ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2025
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IF 11.3
Yongkang Zhang,Haiyu Qin,Bowen Zu,Zichen Yu,Chunsheng Liu,Jianbo Shi,Bingsheng Zhou
Abnormal development and mortality in early life stages pose significant threats to the growth and continuation of fish populations. Tris(2,4-di-tert-butylphenyl) phosphate (TDtBPP) is a novel organophosphate ester contaminant detected in natural waters. However, the potential effects of maternal exposure to TDtBPP on the early development of offspring embryos in fish remain unknown. Here, 30-day-old zebrafish were exposed to TDtBPP at 0, 50, 500, or 5000 ng/L for 180 days, and the exposed females were spawned with unexposed males. TDtBPP accumulation was detected in offspring embryos, accompanied by an increased malformation rate and mortality. The developmental abnormality of offspring embryos was identified to originate from the gastrula stage. Furthermore, based on transcriptome analysis, the down-regulation of RHO family interacting cell polarization regulator 2 gene (ripor2) was considered as a key toxic event, and this was confirmed in the subsequent knockdown experiment. Moreover, molecular docking studies and forkhead box O1 (foxO1) transcription factor inhibitor (AS1842856) exposure experiments demonstrated that the blockade of foxO1 transcriptional regulation was responsible for the decreased expression of ripor2. The results of this study demonstrated that the occurrence of developmental malformation and mortality in zebrafish offspring embryos following maternal TDtBPP exposure were triggered by the blockade of foxO1 transcriptional regulation and the consequent down-regulation of ripor2.
研究领域:
环境科学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2024
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IF 6.1
Fan Wu,Fuer Lu,Hui Dong,Meilin Hu,Lijun Xu,Dingkun Wang
Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the in vivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis in vitro and in vivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.
研究领域:
药理学
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分子生物学
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代谢
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内分泌学
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DOI
PubMed
高影响因子
Open Medicine
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2023
·Vol. 18
·期 1
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IF 2.1
Qi Duan,Junxia Wu
Dihydroartemisinin (DHA) has been found to inhibit the expression of von Willebrand factor (VWF), a marker of endothelial cell injury, but its mechanism in cerebral ischemia/reperfusion (I/R) injury remains obscure. In this study, I/R model was constructed through middle cerebral artery occlusion (MCAO) in rats, followed by DHA administration. The effect of DHA on rat cerebral I/R injury was investigated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin staining, TUNEL staining, and Western blot. Brain microvascular endothelial cells (BMVECs) isolated from newborn rats were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R), and then treated with DHA. The results showed that MCAO treatment induced infarction, nerve cell apoptosis, and brain tissue impairment in rats, which was mitigated by DHA. OGD/R inhibited viability and accelerated apoptosis of BMVECs, which was alleviated by DHA. I/R procedures or OGD/R up-regulated expressions of VWF, ATG7, Beclin1, and LC3-II/LC3-I ratio, while down-regulating Occludin, Claudin-5, ZO-1, P62, SIRT1, and FOXO1 expressions in vivo and in vitro ; however, these effects of I/R procedures or OGD/R were offset by DHA. VWF overexpression reversed the above effects of DHA on OGD/R-induced BMVECs. In summary, DHA ameliorates cerebral I/R injury in rats by reducing VWF level and activating autophagy-mediated SIRT1/FOXO1 signaling pathway.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Xiangjuan Wei,Daqian Yang,Boya Zhang,Xingpei Fan,Haining Du,Ruijiao Zhu,Xiaotong Sun,Meimei Zhao,Ning Gu
Di-(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical (EDC) commonly used as a plasticizer, is responsible for widespread environmental pollution. Epidemiological and experimental data implicate DEHP and its metabolite mono(2-ethylhexyl) phthalate (MEHP) in the occurrence and development of metabolic syndrome. However, the specific effects and potential mechanisms of action of DEHP on glucose and lipid metabolism in adults are currently unclear. In the current study, adult male mice were continuously exposed to DEHP (0, 5, and 25 mg/kg/day) via oral administration and changes in glucose and lipid metabolism explored. Notably, exposure to DEHP led to a significant increase in plasma glucose and hepatic lipid accumulation but had no effect on insulin secretion. Western blot and real-time quantitative PCR showed that DEHP induced insulin resistance and promoted gluconeogenesis and lipid accumulation via overexpression of forkhead box protein O1 (FoxO1), in keeping with hepatic RNA sequencing data. Variations in gut microbiota aggravated these effects while inhibition of FoxO1 reversed the adverse effects of DEHP. Our findings support a key role of FoxO1 in disorders of glucose and lipid metabolism caused by DEHP.
