BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2023
·
IF 6.2
Pei Feng,Peizhuo Pang,Zehang Sun,Zhongyu Xie,Tingting Chen,Shan Wang,Qian Cao,Rujia Mi,Chenying Zeng,Yixuan Lu,Wenhui Yu,Huiyong Shen,Yanfeng Wu
Background Mesenchymal stem cells (MSCs) are pluripotent stem cells capable of differentiating into osteocytes, adipocytes and chondrocytes. However, in osteoporosis, the balance of differentiation is tipped toward adipogenesis and the key mechanism is controversial. Researches have shown that, as upstream regulatory elements of gene expression, enhancers ar involved in the expression of identity genes. In this study, we identified enhancers-mediated gene FOXO3 promoting MSC adipogenic differentiation by activating autophagy. Methods We integrated data of RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and ATAC-sequencing (ATAC-seq) to find the identity gene FOXO3. The expression of FOXO3 protein, adipogenic transcription factors and the substrate of autophagy were measured by western blotting. The Oil Red O (ORO) staining was used to visualize the adipogenesis of MSCs. Immunohistochemistry was used to visualize the FOXO3 expression in adipocytes in bone marrow. Immunofluorescence was used to detect the expression of PPARγ and LC3B. Results During adipogenesis, enhancers redistribute to genes associated with adipogenic differentiation, among which we identified the pivotal identity gene FOXO3. FOXO3 could promote the expression of the adipogenic transcription factors PPARγ, CEBPα, and CEBPβ during adipogenic differentiation, while PPARγ, CEBPα, and CEBPβ could in turn bind to FOXO3 and continue to promote FOXO3 expression to form a positive feedback loop. Consistently elevated FOXO3 expression promotes autophagy by activating the PI3K-AKT pathway which mediates adipogenic differentiation. Conclusions Pivotal identity gene FOXO3 promotes autophagy by activating PI3K-AKT pathway, which provokes adipogenic differentiation of MSCs. Enhancer-regulated adipogenic identity gene FOXO3 could be an attractive treatment for osteoporosis.
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Antioxidants
·
2025
·Vol. 14
·期 12
·1495
·
IF 6.6
Tiantian Zhang,Shuangxi Zhang,Jiayang Ma,Dmitrii Atiakshin,Shujun Han,Mami Noda,Midori Hiramatsu,Jiankang Liu,Yunhua Peng,Jiangang Long
Neuroinflammation driven by microglial activation is a hallmark of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial inflammation, yet strategies to modulate its expression remain limited. Safflower leaves, a vegetable rich in flavonoids—particularly luteolin—were previously shown to attenuate neuroinflammation, reduce oxidative stress, and ameliorate cognitive impairment in APP/PS1 mice. Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice. Luteolin, the major active flavonoid in safflower leaves, exerted anti-inflammatory effects in lipopolysaccharides (LPS)-activated microglia. Mechanistically, luteolin enhancedTrem2transcription by activating forkhead box protein O3 (FOXO3), a novel transcriptional regulator ofTrem2identified through promoter analysis. FOXO3 binding to theTrem2promoter was essential for this regulation, and luteolin further promoted FOXO3 nuclear translocation. Crucially,Trem2knockdown attenuated luteolin’s anti-inflammatory effects, confirming TREM2 as a key mediator. Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant.
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Nature Communications
·
2022
·Vol. 13
·期 1
·1-23
·
IF 17.694
Hao WeiChao,Dian MeiJuan,Zhou Ying,Zhong QiuLing,Pang WenQian,Li ZiJian,Zhao YaYan,Ma JiaCheng,Lin XiaoLin,Luo RenRu,Li YongLong,Jia JunShuang,Shen HongFen,Huang ShiHao,Dai GuanQi,Wang JiaHong,Sun Yan,Xiao Dong
Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m 6 A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m 6 A reader YTHDF3 is essential for autophagy induction. m 6 A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m 6 A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m 6 A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.
