BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Dandan Wu,Zongchao Zuo,Xinning Sun,Xin Li,Fangzhou Yin,Wu Yin
Long-chain fatty acyl-Coa ligase 4 (ACSL4) is an important enzyme that converts fatty acids to fatty acyl-Coa esters, there is increasing evidence for its role in carcinogenesis. However, the precise role of ACLS4 in hepatocellular carcinoma (HCC) is not clearly understood. In the present study, we provide evidence that ACSL4 expression was specifically elevated in HCC and is associated with poor clinical outcomes. ACSL4 significantly promotes the growth and metastasis of HCC both in vitro and in vivo . RNA sequencing and functional experiments showed that the effect of ACSL4 on HCC development was heavily dependent on PAK2. ACSL4 expression is well correlated with PAK2 in HCC, and ACSL4 even transcriptionally increased PAK2 gene expression mediated by Sp1. In addition, emodin, a naturally occurring anthraquinone derivative, inhibited HCC cell growth and tumor progression by targeting ACSL4. In summary, ACSL4 plays a novel oncogene in HCC development by regulating PAK2 transcription. Targeting ACSL4 could be useful in drug development and therapy for HCC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chuyao Liao,Di Wang,Siyuan Qin,Ying Zhang,Jie Chen,Ruijie Xu,Fengguo Xu,Pei Zhang
Irinotecan (CPT-11) in combination with 5-fluorouracil and leucovorin is a first-line chemotherapy regimen for the treatment of colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of colitis. In our previous studies, several bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat colitis model. On the other hand, NLRP3 inflammasome has been reported to play important roles in mediating colitis. Interestingly, BA was stated to activate the NLRP3 inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3 inflammasome in THP-1-differentiated macrophages and promote inflammation. In lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3 inflammasome and reduced inflammation. Further experiments demonstrated that Takeda G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused colitis in rats by inhibiting SP1 with mithramycin A (MitA) or activating TGR5 using oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting chemotherapy-induced colitis.
研究领域:
肿瘤学
·
胃肠病学
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免疫学
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药理学
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DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2021
·
IF 4.418
Bei Sun,Hao Ou,Fei Ren,Yujiao Guan,Ye Huan,Hongwei Cai
Cerebral ischemia-reperfusion (CI/R) injury is a serious central nervous system disease. Propofol (PPF) exerts a neuroprotective effect in CI/R injury; the underlying cause is still unclear. Here, we cultured mouse hippocampal neuron (HT22 cells) in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to mimic CI/R injury in vitro. PPF treatment promoted cell viability and reduced apoptotic cells in the OGD/R-treated HT22 cells, which was effectively abrogated by SNHG14 overexpression. Moreover, we constructed a CI/R injury mouse model on C57BL/6J mice by middle cerebral artery occlusion/reperfusion (MCAO/R), followed by administration of PPF. PPF reduced neuronal damage and loss, enhanced glial cell hyperplasia, and ameliorated cerebral cortex tissue damage and brain infarct in MCAO/R-induced mice. SNHG14 overexpression aggravated MCAO/R-induced CI/R injury in mice. Furthermore, SNHG14 promoted the expression of Atg5 and Beclin 1 via competitively binding miR-30b-5p, which contributed to activate autophagy and apoptosis in HT22 cells. In addition, the levels of p-p38 and p-SP1 were reduced in the OGD/R-treated HT22 cells in the presence of PPF. SP1 interacted with the promoter of SNHG14 and elevated the expression of SNHG14. PPF treatment inhibited the SP1-mediated up-regulation of SNHG14. In conclusion, this work demonstrates that PPF inhibits SNHG14 expression though the p38 MAPK signaling pathway. SNHG14 promotes Atg5 and Beclin 1 expression by sponging miR-30b-5p and thus activates autophagy and aggravates CI/R injury.