研究领域:
内分泌学
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代谢学
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分子生物学
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环境健康
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Yuanyuan Wei,Yimeng Fan,Sijuan Huang,Jianyu Lv,Yannan Zhang,Zhihui Hao
Background Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disease. Besides, baizhu shaoyao decoction (BSD) is an effective treatment for IBS-D; however, its mechanism of action remains unclear. Purpose This study aims to assess the ability of BSD to therapy IBS-D and to elucidate the underlying mechanism. Methods First, comprehensive analyses, including ADME (absorption, distribution, metabolism, excretion) screening, Venn analysis, Gene Ontology (GO) analysis, and network construction, were performed to characterize IBS-D-related pathways and explore the synergistic effects of BSD active compounds. Next, an IBS-D model was constructed using a three-factor superposition method of neonatal maternal separation, chronic immobilization stress stimulation, and Sennae folium aqueous extract lavage. Moreover, the impact of BSD was assessed based on the body weight, fecal water content, and abdominal withdrawal reflex (AWR), and the results of the open field test, sucrose preference test, intestinal permeability assessment, transmission electron microscopy, and TdT-mediated dUTP nick-end labeling (TUNEL) analysis. The factors that regulate the BSD effects on IBS-D were estimated using immunoblotting, quantitative reverse transcription polymerase chain reaction (q-RTPCR), immunohistochemistry, and transcriptome sequencing analyses. Results We found that BSD improved depressive behavior, brain–gut peptide levels, and intestinal permeability induced by IBS-D by increasing the abundance of intestinal tight junctions. In addition, BSD reduced secretory immunoglobulin A levels and the number of intestinal mast cells in IBS-D rats. Network pharmacology and transcriptome sequencing analysis further revealed that the forkhead box O (FoxO) signaling pathway contributed to the BSD-induced alleviation of IBS-D, as BSD regulated the protein and mRNA levels of FoxO1, glycogen synthase kinase 3β, and FoxO3a. Importantly, a FoxO1 inhibitor effectively alleviated IBS-D symptoms in rats, whereas a FoxO3a agonist had the opposite effects. Conclusion These results demonstrate that BSD alleviates depression and intestinal symptoms by regulating brain–gut peptide expression and restoring the intestinal barrier function via the FoxO signaling pathway. Furthermore, our study uses serum pharmacochemistry technology to analyze the in vivo components of TCM formula under effective condition, solving the problem of the discovery of the effective components of TCM to some extent.
研究领域:
药理学
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胃肠病学
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Lu Bocheng,Chen Yongfu,Cai Junjie,Li Ziqi,Guo Lina,Qu Tingli,Tang Li,Zheng Qian
Objective Guzhi Zengsheng Zhitong Decoction (GZZD) is a classic traditional Chinese medicine (TCM) prescription for treating knee osteoarthritis (OA), and has been widely used in clinical practice in China. Given that Forkhead box protein O 1 (FoxO1) has been identified as a potential therapeutic target for OA treatment, this study investigates the chondroprotective effects of GZZD through FoxO1-mediated mitochondrial regulation, bridging traditional medicine with contemporary molecular insights. Methods The therapeutic effects of GZZD on OA and its chondroprotective mechanisms were evaluated both in vivo and in vitro . A rat model of knee OA was established by intra-articular injection of monosodium iodoacetate (MIA), while an in vitro OA model was induced by IL-1β stimulation in chondrocytes. Histological staining, immunohistochemistry, and Western blot analyses were performed to assess cartilage