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MOLECULAR MEDICINE
·
2024
·Vol. 30
·期 1
·1-26
·
IF 6
Wei Xuehua,Xiong Xiangpeng,Wang Pingping,Zhang Shufang,Peng Dongxian
Background The complex interplay between Sirtuin 1 (SIRT1) and FOXO3 in endometrial cancer (EC) remains understudied. This research aims to unravel the interactions of deacetylase SIRT1 and transcription factor FOXO3 in EC, focusing on their impact on mitophagy and hormone resistance.Methods High-throughput sequencing, cell experiments, and bioinformatics tools were employed to investigate the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assay was used to assess the interaction between SIRT1 and FOXO3 in RL95-2 cells. Functional assays were used to assess cell viability, proliferation, migration, invasion, apoptosis, and the expression of related genes and proteins. A mouse model of EC was established to evaluate tumor growth and hormone resistance under different interventions. Immunohistochemistry and TUNEL assays were used to assess protein expression and apoptosis in tumor tissues.Results High-throughput transcriptome sequencing revealed a close association between SIRT1, FOXO3, and EC development. Co-IP showed a protein–protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which in turn promoted cell proliferation, migration, invasion, and inhibited apoptosis in vitro, as well as increased tumor growth and hormone resistance in vivo. These findings highlighted SIRT1 as an upstream regulator and potential therapeutic target in EC.Conclusion This study reveals a novel molecular mechanism underlying the functional relevance of SIRT1 in regulating mitophagy and hormone resistance through the deacetylation of FOXO3 in EC, thereby providing valuable insights for new therapeutic strategies.
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Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Manyu Chen,Yuan Liu,Quanying Liu,Siyan Deng,Yuhan Liu,Jiehao Chen,Yaojia Zhou,Xiaolin Cui,Jie Liang,Xingdong Zhang,Yujiang Fan,Qiguang Wang,Bin Shen
Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered ‘truck’ (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro , and effectively alleviate OA progression in vivo , demonstrating significant potential for clinical applications.
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TOXICOLOGY LETTERS
·
2025
·
IF 2.9
Zhongming Ye,Qihao Huang,Haipeng Wu,Shimei Wang,Boxin Li,Minjuan Zeng,Tikeng Jiang,Biyan Ye,Yixian Wei,Lei Sun,Shaoying Wang,Yutao Zeng,Yuting Chen,Huanwen Tang
Benzene, a recognized carcinogen, is utilized in synthesizing various chemicals. Epidemiological studies have established a positive correlation between benzene exposure and increased incidences of abnormal menstruation and dysmenorrhea. This exposure might also pose risks to the fetal hematopoietic system. However, the precise molecular mechanisms underlying these effects are not fully understood. In this study, a chronic benzene exposure model was established through dynamic inhalation. We assessed the autophagy levels in mouse ovarian granulosa cells and human ovarian granulosa cells treated with 1,4-benzoquinone using molecular biology techniques such as qPCR, Western blot, and transmission electron microscopy (TEM), etc. The experimental results show that Benzene-exposed mice exhibited autophagy, a reduced number of ovarian granulosa cells, and vacuolar lesions in the fallopian tubes. Cell-based experiments demonstrated that benzene exposure significantly upregulated SNHG15 expression in human ovarian granulosa cells ( P < 0.05). The upregulation of SNHG15 enhanced FOXO3 expression via the miR-3143/FOXO3 axis, which in turn increased the transcription of autophagy-related proteins such as Atg5 ( P < 0.05), ultimately leading to excessive autophagy in granulosa cells and ovarian dysfunction. Benzene and its metabolite benzoquinone increase autophagy in ovarian granulosa cells. The lncRNA SNHG15 regulates this autophagy induced by benzene exposure through sponge-like binding to miR-3143/FOXO3, thus impairing ovarian function. Inhibiting SNHG15, miR-3143, and FOXO3 expression markedly reduced autophagy in granulosa cells and ameliorated ovarian dysfunction resulting from benzene exposure. These results suggest that the ceRNA axis involving SNHG15 may be a potential clinical therapeutic target.
