iScience
·
2024
·
IF 4.6
Lele Xu,Yuting Chen,Tao Wu,Jiaqi Fan,Yuying Hu,Xuefeng Gao,Yuliang Wang,Tao Chen,Xueting Zhao,Min Zeng,Fei Wang,Qingyou Zheng,Xiaojuan Pei,Dinglan Wu
Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (m 6 A) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of m 6 A and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an m 6 A-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-21
·
IF 6.1
Guo Qinglong,Wang Yi,Yu Liangchen,Guan Liao,Ji Xuefei,Li Xiaohui,Pang Gang,Ren Zhenhua,Ye Lei,Cheng Hongwei
Background Olfactory dysfunction occurs frequently in Parkinson’s disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice.Methods MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R−) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines.Results Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R− HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis.Conclusion sThis study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yijin Wu,Shaofeng Wang,Hui Huang,Jingling Yu,Jieren Liang,Hai Huang,Jianying Guo,Zhaoxin Tang,Jianzhao Liao
Background With the increasing application of copper nanoparticles (CuNPs) across various fields, its toxicity and hazards are gradually being confirmed. Hesperidin (Hes), a flavonoid compound with extensive antioxidant and anti-inflammatory effects, has recently attracted public attention. Methods Molecular docking was employed to investigate the potential binding sites between Hes and SIRT3. The activation of the SIRT3-FOXO3A signaling pathway by Hes was further validated through a series of experiments in vitro and vivo. Results The results indicate that exposure to CuNPs can cause pathological damage to liver. Compared with the control group, exposure to CuNPs induced the accumulation of reactive oxygen species and mitochondrial UPR mt in broiler liver, specifically manifested as an increase in reactive oxygen species and the gene and protein levels of UPR mt related proteins. The molecular docking results indicate that Hes and SIRT3 have potential binding sites. However, after treatment with Hes, pathological damage in liver was alleviated. At the same time, we found that the SIRT3-FOXO3A signaling pathway was activated, leading to a significant decrease in the expression levels of proteins and genes related to UPR mt . Conclusion Hes can ameliorate hepatic oxidative damage and UPR mt induced by exposure to CuNPs by activating the SIRT3-FOXO3A pathway.
研究领域:
毒理学
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药理学
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分子生物学
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纳米技术
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生物化学
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产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
·
2025
·
IF 1.2
Junling Zhu,Rilian Lai,Qin Zheng,Shuying Huang,Shenghua Hu,Zhangfei Xu,Huixia Sun
1. To study the effects of calycosin on palmitic acid-induced HepG2 cells, as well as the potential mechanisms of action.2. Potential targets of calycosin for the alleviation of insulin resistance were predicted by network pharmacology. Glucose concentration in the culture medium was determined by the GOD-POD method. The model of insulin resistance was established by palmitic acid-induced HepG2 cells. Effects of palmitic acid and calycosin on HepG2 cell activity were determined using an MTT assay kit. The expression levels of AKT1 and FOXO3a were detected by western blot.The expression level of hsa-miR-324-3p was detected by RT-qPCR. Dual luciferase reporter assay to detect targeting of AKT1 by hsa-miR-324-3p.3. AKT1 was predicted and validated as a potential target of calycosin for treatment of insulin resistance. The model of insulin resistance was successfully established by palmitic acid-induced HepG2 cells. Up-regulation of AKT1 expression inhibits FOXO3a entry into the nucleus. Calycosian was demonstrated to concentration-dependently increase the sensitivity of insulin resistance cells to insulin. The hsa-miR-324-3p was proven to exist in insulin-resistant cells. Hsa-miR-324-3p was found to target AKT1 involved in the alleviation of insulin resistance.4. Calycosin inhibits FOXO3a nuclear translocation by regulating the hsa-miR-324-3p/AKT pathway, thus alleviating insulin resistance.