protection. Serum ingredients of GZZD were identified using LC-MS/MS, and the core pathways involved in GZZD-mediated chondroprotection were explored through transcriptomics and network pharmacology. Key protein expression was examined, and molecular biology techniques were applied to validate the role of FoxO1 and its downstream pathways in regulating chondrocyte autophagy, apoptosis, and mitochondrial dysfunction. Additionally, molecular docking and molecular dynamics simulations were conducted to analyze interactions between bioactive compounds and FoxO1. Results GZZD significantly ameliorated MIA-induced knee joint damage, reduced cartilage degradation and subchondral bone destruction, and decreased OARSI scores. Treatment with GZZD markedly decreased serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while enhancing protective autophagy in chondrocytes. Furthermore, GZZD inhibited chondrocyte apoptosis and mitochondrial dysfunction, accompanied by the upregulation of the cartilage matrix protein COL2A1 and the anti-apoptotic protein BCL2, along with downregulation of catabolic factors (MMP13, IL-1β). Mechanistically, GZZD activated the FoxO1/PINK1/Parkin pathway, restoring mitochondrial homeostasis and mitigating mitochondrial-dependent apoptosis, ultimately protecting chondrocytes from OA-related damage. Conclusion For the first time, this study demonstrates that the traditional Chinese medicine formula GZZD alleviates osteoarthritis by activating the FoxO1/PINK1/Parkin pathway, thereby restoring mitochondrial function and protecting chondrocytes from injury. These findings not only establish GZZD as a promising complementary therapy for OA but also provide a scientific foundation for developing FoxO1-targeted therapeutics.
研究领域:
中医中药
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分子生物学
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药理学
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风湿病学
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线粒体生物学
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系统生物学
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计算生物学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2025
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IF 3.7
Yanxue Zhao,Xinpei Liu,Zining Wu,Guotao Ma,Quanli Gao,Jun Zheng,Chaoji Zhang
Rhabdomyosarcoma (RMS), a common malignant tumor in children, presents numerous challenges in clinical treatment. This study investigated the specific functions and regulatory mechanisms of distal-less homeobox 5 ( DLX5 ) in RMS. Data from TCGA, GEO and GEPIA databases were downloaded and analyzed. The effect of DLX5 and PAX3-FOXO1 on RMS cells was examined through cellular experiments. Binding activity between DLX5 and H3K9me2 was assessed using pull-down and chromatin immunoprecipitation-qPCR assays. Additionally, RMS model mice were constructed via xenotransplantation to validate the in vivo effects of DLX5 on RMS. The results revealed that DLX5 was upregulated in RMS tissues and increased in various RMS cell lines, particularly in alveolar RMS cell lines. DLX5 knockdown inhibited malignant biological behaviors. Besides, DLX5 expression was associated with myogenic differentiation of RMS cells. While the overexpression or knockdown of DLX5 did not affect PAX-FOXO1 expression. PAX3-FOXO1 knockdown reduced DLX5 expression, indicating that DLX5 act as a downstream effector of PAX3-FOXO1 . Mechanistically, PAX3-FOXO1 regulated DLX5 expression through KDM4B/H3K9me2 axis. In vitro experiments further demonstrated that knockout of DLX5 or KDM4B inhibited tumor growth. In conclusion, DLX5 expression was increased in PAX3-FOXO1 –driven RMS, and its knockdown inhibited malignant biological behaviors of RMS cells. Moreover, the aberrant expression of DLX5 in PAX3-FOXO1 –driven RMS was regulated by KDM4B/H3K9me2 axis. These findings provided potential therapeutic targets for RMS treatment.