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PHYTOMEDICINE
·
2024
·
IF 6.7
Yang-yang Lu,Yuan-yuan Fang,Sha-sha Wang,Jing Guo,Jia-lin Song,Liang Zhu,Zhong-kun Lin,Rui Wang,Si-yi Zhang,Wen-sheng Qiu,Wei-wei Qi
Background Gastric cancer is among the common solid tumors. Chemotherapy resistance is the most common issue in gastric cancer treatment. Inhibiting intracellular autophagy may be a feasible method for overcoming chemotherapy resistance. Cepharanthine (CEP), a natural small molecule extracted from the stephania cephalantha Hayata plant, has been demonstrated to significantly inhibit cancer growth and can regulate autophagy. Although CEP can significantly inhibit cancer growth, it remains unclear whether CEP can regulate autophagy in gastric cancer. This study aimed to investigate whether CEP can enhance the sensitivity of gastric cancer to chemotherapy and elucidate its molecular mechanism. Methods Three gastric cancer cell lines (AGS, SGC7901, and MFC) and one normal gastric mucosal epithelial cell line (GES-1) were used for in vitro experiments. The characterization of autophagy in gastric cancer cells included the detection of autophagy markers and autophagy flux through immunofluorescence staining and Western blotting, as well as the assessment of lysosomal function using fluorescence staining (LysoTracker Red DND-99, Acridine Orange staining) and Western blotting. The cytotoxicity of CEP, autophagy inhibitors (chloroquine [CQ] and 3-methyladenine [3MA]), and chemotherapy drugs (doxorubicin [DOX] and cisplatin [CIS]) was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell colony formation, and fluorescence staining techniques (H2DCFDA, Dihydroethidium, and JC-1 staining). The interaction between CEP and autophagy inhibitors was tested in a 615 mice model, and changes in the gut microbiota were determined through accurate 16S absolute quantification sequencing. The signaling pathway and autophagy regulatory target TRIB3-FOXO3-FOXM1 were confirmed through molecular docking, RNA sequencing, bioinformatic analysis, transfection techniques, and Western blotting. Results CEP blocked autophagic flux in gastric cancer cells without affecting lysosomal function. As a novel autophagy inhibitor, CEP could combine with conventional autophagy inhibitors (CQ and 3MA) to block intracellular autophagy, thereby inhibiting gastric cancer growth. During this process, changes in the gut microbiota were observed, including low-level changes in Odoribacterium, Erysipelatoclostridium , and ParaPrevotella and high-level changes in Ileibacterium, Enterorhabdus , and Bifidobacterium . Additionally, CEP synergistically inhibited the growth of gastric cancer when combined with chemotherapy drugs. Mechanistically, the TRIB3-FOXO3-FOXM1 signaling axis was found to be involved in the inhibition of gastric cancer by CEP combined with autophagy inhibitors and chemotherapy drugs, thereby mediating cell apoptosis. Conclusion This study links the TRIB3-FOXO3-FOXM1 axis with chemotherapy efficacy. Our findings demonstrated that CEP inhibits autophagy by modulating the FOXO3-FOXM1 axis. When combined with chemotherapy drugs (DOX and CIS), CEP, as an autophagy inhibitor, can limit TRIB3 protein expression, thereby regulating the FOXO3-FOXM1 axis and enhancing its ability to prevent gastric cancer growth. These findings may contribute to improving the prognosis of patients with gastric cancer. Furthermore, these results enrich the fundamental understanding of how autophagy inhibition can enhance clinical cancer treatment efficacy and provide insights into the potential mechanisms by which CEP functions as an anti-tumor drug, thereby exploring its value for clinical application.
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Journal of Translational Medicine
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2024
·
IF 6.1
Wenbin Hua,Lin Xie,Chenpeng Dong,Guoyu Yang,Shouyuan Chi,Zhiqiang Xu,Cao Yang,Huiwen Wang,Xinghuo Wu
Intervertebral disc degeneration (IVDD) is a common cause of low back pain. Procyanidin C1 (PCC1) has been demonstrated to exert a protective effect on nucleus pulposus (NP) cells, and therefore, plays a critical role in the prevention and therapy of IVDD. Clarifying the pathophysiological characteristics and molecular mechanisms of IVDD may be helpful in establishing novel preventive and therapeutic strategies. This study aimed to investigate the probable mechanisms underlying the protection against acidic pH stress induced human NP cell injury. In vitro, acidic pH stress induced degeneration, mitochondrial dynamics imbalance, mitophagy, and mitochondria-mediated apoptosis in NP cells, all of which were ameliorated by PCC1. Autophagy inhibition partially eliminated the protective effects of PCC1 on mitochondrial homeostasis in NP cells. Moreover, PCC1 activated the sirtuin 3 (SIRT3)/forkhead box O3 (FOXO3) signaling pathway, a pivotal signaling pathway involved in the regulation of mitochondrial homeostasis in NP cells. In vivo, PCC1 ameliorated IVDD in a rat model and preserved the extracellular matrix of NP cells. Consequently, the protective effects of PCC1 on NP cells may inhibit IVDD progression via regulation of the SIRT3/FOXO3 signaling pathway. Therefore, regulation of the SIRT3/FOXO3 signaling pathway may be a novel preventive and therapeutic strategy for IVDD.