研究领域:
药理学
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分子生物学
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内分泌学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Wan-He Li,Zheng-Ting-Yan Xiang,An-Xin Lu,Su-Su Wang,Chong-Huai Yan
Manganese (Mn) is an essential trace element that maintains many normal physiological functions. However, multi-system disorders would occur once overexposure to Mn, especially neurotoxicity. Despite evidence demonstrating the critical role of ROS-activated JNK/FOXO3a signaling pathway in neuronal survival, the specific mechanisms by which it contributes to Mn-induced neurotoxicity are still unclear. The objectives of this study was to examine the modulation of the JNK/FOXO3a signaling pathway, which is activated by ROS, in Mn-induced apoptosis, using a rat brain astrocyte cell line (CTX cells). This study found that a dose-dependent decrease in cell viability of CTX cells was observed with 150, 200, 250, 300 μmol/L Mn. The results of apoptosis-related protein assay showed that Mn decreased the expression of anti-apoptotic protein Bcl-2 and enhanced the expression of apoptosis-related proteins like Bax and Cleaved-Caspase3. In addition, treatment with Mn resulted in elevated ROS levels and increased phosphorylation levels of JNK. Conversely, phosphorylation of nuclear transcription factors FOXO3a, which regulates expression of transcription factors including Bim and PUMA, was decreased. Depletion of ROS by N-acetyl- L -cysteine (NAC) and inhibition of the JNK pathway by SP600125 prevented Mn-induced JNK/FOXO3a pathway activation and, more importantly, the level of apoptosis was also significantly reduced. Confirmation of Mn-induced apoptosis in CTX cells through ROS generation and activation of the JNK/FOXO3a signaling pathway was the outcome of this study. These findings offer fresh insights into the neurotoxic mechanisms of Mn and therapeutic targets following Mn exposure.
研究领域:
神经科学
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细胞生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Mengxin Li,Jun Wang,Zihan Xu,Yue Lin,Jingquan Dong
Background Obstructive sleep apnea syndrome (OSAS), a chronic disorder affecting approximately 10% of adults worldwide with heightened prevalence in males and obese populations, induces irreversible neurocognitive impairment. Atraric Acid (AA), a natural depside compound derived from lichens, exhibits dual functional properties through its molecular groups capable of free radical scavenging and metal chelation. However, its therapeutic potential in OSAS-related pathologies remains unexplored. Objective This study aims to investigate the neuroprotective effects and molecular mechanisms of AA against CIH-induced neuronal damage. Methods CIH mouse models and hypoxic injury models in HT22 neurons were established. AA was administered to mice at doses of 5, 10, and 20 mg/kg (selected based on literature references and preliminary experiments), and to cells at an optimal concentration of 20 μM (determined by CCK-8 assays). Therapeutic efficacy was evaluated through behavioral tests including the Morris Water Maze, Elevated Plus Maze, and Open Field Test. Neuroprotective effects were assessed via histopathological examination (e.g., neuronal survival in hippocampal CA3 and DG sub-regions) and detection of oxidative stress/ferroptosis markers (e.g., MDA levels, GPX4 expression, and related biomarkers). Transcriptomic sequencing and molecular docking analyses were employed to investigate differentially expressed genes, pathway enrichment, and underlying mechanisms. Results In vivo and in vitro experiments demonstrated that AA significantly alleviated neuronal damage in CIH mice and enhanced HT22 cell viability. AA down-regulated oxidative stress- and ferroptosis-related gene expression. Transcriptomic sequencing identified AMPK signaling as a key target. Combined AMPK inhibitor (Compound C) and nuclear-cytoplasmic fractionation experiments confirmed that AA synergistically regulates dual antioxidant pathways (Nrf2/HO-1 and FoxO3a/SOD2) via AMPK activation. Conclusion AA mitigates CIH-induced neurocognitive impairment by AMPK-dependent activation of the Nrf2/HO-1 and FoxO3a/SOD2 axes, establishing a dual antioxidant-ferroptosis defense barrier. This study is the first to systematically elucidate AA's molecular mechanisms using transcriptomics data integrated with computational simulations, providing novel therapeutic targets and a translational paradigm for developing natural compound-based therapies for OSAS.
研究领域:
神经生物学
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睡眠医学
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分子药理学
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氧化应激
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信号转导
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转化医学
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天然产物药理学
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产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 2
·257-263
·
IF 1.5
Qingzhi Wan,Lisha Tang,Kaili Jin,Xuanyi Chen,Yinghuan Li,Xiaofeng Xu
Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.
研究领域:
药理学
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细胞生物学
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中医药
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生殖生物学
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2024
·
IF 4.4
Xin Chen,Liming Yu,Shan Meng,Jikai Zhao,Xinyi Huang,Zhishang Wang,Zijun Zhou,Yuting Huang,Tao Hong,Jinfeng Duan,Tong Su,Zijun Cao,Yanbang Chi,Tao Huang,Huishan Wang
Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.
