‘collagen-containing extracellular matrix’ was a key pathway in DN progression. Serpine2 was one of the crucial genes involved in regulating this pathway. Therefore, we speculated that the regulation of the ‘collagen-containing extracellular matrix’ pathway by Serpine2 was an important mechanism. Importantly, WB and IF staining confirmed that Serpine2 expression was upregulated in the MCs of diabetic mice. Knockdown of Serpine2 in cultured MCs alleviated high-glucose-induced excessive MCs proliferation and ECM accumulation. Finally, we found that ERK agonist Ro 67-7476 eliminated the effect of Serpine2 siRNA. Conclusions In summary, Serpine2 regulates MCs proliferation and ECM synthesis through activation of the ERK1/2 pathway, which is an important pathogenesis mechanism of DN. These findings offer fresh perspectives on the mechanisms of glomerulosclerosis in DN pathogenesis and may provide new targets for treating DN.
研究领域:
分子生物学
·
肾脏病学
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DOI
高影响因子
MOLECULAR BIOLOGY REPORTS
·
2022
·Vol. 49
·期 8
·7665-7676
·
IF 2.742
Jiang Haoran,Wen Xianxin,Zhang Xue,Zhong Xianhua,Li Zhangyong,Zhang Bingyu
Background Hepatocellular carcinoma (HCC) is the main types of primary liver cancer, which shows some abnormal glycosylation, such as the increase of fucose. Lens culinaris agglutinin (LCA), a natural plant lectin that can bind to mannose and fucose, has been reported to be antiproliferative to may tumors. However, the effect of LCA on the vitality and migration ability of human hepatoma cells is not demonstrated. Therefore, the aim of this study is to investigate the effects of LCA on vitality and migration in human hepatoma cells and its potential mechanisms. Methods and results LCA had no significant effect on viability of human hepatoma cells (HCCLM3, MHCC97L and HepG2) and hepatocytes (L02) by CCK-8 kit, but it could inhibit human hepatoma cells migration significantly without affecting hepatocytes by Transwell method. Sugar inhibition assay was used to verify the possible binding site between LCA and human hepatoma cells. The result showed that Mannose- and fucose- related sites were associated with LCA inhibiting human hepatoma cells migration. Moreover, LCA could affect HCCLM3 migration by activating ERK1/2 and JNK1/2/3 signalling pathways. LCA did not affect MMP-2 and MMP-9 of HCCLM3 through gelatinase zymography. However, the results of immunofluorescence standing showed that LCA could reduce the F-actin formation in HCCLM3 via ERK1/2 and JNK1/2/3 signalling pathways. Conclusions LCA might inhibit human hepatoma cell migration by reducing the F-actin formation via the mannose and fucose-mediated ERK1/2 and JNK1/2/3 signalling pathway. This result will deepen people’s understanding on plant lectin as a drug in tumor glycobiology.
研究领域:
肿瘤生物学
·
分子生物学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jia Liu,Senlin Li,Hong Zhou,Mengheng Wang,Chengliang Zhang,Cheng Tian,Yue Xu,Mengxuan Wang,Xin Li,Qing Li,Ming Xiang
Gemcitabine is a widely employed first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the rapid emergence of gemcitabine resistance poses a major clinical hurdle. Here, we identified REG3A as a crucial determinant of poor prognosis in PCa. Notably, REG3A was upregulated in tumor tissues from clinical gemcitabine-resistant PCa patients. Through comprehensive in vitro cellular assays and in vivo studies using Reg3g (the murine homolog of REG3A) knockout mice, we demonstrated that REG3A deficiency sensitized PCa to gemcitabine treatment. Mechanistically, RNA sequencing (RNA-Seq) combined with Protein-Protein Interaction (PPI) analysis revealed that REG3A functioned as an exocytosis protein binds to the novel membrane receptor GPR54. The interaction increased membrane localization of GPR54, which subsequently engaged ARRB2 as a scaffolding molecule, leading to activation of the ERK1/2 pathway and suppression of gemcitabine-induced apoptosis. Moreover, the GPR54 agonist KP10 synergistically enhanced gemcitabine resistance in conjunction with REG3A, while interference with GPR54 or its antagonist KP234 attenuated REG3A-induced gemcitabine resistance. Targeting REG3A or pharmacologically inhibiting its downstream signaling molecules may represent a promising strategy to overcome gemcitabine resistance. Overall, REG3A could serve as a potential biomarker for gemcitabine resistance in PCa, offering a new avenue for therapeutic intervention and patient stratification.