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JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Xinyi Wen,Meiyan Li,Zhongyuan Zhang,Jingwen Wang,Hao Hu,Weihong Wang,Jing Jin,Kairong Wang,Jian Sun,Rui Zhang
Imidacloprid (IMI), a widely used neonicotinoid insecticide, has been frequently detected in drinking water and food; however, whether long-term low-dose exposure to environmentally relevant levels of IMI induces neurotoxic effects in the central nervous system remains unclear. In this study, C57BL/6 N mice were exposed to IMI in drinking water for three、six months at doses derived from human exposure estimates (0, 3 μg/kg, 103 μg/kg, and 6.55 mg/kg). Behavioral tests, including the Morris water maze and novel object recognition, revealed no overt cognitive impairment following IMI exposure. Nevertheless, IMI significantly increased microglial apoptosis in the hippocampus. Mechanistic analyses showed that IMI exposure enhanced JNK phosphorylation and promoted nuclear translocation of FOXO3, accompanied by increased expression of pro-apoptotic proteins BIM and BAX and decreased BCL-2 levels. Consistently, IMI induced apoptosis in BV2 microglial cells through activation of the JNK–FOXO3 signaling pathway, whereas FOXO3 knockdown or JNK inhibition with SP600125 markedly attenuated this effect. These findings indicate that environmentally relevant IMI exposure can trigger hippocampal microglial apoptosis via JNK–FOXO3 signaling even in the absence of overt behavioral deficits, suggesting a potential early neurotoxic effect of neonicotinoid exposure.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2026
·Vol. 30
·期 17
·e71359
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IF 4.7
Xuesong Xu,Shichong Qiao
Apoptosis and functional loss of articular chondrocytes serve as initiating events in temporomandibular joint osteoarthritis (TMJOA), and FoxO3 represents a critical molecule for sustaining chondrocyte homeostasis. This study investigates the regulatory mechanism of the lncRNA‐OIP5‐AS1/hsa‐miRNA‐223‐3p/FoxO3 axis in TMJOA, aiming to identify potential therapeutic targets for this disease. Single‐cell database analysis first revealed markedly reduced FoxO3 expression in TMJOA‐derived chondrocytes. A rat TMJOA model was then constructed and assigned to control, model, and FoxO3 overexpression groups; micro‐CT and histological staining, including HE and Safranin O‐fast green staining, were applied to assess articular cartilage injury, while immunohistochemistry was used to detect cartilage‐associated proteins Col2a1, MMP‐13, Aggrecan, and ADAMTS‐5. Further in vitro experiments validated the chondroprotective function of FoxO3 as well as the binding interaction between FoxO3 and rno‐miRNA‐223‐3p. Database screening confirmed significant down‐regulation of FoxO3 in TMJOA cartilage. Animal experiments demonstrated that FoxO3 overexpression mitigated chondrocyte injury in rat TMJOA lesions, increased Col2a1 and Aggrecan levels, and suppressed MMP‐13 and ADAMTS‐5 expression. Cellular assays showed that FoxO3 overexpression enhanced chondrocyte proliferation and matrix synthesis and preserved chondrocyte function. Sequencing and cellular evidence indicated that rno‐miRNA‐223‐3p directly targets FoxO3 mRNA to repress its transcription and negatively modulate FoxO3 abundance, consequently aggravating chondrocyte apoptosis. Collectively, rno‐miRNA‐223‐3p suppresses FoxO3 activity to facilitate TMJOA pathogenesis, and the lncRNA‐OIP5‐AS1/rno‐miRNA‐223‐3p/FoxO3 regulatory cascade may act as a promising molecular target for TMJOA clinical intervention.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
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2022
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IF 5.228
Weimin Lin,Lei Chen,Wenjing Meng,Kai Yang,Shengjuan Wei,Wei Wei,Jie Chen,Lifan Zhang
