ANTI-CANCER DRUGS
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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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高影响因子
Advanced Science
·
2026
·
IF 14.1
Chi Zhan,Zhaocai Zhou,Yue Ding,Rong Lian,Xinyu Li,Xintong Zhang,Jie Cao,Zhonghui Tang,Zhengmei Lin,Zhi Song,Feng He
Osteoporosis is a prevalent age- and disease-associated skeletal disorder characterized by bone loss, remodeling imbalance, and vascular niche deterioration, yet how endothelial redox dysfunction drives this process remains unclear. Here, we identify mitochondrial thioredoxin-2 (TRX2) as an endothelial safeguard against osteoporotic bone loss. TRX2 was markedly reduced in aging bone vascular endothelial cells, and endothelial Trx2 deficiency accelerated skeletal degeneration by suppressing osteogenic activity and enhancing osteoclastogenesis. Mechanistically, TRX2 directly bound FOXO3a through a redox-sensitive Cys90–Cys31 disulfide interaction, retaining FOXO3a at the mitochondrial outer membrane and limiting its nuclear translocation. TRX2 loss or oxidative stress disrupted this complex, enabling FOXO3a-dependent transcriptional activation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and generating a pro-osteoclastogenic vascular niche. TRAIL neutralization or endothelial TRX2 restoration attenuated ovariectomy-induced osteoporosis by preserving angiogenic–osteogenic coupling. These findings establish the endothelial TRX2–FOXO3a–TRAIL axis as a vascular redox checkpoint and potential therapeutic target for osteoporosis.
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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.
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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.
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高影响因子
Frontiers in Genetics
·
2022
·
IF 4.772
Tang Han,Du Han,Kuang Xielan,Huang Hao,Zeng Jingshu,Long Chongde,Zhu Binbin,Fu Licheng,Wang Hua,Zhang Qingjiong,Lin Shuibin,Yan Jianhua,Shen Huangxuan
Age-related macular degeneration (AMD), which is the leading cause of blindness among the elderly in western societies, is majorly accompanied by retinal pigment epithelium (RPE) degeneration. Because of the irreversible RPE cell loss among oxidative stress, it is crucial to search for available drugs for atrophic (dry) AMD. RNA-Seq analysis revealed that genes related to aging and mitochondrial health were differentially expressed under Arbutin treatment, whereas compared to oxidative injury, our study demonstrated that Arbutin substantially abrogated oxidative stress-induced cell senescence and apoptosis linked to intracellular antioxidant enzyme system homeostasis maintenance, restored mitochondrial membrane potential (MMP), and reduced the SA-β-GAL accumulation in RPE. Furthermore, Arbutin alleviated oxidative stress-mediated cell apoptosis and senescence via activation of SIRT1, as evidenced by the increase of the downstream FoxO3a and PGC-1α/β that are related to mitochondrial biogenesis, and the suppression of NF-κB p65 inflammasome, whereas rehabilitation of oxidative stress by SIRT1 inhibitor attenuated the protective effect of Arbutin. In conclusion, we validated the results in an in vivo model constructed by NAIO3-injured mice. OCT and HE staining showed that Arbutin sustained retinal integrity in the case of oxidative damage in vivo, and the disorder of RPE cytochrome was alleviated through fundus observation. In summary, our findings identified that oxidative stress-induced mitochondrial malfunction and the subsequent senescence acceleration in RPE cells, whereas Arbutin inhibited TBHP-induced RPE degeneration via regulating the SIRT1/Foxo3a/PGC-1α/β signaling pathway. These findings suggested that Arbutin is a new agent with potential applications in the development of AMD diseases.
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高影响因子
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.
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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.