研究领域:
心脏病学
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
·
2024
·Vol. 42
·期 8
·e70015
·
IF 2.8
Yang Yu,Tianchan Zhang,Xin Li,Tianyang Yu,Fanci Meng,Yifeng Luan,Huifang Cong,Xiuhong Wu
Perimenopausal syndrome is a significant issue that disturbs women's metabolism, mood and quality of life. Apigenin (4′,5,7-trihydroxyflavone) is a natural flavonoid that exhibits antioxidant, anti-inflammatory and anticancer effects. The present study aims to investigate the effect of apigenin on perimenopausal syndrome by combining bioinformatics analysis with in vivo experiments. The mouse model with perimenopausal syndrome was established using 4-vinylcyclohexene diepoxide (VCD) treatment. Apigenin alleviated VCD-induced disorder of estrous cycle and shrinkage of ovarian tissue. The reduction of anti-Muller hormone and the increase of follicle stimulation hormone and luteinizing hormone triggered by VCD were reversed by apigenin in a dose-dependent manner. Apigenin suppressed the VCD-induced decrease of primordial, primary, secondary and antral follicle number in ovarian tissue. Oxidative stress in ovarian tissue was activated by VCD treatment through increasing the reactive oxygen species production. High concentration of apigenin significantly reversed the alteration induced by VCD. Apigenin alleviated VCD-induced cell apoptosis through regulating Bax, Bcl-2, cleaved PARP1 and caspase-3. Furthermore, the phosphorylation of AKT and FOXO3a was inhibited by VCD and activated by apigenin in a dose-dependent manner. Collectively, apigenin effectively mitigates the ovarian dysfunction through suppressing oxidative stress and apoptosis via the AKT/FOXO3a signaling pathway. Summary Perimenopausal syndrome characterized by endocrine disorders, and hormone disorders has caused physical and mental damage to the majority of women. This study aims to explore a safe and effective method for perimenopausal syndrome treatment. Apigenin is a natural flavonoid that has protective effects on ovary, while the effect and mechanism of apigenin on perimenopausal syndrome is still unclear. This study's principal finding was that apigenin alleviated the estrous cycle disorder, follicle development inhibition and hormone level disorder in model with perimenopausal syndrome. Additionally, apigenin suppressed oxidative stress and apoptosis via activating the AKT/FOXO3a signaling pathway in the ovarian tissue of perimenopausal mice model. This work provides an effective approach for the remission and treatment of perimenopausal syndrome.
研究领域:
药理学
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内分泌学
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妇科学
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生物信息学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Xiaolin Zhang,Zhen Dong,Yuanmiao Yang,Chaolong Liu,Jisheng Li,Wenli Sun,Yikang Zhu,Yang Shen,Zhi Wang,Muhan Lü,Hongjuan Cui
The incidence rate of colorectal cancer (CRC) has been increasing significantly in recent years, and it is urgent to develop novel drugs that have more effects for its treatment. It has been reported that many molecules extracted from the root bark of Morus alba L. (also known as Cortex Mori) have antitumor activities. In our study, we identified morusinol as a promising anticancer agent by selecting from 30 molecules extracted from Morus alba L. We found that morusinol treatment suppressed cell proliferation and promoted apoptosis of CRC cells in vitro. Besides this, we observed that morusinol induced cytoprotective autophagy. The GO analysis of differentially expressed genes from RNA-seq data showed that morusinol affected cholesterol metabolism. Then we found that key enzyme genes in the cholesterol biosynthesis pathway as well as the sterol regulatory element binding transcription factor 2 (SREBF2) were significantly downregulated. Furthermore, additional cholesterol treatment reversed the anti-CRC effect of morusinol. Interestingly, we also found that morusinol treatment could promote forkhead box O3 (FOXO3a) nuclear accumulation, which subsequently suppressed SREBF2 transcription. Then SREBF2-controlled cholesterol biosynthesis was blocked, resulting in the suppression of cell proliferation, promotion of apoptosis, and production of autophagy. The experiments in animal models also showed that morusinol significantly impeded tumor growth in mice models. Our results suggested that morusinol may be used as a candidate anticancer drug for the treatment of CRC.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ANTI-CANCER DRUGS
·
2019
·Vol. 30
·期 1
·46-55
·
IF 1.801
Lin Fuxing,Yang Jie,Muhammad Umair,Sun Jing,Huang Zhenghua,Li Wei,Lv Fengxia,Lu Zhaoxin
Bacillomycin D can inhibit the growth of Aspergillus ochraceus in food samples. In addition, it can induce apoptosis in and inhibit the proliferation of cancer cells, although the details of this mechanism are unknown. In this study, we separated bacillomycin D-C14, D-C15, D-C16
monomers from the Bacillus subtilis strain fmbJ. The bacillomycin D monomers containing longer fatty acid chains better induced apoptosis in Bgc-823, Sgc-7901, and Hgc-27 gastric cancer cells. The Bgc-823 cell line was the most sensitive. Acridine orange-ethidium bromide staining indicated
that bacillomycin D-C16-induced Bgc-823 cell death by triggering apoptosis, characterized by membrane blebbing, cellular shrinkage, and DNA fragmentation. Flow cytometric analysis showed a bacillomycin D-C16 dose-dependent trigger of Bgc-823 apoptosis. Bacillomycin D-C16-induced the mitochondrial
pathway, as indicated by a reduced Bcl-2/Bax expression ratio, enhanced cytochrome C release, and higher levels of cleaved caspase-3. Furthermore, bacillomycin D-C16 effectively repressed phosphorylation of the serine–threonine protein kinase Akt at Ser-473 and increased the levels of
the FoxO3a protein. The combination of the PI3K/Akt-inhibitor BEZ235 with bacillomycin D-C16 enhanced the apoptosis of Bgc-823 cells. Together, these findings indicated that bacillomycin D-C16 induces apoptosis through the PI3K/Akt and FoxO3a signaling pathways.