As a key adipogenic marker, C/EBPα (CCAAT/enhancer binding protein α) is also an important factor in regulating targets containing CCAAT element for transcription, whose products include coding and non-coding RNAs (ncRNAs). However, knowledge of the mechanism of C/EBPα affecting pre-adipocyte proliferation and adipogenesis through regulating ncRNA is still limited. In this study, we firstly conducted an investigation concerning the impact of C/EBPα knockdown on porcine pre-adipocytes by using RNA sequencing (RNA-Seq) to identify the role of key ncRNAs, especially lncRNAs and their correlated mRNAs in regulating proliferation and differentiation of porcine pre-adipocytes. 97 differentially expressed (DE) mRNAs and 4 DE lncRNAs were identified in si-C/EBPα groups compared with the si-NC groups. Meanwhile, we found C/EBPα directly target the promoter of a novel lncRNA , namely MSTRG.12568.2 , which was trans -correlated with STYX (serine/threonine/tyrosine interacting protein), an important candidate gene for regulating cell proliferation . Moreover, FOXO3 (forkhead box O3) was identified as a co-regulator with MSTR.12568.2 for STYX . Overexpression and knockdown of any of the MSTRG.12568.2 , STYX , and FOXO3 increased and decreased the levels of pre-adipocyte proliferation and differentiation, respectively, which demonstrated that they played a positive role in adipogenesis of pre-adipocytes. Furthermore, our results revealed that FOXO3 was necessary for MSTRG.12568.2 to trans -activate STYX . We revealed that C/EBPα regulated pre-adipocyte proliferation and differentiation through mediating trans -activation of MSTRG.12568.2 -FOXO3 to STYX . These results provide a novel regulation signal for C/EBPα to influence porcine pre-adipocyte proliferation and differentiation and greatly benefit to our understanding of molecular mechanism regulating subcutaneous adipogenesis.
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Cartilage
·
2021
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IF 4.634
Zhaoxun Chen,Chen Zhao,Pengcheng Liu,Haohan Huang,Shuhong Zhang,Xiaoqing Wang
ObjectiveEmerging evidence has indicated that excessive reactive oxygen species (ROS) have detrimental effects on osteoarthritis (OA). This study aimed to elucidate the effects of melatonin (MT), an antioxidant indolamine secreted from the pineal gland, on chondrocyte senescence and cartilage degeneration, thereby clarifying the underlying mechanisms of ROS-induced OA pathogenesis.DesignHydrogen peroxide (H2O2) was used to induce oxidative stress in rat chondrocytes. ROS levels were evaluated using cytometry and immunofluorescence. Cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay. Western blotting and qPCR (Quantiative Real-Time Polymerase Chain Reaction) were used to examine apoptosis and autophagy. For in vivo experiments, male Sprague-Dawley rats were randomly divided into a sham-operated group, DMM (destabilization of the medial meniscus) surgery group, and surgery groups that received melatonin. Knee joints were collected and stained for histological analysis.ResultsThe data demonstrated that melatonin treatment significantly suppressed H2O2-induced matrix degradation and apoptosis, and maintained mitochondrial redox homeostasis. In addition, an enhancement of autophagic flux was observed through western blotting. These findings corresponded with activation of the AMPK/Foxo3 signaling pathways upon melatonin treatment. Histological staining and transmission electron microscopy (TEM) micrographs also demonstrated that melatonin alleviated cartilage ossification and chondrocyte hypertrophy in vivo.ConclusionsOur results indicated that melatonin protected chondrocytes via mitochondrial redox homeostasis and autophagy. The effects of melatonin on senescence may apply to other age-related diseases. Thus, melatonin may have multiple potential therapeutic applications.
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