研究领域:
神经科学
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药理学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Shirong Peng,Weilong Lin,Zean Li,Ruilin Zhuang,Shengmeng Peng,Bingheng Li,Bingliang Chen,Yong Luo,Yuan Ou,Wei Zhuang,Tao Du,Kaiwen Li,Hai Huang
Cholesterol metabolism influences prostate cancer (PCa) progression, especially by affecting the tumor microenvironment. The present study demonstrated that cancer cell-intrinsic cholesterol promoted the S-palmitoylation of specificity protein 1 (SP1), enhancing SP1 nuclear translocation and driving the transcription and secretion of midkine (MDK), which in turn facilitated the differentiation of macrophages into a lipid-associated phenotype. Furthermore, targeting cholesterol metabolism with simvastatin significantly reduced MDK levels, inhibited immunosuppressive macrophage polarization, and enhanced the efficacy of enzalutamide in vivo. These findings suggested that targeting the cancer cell-intrinsic cholesterol-induced immunosuppressive tumor microenvironment could be an effective strategy to improve therapeutic outcomes in prostate cancer patients.
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高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 6
·1-8
·
IF 2.447
Chun Lei,Yafeng Hou,Jiong Chen
Bone marrow stromal cell antigen 2 (BST2) has been reported to act as an oncogene in the tumorigenesis of numerous types of cancer. Bioinformatics analysis has predicted the binding interaction between BST2 and specificity protein 1 (SP1) and the involvement of SP1 in pancreatic cancer. Therefore, the present study set out to verify this interaction and determine how it may affect pancreatic cancer progression. Normal human pancreatic duct epithelial cells (HPDE6‑C7) and pancreatic cancer cell lines (SW1990, BxPC3, PANC1 and PSN‑1) were selected for western blotting and reverse transcription‑quantitative PCR detection of BST2 expression. Colony formation, Cell Counting Kit‑8 and wound healing assays were performed to detect the proliferative and migratory abilities of PANC1 cells following transfection with small interfering RNA against BST2. The expression of proliferation and migration markers were assayed using western blotting. Chromatin immunoprecipitation and luciferase reporter assays were employed to verify the bioinformatics prediction of BST2‑SP1 binding. PANC1 cell proliferation and migration were analyzed following BST2 knockdown and SP1 overexpression. In comparison with HPDE6‑C7 cells, all four pancreatic cancer cell lines were found to exhibit increased BST2 expression levels to varying degrees, with the highest levels observed in PANC1 cells. BST2 knockdown inhibited PANC1 cell colony formation, proliferation and migration. Additionally, SP1 was shown to bind to the BST2 promoter and could promote PANC1 cell proliferation and migration when overexpressed. However, BST2 knockdown rescued SP1 overexpression‑induced PANC1 cell colony formation, proliferation and migration. In conclusion, activation of BST2 by the transcription factor SP1 was shown to accelerate pancreatic cancer cell proliferation and migration, suggesting that BST2 and SP1 may be plausible therapeutic targets in targeted therapy for pancreatic cancer.