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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药理学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Canchao Jia,Minjuan Yang,Guanlin Xiao,Zhihao Zeng,Lingjie Li,Yangxue Li,Jieyi Jiang,Aili Xu,Jinyan Qiu,Ruiyin Tang,Dongmei Li,Dezheng Jia,Canhui Xie,Guangying Wu,Dake Cai,Xiaoli Bi
Backgrounds Idiopathic pulmonary fibrosis (IPF) is a persistent and advanced pulmonary ailment. The roles of innate immunity and adaptive immunity are pivotal in the evolution of IPF. An ill-adjusted interaction between epithelial cells and immune cells is responsible for initiating the epithelial–mesenchymal transition (EMT) process and sustaining chronic inflammation, thereby fostering fibrosis progression. The intricacy of IPF pathogenesis has hindered the availability of efficacious agents. Elephantopus scaber Linn. (ESL) is a canonical Chinese medicine with significant immunoregulatory effects, and its aqueous extract has been proven to attenuate IPF symptoms in bleomycin (BLM)-induced mice. However, the underlying mechanism through which ESL relieves IPF remains unclear. Aim To validate whether ESL reverses IPF by mediating the immune response and EMT. Methods : Ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and UPLC were used to identify the components and determine the concentrations of the specific compounds in the ESL. Network pharmacology and molecular docking were applied to predict the potential mechanism underlying the anti-IPF effect of ESL. BLM-induced IPF mice were used to validate the anti-IPF effect of ESL, and lung tissue was collected to test putative pathways involved in inflammation and EMT via immunohistochemistry (ICH), real-time quantitative polymerase chain reaction (RT–qPCR) and Western blotting. Results Sixty-one compounds were identified, and thirteen main ingredients were quantified in the ESL. In silico experiments predicted that the IPF-mediated reversal of adverse effects by ESL would be related to interruption of the Toll-like receptor 4 (TLR4)/nuclear factor-k-gene binding (NF- ĸ B) inflammatory pathway and the transforming growth factor-beta l (TGF-β1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/forkhead box O3 (FOXO3a) fibrosis pathway. In vivo experiments showed that ESL alleviates BLM-induced lung inflammation and fibrosis by reducing neutrophil aggregation and fibroblast foci, similar to the effects of the positive control drug pirfenidone (PFD). ESL markedly inhibited the transcription of TNF-α, IL-1 β, and IL-6, which are downstream genes of the NF-κB signaling pathway. Furthermore, the protein levels of TLR4 and p-NF- κ B were correspondingly inhibited in response to ESL treatment. Additionally, ESL reverses BLM-induced changes in the expression of EMT-related biological characteristic indicators (collagen I [COLIA1], E-cadherin, and alpha smooth muscle actin [ α -SMA]) at the messenger ribonucleic acid (mRNA) level and markedly inhibits the expression of EMT-related upstream proteins (TGF- β 1, p-PI3K, p-Akt, and p-FOXO3a). Conclusion Our research suggested that ESL attenuates BLM-induced IPF through mediating the EMT process via the TGF-β1/PI3K/Akt/FOXO3a signaling pathway and inhibiting inflammation through the TLR4/NF-κB signaling pathway, highlighting that ESL can serve as an immunoregulator for relieving the abnormal immune response and reversing the EMT in IPF.
研究领域:
药理学
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免疫学
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呼吸医学
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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）