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高影响因子
AGING CELL
·
2021
·Vol. 20
·期 7
·e13367
·
IF 9.304
De-bo Zou,Zongyou Mou,Wenliang Wu,Haichun Liu
This study aimed to probe into the effect of TRIM33 on oxidative stress-induced apoptosis of osteoblasts in osteoporosis and to probe into the underlying mechanism. The apoptosis of osteoblasts was induced by H 2 O 2 treatment and tested by flow cytometry. A mouse osteoporosis model was conducted by ovariectomy (OVX). The function of TRIM33 was assessed by in vitro and in vivo experiments. The mechanism of TRIM33 was determined by immunoprecipitation, immunofluorescent staining and co-transfection experiments. Here, we found that TRIM33 expression was lessened in the osteoblasts of patients with osteoporosis and was positively correlated with the bone mineral density of these patients. FOXO3a and TRIM33 were co-localized in the osteoblasts nuclei. TRIM33 silence boosted FOXO3a degradation in normal osteoblasts, while TRIM33 overexpression restrained FOXO3a degradation in H 2 O 2 -treated osteoblasts. The binding of TRIM33 to CBP and its overexpression restrained CBP-mediated FOXO3a acetylation, thereby attenuating FOXO3a ubiquitylation. The H 2 O 2 -induced apoptosis of osteoblasts was restrained by TRIM33 overexpression, while the FOXO3a knockdown reversed this trend. The in vivo experiments corroborated that TRIM33 overexpression attenuated the OVX-driven impacts in mice. In general, our findings expounded that TRIM33 protected osteoblasts against oxidative stress-induced apoptosis in osteoporosis and that the underlying mechanism was the restraint of FOXO3a ubiquitylation and degradation.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Xiaohui Yang,Jie Li,Yilang Zhong,Yuanjiayi Shen,Chenqin Xu,Zhouyu Nie,He Wang,Rui Cao,Miaomiao Wang,Jinyu Zhang,Chao Ma,Tongkai Cai,Chenglin Jia,Ruilian Wang,Hao Yin,Jian Chen,Yongbing Cao
Background Candida auris ( C. auris ) is an emerging multidrug-resistant fungal pathogen. Current antifungals are often insufficient, creating a need for host-directed strategies. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that regulates redox homeostasis, but its role in antifungal macrophage defense is not well defined. We examined how SIRT3 shapes macrophage responses to C. auris . We also evaluated ethyl caffeate (EC) as a host-directed modulator. Methods We used murine macrophages with Sirt3 knockdown or overexpression. We quantified phagocytosis, intracellular fungal survival, mitochondrial ROS dynamics, and macrophage cell integrity using imaging, flow cytometry, CFU assays, and LDH release. We profiled infection-induced transcriptional programs by RNA-seq and performed pathway analyses. We tested EC both in vitro and in systemic infection models in Drosophila and mice. We assessed pathway markers by immunoblotting and immunofluorescence. We used the SIRT3 inhibitor 3-TYP to test inhibition sensitivity. Results SIRT3 deficiency impaired macrophage antifungal function and was accompanied by redox imbalance. mtROS regulation was disrupted in a biphasic pattern, with an early spike followed by late depletion. Transcriptomics linked SIRT3-dependent programs to FOXO and PI3K–AKT signaling. In macrophages, SIRT3 status tracked with FOXO3A acetylation and AKT phosphorylation. EC showed weak direct antifungal activity in vitro but improved outcomes in systemic infection models. EC treatment increased SIRT3 abundance and was associated with reduced FOXO3A acetylation and restrained infection-associated AKT activation. These functional and signaling effects were largely sensitive to SIRT3 inhibition by 3-TYP. Conclusion This study connects SIRT3-dependent redox control to FOXO3A–AKT signaling during C. auris infection. It also supports EC as a host-directed candidate that improves antifungal defense in vivo while limiting inflammatory injury.
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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.
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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.
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JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
·
2026
·
IF 3.5
Ruya Mei,Rong Zhang,Zhengyang Li,Jie Luo,Xinyue Zhang,Tong Zhang,Guanglei Lv,Juhua Zhang,Bingqing Liang,Yuzhong Yan
Background and Aim Mitochondrial dysfunction in macrophages drives pro-inflammatory M1 polarization in ulcerative colitis (UC). We developed a colon-targeted, mitochondria-directed nanoplatform (KSF@SS31@S100Ns) to restore mitochondrial fitness and alleviate UC. Methods Kaempferol-loaded silk fibroin (SF) nanoparticles were conjugated with SS-31 peptide and coated with pH-sensitive Eudragit S100. Physicochemical properties, release profile, and uptake were characterized. Mitochondrial function, macrophage polarization, and SIRT3/FOXO3a signaling were assessed in LPS-stimulated RAW264.7 cells. Efficacy and mechanisms were evaluated in a DSS-induced colitis mouse model. Results Nanoparticles showed uniform size (~307 nm), high stability, and pH-dependent release. SS-31 enhanced macrophage uptake and mitochondrial localization. In vitro, KSF@SS31Ns restored mitochondrial membrane potential and ATP, reduced ROS, promoted mitophagy, and shifted macrophages toward the M2 phenotype via SIRT3/FOXO3a activation. In vivo, oral KSF@SS31@S100Ns accumulated in inflamed colons, reduced disease severity, suppressed pro-inflammatory cytokines, elevated IL-10, restored tight-junction proteins, and increased M2 macrophages. Conclusions KSF@SS31@S100Ns effectively treats experimental colitis by restoring mitochondrial homeostasis, reprogramming macrophage polarization, and repairing the intestinal barrier, offering a translational nanotherapeutic strategy for UC. Graphical IBD by KSF@SS-31@S100N treatment repair
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