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
American Journal of Cancer Research
·
2026
·Vol. 16
·期 3
·1115
·
IF 3.1
Nan Liu,Mingyue Zhao,Lei Xu,Yeting Cui,Yu Tian,Juan Li,Xiaoyu Hu,Tongcun Zhang,Haining Zhen,Yanyang Tu
Glioma is the most aggressive tumor of the central nervous system and is associated with poor prognosis, especially in patients with high-grade gliomas. In this study, we investigated the biological role of inhibitor of kappa B kinase interacting protein (IKBIP) in promoting the progression of glioma. Analysis of the TCGA and GTEx databases revealed that IKBIP is upregulated in both lower-grade gliomas (LGG) and glioblastomas (GBM) compared with normal brain tissues. Kaplan-Meier survival analysis demonstrated that IKBIP upregulation is associated with shorter overall survival (OS) and disease-specific survival (DSS) in patients with LGG. Pan-cancer analysis indicated that IKBIP is aberrantly expressed in various malignant tumors, including gliomas. IKBIP knockdown inhibited the proliferation of glioma cells both in vitro and in vivo . Additionally, IKBIP knockdown in U251 and U87 glioma cell lines significantly suppressed their invasive capacity. Furthermore, IKBIP knockdown resulted in decreased expression of proteins associated with Wnt/β-catenin/epithelial-mesenchymal transition (EMT) pathway, including β-catenin, ZEB1, ZEB2, N-cadherin, whereas the expression of E-cadherin was increased. Conversely, IKBIP overexpression reduced the level of phosphorylated β-catenin (p-β-catenin) while increasing the expression of total β-catenin in glioma cells. Furthermore, we identified that transcription factor SP1 (Specificity Protein 1), which is also upregulated in glioma tissues and cell lines and is associated with the malignant phenotype of glioma, can bind to the promoter region of IKBIP. Upregulation of SPI in glioma cells significantly increased the expression level of IKBIP, while inhibiting the phosphorylation of β-catenin. These findings collectively suggest that upregulation of IKBIP promotes the proliferation and invasive behaviors of glioma cells by activating the Wnt/β-catenin/EMT pathway. Overall, our findings suggest that SP1-IKBIP axis facilitates the proliferation and invasion of glioma through Wnt/β-catenin-associated EMT, and SP1-IKBIP axis may represent a promising target for the clinical diagnosis and treatment of glioma.
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DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2019
·Vol. 47
·期 3
·372-382
·
IF 2.336
Ruili Wang,Ying Yang,Hui Wang,Ya He,Chen Li
MicroRNAs (miRNAs) have been shown to have complicated implications in the pathogenesis of Parkinson's disease (PD). However, the role of miR-29c and the underlying mechanism in the development of PD remain not well understood. In this work, the MPTP-treated mice or MPP + -intoxicated SH-SY5Y cells were established as an in vivo or in vitro PD model. Then the specific agomir of miR-29c was employed to examine its biological function on PD progress. We found that miR-29c was down-expressed but SP1 was high-expressed in substantia nigra pars compacta (SNpc) of MPTP-induced PD mice. Overexpression of miR-29c attenuated dopaminergic neuron loss and α-synuclein accumulation in SNpc of PD mice. Furthermore, the increments of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and TUNEL-positive apoptotic cells in MPTP-treated mice were ameliorated by miR-29c. Similarly, in SH-SY5Y cell models of PD, we also found that miR-29c inhibited inflammatory cytokine production, reduced apoptotic rate and suppressed pro-apoptotic regulator activity. In addition, the increased expression of SP1 in PD models was found to be inhibited by miR-29c. Luciferase reporter assay confirmed that SP1 was complementary with miR-29c. Knockdown of SP1 with siRNA restored α-synuclein accumulation, inflammation and apoptosis in MPP + -induced SH-SY5Y cells. Collectively, this current work presents that miR-29c may directly target SP1 to protect against the neuroinflammatory and apoptotic responses in PD, providing a potential biomarker for PD diagnosis and treatment.