研究领域:
肿瘤学
·
分子生物学
·
癌症药理学
·
信号转导
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2022
·Vol. 18
·期 16
·6008-6019
·
IF 10.75
Li Chao,Lv Li-fang,Qi-Li Mu-ge,Yang Rui,Wang Yu-jing,Chen Shuang-shuang,Zhang Ming-xiu,Li Tian-yu,Yu Tong,Zhou Yu-hong,Liang Hai-hai,Shan Hong-li,Li Xue-lian
Cardiac fibrosis is one of the common pathological processes in many cardiovascular diseases characterized by excessive extracellular matrix deposition. SerpinE2 is a kind of protein that inhibits peptidase in extracellular matrix and up-regulated tremendously in mouse model of cardiac fibrosis induced by pressure-overloaded via transverse aortic constriction (TAC) surgery. However, its effect on cardiac fibroblasts (CFs), collagen secretion and the underlying mechanism remains unclear. In this study, DyLight® 488 green fluorescent dye or His-tagged proteins were used to label the exogenous serpinE2 protein. It was showed that extracellular serpinE2 translocated into CFs by low-density lipoprotein receptor-related protein 1 (LRP1) and urokinase plasminogen activator receptor (uPAR) of cell membrane through endocytosis. Knockdown of LRP1 or uPAR reduced the level of serpinE2 in CFs and down-regulated the collagen expression. Inhibition of the endocytosis of serpinE2 could inhibit ERK1/2 and β-catenin signaling pathways and subsequently attenuated collagen secretion. Knockdown of serpinE2 attenuates cardiac fibrosis in TAC mouse. We conclude that serpinE2 could be translocated into cardiac fibroblasts due to endocytosis through directly interact with the membrane protein LRP1 and uPAR, and this process activated the ERK1/2, β-catenin signaling pathways, consequently promoting collagen production.
研究领域:
心血管疾病
·
细胞生物学
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分子生物学
·
病理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Li Guo,Sai Zhang,Cong Zhang,Shuang Ren,Zihan Zhou,Fengyuan Wang,Yuexuan Wang,Qiqi Chen,Yubing Wang,Wen-Hui Lee,Kui Zhu,Di Qin,Yuanyuan Gao,Tongyi Sun
Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient’s life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1β) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.
研究领域:
药理学
·
疼痛管理
·
传统中药
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Stem Cells International
·
2024
·Vol. 2024
·期 1
·5512423
·
IF 3.8
Hailong Li,Yiqun He,Xujun Chen,Aolei Yang,Feizhou Lyu,Youhai Dong
Exosomes secreted from osteoblasts (OBs) can regulate the angiogenesis of endothelial cells (ECs); however, whether cerebrospinal fluid pulsation (CSFP) stress, a special mechanical stimulation, can influence the cell’s communication in the context of angiogenesis remains unknown. In this study, the effect of exosomes derived from CSFP stress-stimulated OBs on facilitating the angiogenesis of ECs was investigated. First, OBs were cultured in a CSFP bioreactor, and exosomes derived from OBs were isolated and identified. Cell Counting Kit 8 assay, transwell migration assay, wound healing migration assay, and tube formation assay were conducted to assess the effects of CSFP stress-stimulated OBs-derived exosomes (CSFP-Exos) on the angiogenesis of ECs. Then high-throughput RNA sequencing was used to determine the miRNA profiles of Non-CSFP stress-stimulated OBs-derived exosomes (NCSFP-Exos) and CSFP-Exos, and the luciferase reporter gene assay was performed to confirm the binging of miR-423-5p to DUSP8. In addition, the Matrigel plug assay was performed to explore whether exosomal miR-423-5p has the same effects in vivo . Our results suggested that CSFP-Exos can promote the angiogenesis of ECs, and miR-423-5p was enriched in CSFP-Exos. Moreover, miR-423-5p could promote the effect of angiogenesis via directly targeting dual-specificity phosphatase 8 (DUSP8), which inhibited the ERK1/2 signaling pathway. In conclusion, exosomal miR-423-5p derived from CSFP stress-stimulated OBs could promote the angiogenesis of ECs by the DUSP8/ERK1/2 signaling pathway.