研究领域:
神经科学
·
分子生物学
·
药理学
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DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Zhengquan Zhu,Yihan Wang,Haiyun Chen,Xinye Yu,Tingyu Wang,Yajing Weng,Meihong Guo,Ying Huang,Gaojian Tao,Wangsen Cao,Yong Wang,Daojuan Wang
Persistent androgen receptor (AR) activation is an important contributor to polycystic ovary syndrome (PCOS) and is affected by transcriptional regulation via histone acetylation; however, the underlying mechanisms are partially understood. This study demonstrated that AR activation in ovarian granulosa cells (GCs) of both dehydroepiandrosterone (DHEA) and high-fat diet-induced PCOS mouse models correlated with a significant increase in the histone acetyltransferase p300 and histone acetylation. Conversely, GC-specific p300 knockout or pharmacological inhibition with C646/A-485 effectively reduced AR activation, histone 3 acetylation (H3K18ac/H3K27ac), and ovarian fibrosis in PCOS mice, highlighting p300 as a critical driver. ATAC-seq and RNA-seq identified “open” chromatin regions at the AR promoter in PCOS ovaries, corresponding with increased AR transcription and histone acetylation. p300, along with transcription factor SP1 and the acetyl-reader BRD4, bound to H3K18ac and H3K27ac of the AR promoter in PCOS-modeled ovaries and GCs, which was blocked by C646 and the SP1 inhibitor Plicamycin, respectively. Importantly, continuous AR activation by its ligand DHT largely diminished the anti-fibrotic and ovarian-protective effects of C646. These findings suggest that p300, SP1, and BRD4, form a critical transcriptional complex driving AR activation and PCOS development, and that targeting the p300/AR axis may present a promising therapeutic approach for treating PCOS.
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DOI
PubMed
高影响因子
Cell Discovery
·
2024
·Vol. 10
·期 1
·1-14
·
IF 13
Li Hao,Du Yu,Cheng Kaiwen,Chen Yuxi,Wei Ling,Pei Yujun,Wang Xiaoyu,Wang Lan,Zhang Ye,Hu Xiaoxin,Lu Yi,Zhu Xiangjia
High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM’s gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.
研究领域:
眼科学
·
微生物学
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分子生物学
·
遗传学
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2021
·Vol. 47
·期 3
·713-722
·
IF 3.996
Zhang Haiju,Yu Shiqian,Xia Liping,Peng Xia,Wang Shun,Yao Baozhen
Epilepsy (SE) is a common and serious neurological disease. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome participates in the pathogenesis of SE, while its underlying mechanism is still unclear. Here, we attempted to explore the mechanism of action of NLRP3 inflammasome in SE. SE mouse model was constructed by administration of kainic acid (KA). Astrocytes were treated with KA to mimic SE cell model. MCC950 (NLRP3 inhibitor) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat astrocytes to inhibit the activity of NLRP3 and Caspase-1. Nissl staining was performed to examine the morphology of neuron. Western blot, enzyme-linked immunosorbent assay and immunofluorescence staining were performed to assess protein expression. SE mouse model exhibited an increase of neuronal loss, and an up-regulation of Cleaved-Caspase-1, IL-1β and IL-18 in hippocampus. The levels of GFAP + ADK + cells were significantly increased in SE mice. MCC950 or Z-YVAD-FMK abolished these impacts conferred by KA in SE mice. Moreover, KA treatment enhanced the expression of NLRP3, Cleaved-Caspase-1, IL-1β and IL-18 in astrocytes, which was rescued by knockdown of NLRP3 or Caspase-1. Additionally, CREB, p-CREB, REST were up-regulated, and SP1 was down-regulated in the KA-treated SE mice and KA-treated astrocytes. Inhibition of NLRP3 or Caspase-1 rescued these proteins expression in KA-treated astrocytes. CREB or REST silencing reduced adenosine kinase (ADK) expression, while SP1 knockdown enhanced ADK expression in KA-treated astrocytes. In conclusion, NLRP3 inflammasome activation enhances ADK expression to accelerate SE in mice through regulating CREB/REST/SP1 signaling pathway. Thus, inhibition of NLRP3 inflammasome may be a treatment for SE.
研究领域:
神经科学
·
免疫学
·
药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2021
·
IF 2.63
Huanhuan Zhang,Wenying Yu,Liting Ji,Yusen Zhong,Yiyou Lin,Huazhong Ying,Chenhuan Yu,Changyu Li
Mucus hypersecretion is a hallmark of chronic obstructive pulmonary disease (COPD) and is associated with increasing sputum production and declining pulmonary function. Therefore, reducing mucus secretion can be a new therapeutic opportunity for preventing COPD. The Guifu Dihuang pill (GFDHP) is a classical Chinese medicine and has been used as an immunoregulator for treatment of kidney yang deficiency syndrome, including hypothyroidism, adrenocortical hypofunction, chronic bronchitis, and COPD, for more than 2000 years. However, the protective effects and mechanisms of GFDHP against mucus hypersecretion in COPD remain obscure. The aim of the present study was to explore the inhibitory effects of GFDHP on lipopolysaccharide/cigarette smoke- (LPS/CS-) induced Mucin5ac (Muc5ac) overproduction and airway goblet cell hyperplasia in mice. The mice were randomly assigned into 6 groups: control, model, GFDHP-L, GFDHP-M, GFDHP-H, and dexamethasone. The mice were given LPS twice through intranasal inhalation and then exposed to CS daily for 6 weeks. Three doses of GFDHP were orally administered daily during the last 3 weeks of the experiment. Pulmonary function was examined with an EMKA pulmonary system, and pulmonary hyperpermeability and lung damage were evaluated with an in vivo imaging system. Inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were detected with a cell count analyzer and though ELISA analysis, respectively. Lung pathological changes and airway goblet cell hyperplasia were analyzed with hematoxylin and eosin and Alcian blue periodic acid Schiff staining. The protein expression levels of Muc5ac and extracellular signal-regulated kinase (ERK)-specificity protein1 (SP1) signaling pathway were measured with Western blot and immunohistochemistry. The results demonstrated that GFDHP improved pulmonary function and suppressed mouse pulmonary hyperpermeability and edema. GFDHP suppressed inflammatory cell infiltration and cytokine release in BALF, thereby elevating pulmonary function. It ameliorated lung pathological changes and airway goblet cell hyperplasia, and suppressed expression levels of Muc5ac mRNA and protein and phospho-ERK and SP1 levels in the lung tissues of the COPD mice. In conclusion, GFDHP inhibited mucus hypersecretion induced by LPS/CS by suppressing the activation of the ERK-SP1 pathway.
研究领域:
药理学
·
呼吸医学
·
中医
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Zhe Du,Qingping Liu,Mengruo Wang,Yifu Gao,Qi Li,Yizhe Yang,Tianyu Lu,Lei Bao,Yaxian Pang,Haijun Wang,Yujie Niu,Rong Zhang
Accumulating evidence indicates that maternal exposure to carbon black nanoparticles (CBNPs) during gestation can induce multiple system abnormalities in offspring, whereas its potential mechanism in respiratory disease is still largely unknown. In order to explore the effect of maternal exposure to CBNPs on offspring’s lung and latent pathogenesis, we respectively established in vivo model of pregnant rats exposed to CBNPs and ex vivo model of lung epithelial cells treated with pups’ serum of pregnant rats exposed to CBNPs. After maternal exposure to CBNPs, epithelial-mesenchymal transition (EMT) and fibrosis levels increased as a result of DDRGK1-mediated reticulophagy upregulated in offspring’s lung. DDRGK1 as FAM134B’s cargo bound with FAM134B to mediate reticulophagy. Transcription factor “SP1” positively regulated DDRGK1 gene expression by binding to its promoter. Furthermore, the upregulation of NSUN2 elevated m 5 C methylation of SP1 mRNA and the protein level of SP1 subsequently increased through Ybx1 recognizing and stabilizing m 5 C-methylated SP1 mRNA, followed by the increased levels of reticulophagy and fibrosis in lung epithelial cells treated with offspring’s serum of matrix exposed to CBNPs during gestation. In conclusion, NSUN2/Ybx1/m 5 C-SP1 axis promoted DDRGK1-mediated reticulophagy, which played an important role in EMT-induced fibrosis in offspring’s lung tissue after maternal exposure to CBNPs during gestation.
研究领域:
呼吸系统疾病
·
纳米毒理学
·
分子生物学
·
表观遗传学
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DOI
PubMed
高影响因子
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