研究领域:
细胞生物学
·
分子生物学
·
生物医学工程
·
神经科学
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DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2017
·
IF 1.683
Yan Fang,Lisheng Chu,Lin Li,Jun Wang,Yan Yang,Jingjing Gu,Jianping Zhang
Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation is one of the new therapeutic strategies for treating ischemic stroke. However, the poor survival rate of transplanted BMSCs in ischemic tissue limits the therapeutic efficacy of this approach. Oxidative stress is a major mechanism underlying the pathogenesis of brain ischemia and has a negative impact on the survival of transplanted BMSCs. Tetramethylpyrazine (TMP) has been reported to possess potent antioxidant activity. In the present study, we aimed to investigate the protective effects of TMP pretreatment on BMSCs survival of hydrogen peroxide (H2O2)-induced apoptosis in vitro and to elucidate the potential antiapoptotic mechanisms of TMP pretreatment on BMSCs. BMSCs were pretreated with TMP (10, 25, 50, 100, and 200 µmol/L) for 24 h and then exposed to 500 µmol/L of H2O2 for 24 h. We found that TMP pretreatment significantly increased cell viability and decreased cell apoptosis and intracellular reactive oxygen species (ROS) generation. Furthermore, the protective effects of TMP were related to increased Bcl-2 expression, attenuated Bax expression, and enhanced levels of phosphorylated Akt (p-Akt) and extracellular regulated protein kinases1/2 (p-ERK1/2). Further studies found that these beneficial effects of TMP were significantly blocked by wortmannin (an inhibitor of phosphoinositide-3 kinase (PI3K)) or PD98059 (an inhibitor of ERK1/2). In conclusion, our results confirm that TMP protects BMSCs against H2O2-induced apoptosis by regulating the PI3K/Akt and ERK1/2 signaling pathways, suggesting that TMP may be used in combination with BMSCs to improve cell survival for the treatment of ischemic stroke.
研究领域:
药理学
·
干细胞生物学
·
神经科学
·
细胞与分子生物学
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产品关联
DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2020
·Vol. 39
·期 3
·355-367
·
IF 3.314
Jiuwei Zhang,Yaodong Chen,Jing Lin,Ruimei Jia,Tingting An,Tianxiu Dong,Yu Zhang,Xiuhua Yang
Hepatocellular carcinoma (HCC), the sixth most common malignancy worldwide, is characterized by a dismal prognosis due to high recurrence and metastasis rates. Thus, the need for the development of novel chemotherapeutic drugs is urgent. Cyclovirobuxine D (CVB-D), a steroidal alkaloid extracted from Buxus microphylla that has been extensively used to relieve the symptoms of cardiovascular diseases, has shown promising antineoplastic effects in recent studies. However, the therapeutic effects and underlying mechanisms of CVB-D on HCC remain largely unelucidated. This study experimentally indicated that CVB-D can repress HCC cell proliferation by arresting the cell cycle in G2 phase and can facilitate apoptosis. In addition, the migratory and invasive capabilities of HCC cells were noticeably attenuated by a nonlethal dose of CVB-D, and this attenuation was correlated with the inhibition of epithelial–mesenchymal transition (EMT). Moreover, in vivo, CVB-D displayed excellent anticancer effects in HCC tumor-bearing nude mice. Regarding the molecular mechanisms of CVB-D activity, decreased Slug expression was determined to be associated with the aforementioned anti-HCC functions of this extract, which might be regulated by epidermal growth factor receptor (EGFR) through the focal adhesion kinase (FAK)-associated PI3K/AKT and MEK/ERK1/2 signaling pathways. Collectively, our results revealed the suppressive effects of CVB-D on progressive behaviors of HCC, including proliferation, migration, invasion, and EMT, in addition to its outstanding proapoptotic effects, which were correlated with the inhibition of the EGFR-FAK-AKT/ERK1/2-Slug signaling pathway. These discoveries provide an experimental and theoretical foundation for the use of CVB-D as a promising candidate for HCC therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2017
·
IF 5.012
Mei-Xue Dong,Chen-Meng Li,Peng Shen,Qing-Chuan Hu,You-Dong Wei,Yi-Fei Ren,Jia Yu,Si-Wen Gui,Yi-Yun Liu,Jun-Xi Pan,Peng Xie
Objectives Recombinant tissue plasminogen activator (rtPA) is widely used for patients with thromboembolic disease , and increasing evidence indicates that it can directly induce neurotoxicity independent of its thrombolysis property. Here, we aimed to confirm the long-term effect of rtPA on animal's behavior , and investigate the underlying pathogenesis. Methods and results Male Sprague-Dawley rats randomly received a dose of rtPA (10 mg/kg) or sterile saline. Three months later, the animals receiving rtPA displayed anxiety-like behaviors in the open field and novelty-suppressed feeding tests. To investigate the possible pathogenesis, gas chromatography-mass spectrometry-based metabolomics analysis was performed, with 18 differential metabolites identified in the hippocampus 24 h after the treatments. Based upon these differential metabolites, a metabolite-protein integrated network was generated, which indicated that ERK1/2-glutamic acid decarboxylase (GAD) 1-γ aminobutyric acid (GABA) cascade may be related to long-term anxiety-like behaviors. The GABA levels in hippocampus were decreased 24 h post-treatment and three months later, confirmed by a high performance liquid chromatography method. We also examined the expression of GAD1 and GAD2 using western blotting or immunohistochemical staining . Levels of GAD1 were persistently decreased after treatment, while GAD2 levels, GAD1-immunoreactive, and GAD2-immunoreactive neurons showed no significant differences. The underlying pathogenesis also involved activation of ERK1/2, confirmed by increased phospho-ERK1/2 24 h post-treatment. Conclusions RtPA can induce long-term anxiety-like behaviors after a clinical injected dose. The underlying pathogenesis involves the ERK1/2-GAD1-GABA cascade in the hippocampus. This pharmacological side effect of rtPA may further exacerbate post-stroke anxiety disorder for stroke patients.
研究领域:
神经科学
·
药理学
·
行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Ziyun Hu,Di Xu,Huihui Meng,Wenya Liu,Qi Zheng,Junsong Wang
4-octyl itaconate (4-OI) is a cell-permeable itaconate derivative with anti-inflammatory and antioxidant properties. However, its therapeutic potential for oxidative stress-induced liver injury remains unknown. This study investigated the hepatoprotective effects and mechanisms of 4-OI against oxidative damage in in vitro and in vivo models. 4-OI attenuated H 2 O 2 -induced cytotoxicity, oxidative stress, and mitochondrial dysfunction in L02 and HepG2 cells. Untargeted metabolomics profiling and pathway analysis identified the PI3K/AKT/mTOR and MAPK pathways as key regulators of 4-OI's protective effects. Specifically, 4-OI induced phosphorylation of AKT and ERK1/2, leading to activation of the Nrf2 signaling pathway. Nrf2 upregulated expression of the mitochondrial deacetylase Sirt3, which subsequently alleviated H 2 O 2 -induced cell injury. In mice, 4-OI reduced acetaminophen (APAP)-induced liver injury as evidenced by attenuated hepatocellular necrosis and decreased serum liver enzymes . It also elevated hepatic expression of Nrf2, Sirt3, p-AKT and p-ERK1/2. Inhibition of AKT, ERK1/2 or Nrf2 blocked the protective effects of 4-OI in vitro, suggesting its antioxidant activity is mediated by activating the Nrf2/Sirt3 pathway via AKT and ERK1/2 phosphorylation. In summary, 4-OI exerted antioxidant and hepatoprotective effects by activating the Nrf2/Sirt3 signaling pathway through AKT and ERK1/2 phosphorylation, which were elucidated using in vitro and in vivo oxidative stress models. This provides novel insights into the mechanisms of 4-OI against oxidative stress-related liver diseases.
研究领域:
药理学
·
毒理学
·
细胞生物学
·
分子生物学
✓ 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）