研究领域:
分子生物学
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肿瘤学
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表观遗传学
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DOI
PubMed
高影响因子
BONE
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2021
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IF 4.398
FeiFei Liu,Hao Yang,DongZhe Li,XueJian Wu,QiCai Han
Background Punicalagin (PUN) is a common anti-inflammatory polyphenol. However, the function and mechanism of PUN in osteoarthritis remains unknown. Methods Chondrocytes were isolated from rats, and confirmed by toluidine blue staining and immunofluorescence. Chondrocytes were challenged by lipopolysaccharide (LPS), and rat osteoarthritis model was established by Hulth method. The secretion of inflammatory factors, cell viability and apoptosis were tested via enzyme linked immunosorbent assay (ELISA), MTT and flow cytometry. The levels of forkhead box O1 (Foxo1), proteoglycan 4 (Prg4), hypoxia-inducible factor-3α (HIF3α), autophagy-related genes or extracellular matrix (ECM)-related proteins were examined via quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot or immunohistochemistry . The cartilage tissue damage was assessed via hematoxylin-eosin (HE) staining, toluidine blue staining and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) staining. Results LPS triggered inflammatory injury in chondrocytes. PUN promoted autophagy to mitigate LPS-induced inflammatory injury. Foxo1 silence attenuated the effect of PUN on LPS-mediated autophagy inhibition and inflammatory injury. Promotion of Prg4/HIF3α axis abolished the influence of Foxo1 knockdown on LPS-mediated chondrocytes injury. PUN mitigated the inflammatory injury in rat osteoarthritis model by promoting autophagy and inhibiting inflammation and ECM degradation via Foxo1/Prg4/HIF3α axis. Conclusion PUN attenuates LPS-induced chondrocyte injury and osteoarthritis progression by regulating Foxo1/Prg4/HIF3α axis.
研究领域:
药理学
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风湿病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Scientific Reports
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2026
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IF 4.9
Chen Cong,Tao Wen,Chen Fei,Gong Jie
Cerebral ischemia–reperfusion (I/R) injury remains a major therapeutic challenge, primarily due to complex mechanisms involving oxidative stress and apoptosis. Growth arrest and DNA damage-inducible protein α (Gadd45α), a stress sensor linked to cellular stress responses, has been implicated in I/R injury, yet its precise role in ischemic stroke is incompletely understood. This study aimed to elucidate the function and underlying mechanisms of Gadd45α in cerebral I/R injury using both in vivo and in vitro models. In rats subjected to middle cerebral artery occlusion (MCAO) and in neurons exposed to oxygen–glucose deprivation/reperfusion (OGD/R), Gadd45α expression was significantly upregulated. Lentivirus-mediated knockdown of Gadd45α (sh-Gadd45α) reduced infarct volumes, improved neurological function and increased miniature excitatory postsynaptic current (mEPSC) amplitude. In primary cortical neurons exposed to OGD/R, Gadd45α knockdown decreased reactive oxygen species (ROS) production, DNA damage, and apoptosis, while Gadd45α overexpression exacerbated these effects. Mechanistically, Gadd45α directly interacts with forkhead box O1 (FOXO1) and positively regulates its transcriptional activity. Gadd45α knockdown attenuated the ischemia-induced upregulation of both total FOXO1 and its phosphorylated form (p-FOXO1), thereby suppressing FOXO1 signaling and mitigating cerebral I/R injury. Furthermore, FOXO1 overexpression reversed the neuroprotective effects of Gadd45α silencing, confirming that FOXO1 acts as a critical downstream mediator. These findings demonstrate that Gadd45α silencing alleviates cerebral I/R injury by suppressing FOXO1 signaling, suggesting the Gadd45α/FOXO1 axis as a promising therapeutic target for ischemic stroke.
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DOI
PubMed
高影响因子
eLife
·
2021
·
IF 8.146
Chunbo Zhang,Tianyu Zhong,Yuanyuan Li,Xianfeng Li,Xiaopeng Yuan,Linlin Liu,Weilin Wu,Jing Wu,Ye Wu,Rui Liang,Xinhua Xie,Chuanchuan Kang,Yuwen Liu,Zhonghong Lai,Jianbo Xiao,Zhixian Tang,Riqun Jin,Yan Wang,Yongwei Xiao,Jin Zhang,Jian Li,Qian Liu,Zhongsheng Sun,Jianing Zhong
Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. Tet1 deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with silent information regulator T1 (SIRT1) via its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular translocalization of transcriptional factors PGC-1α and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes PPARGC1A, G6PC, and SLC2A4. Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in Tet1 heterozygous mice livers. The adenosine 5’-monophosphate-activated protein kinase (AMPK) activators metformin or AICAR—two compounds that mimic fasting—elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.
研究领域:
分子生物学
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代谢学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Yihuang Liu,Xiaofeng Li,Xia Zhang,Hua Cao,Nailin Zhang,Jianhui Sun,Pingping Chen
Introduction This research sought to investigate the therapeutic efficacy and underlying mechanisms of Shengjiang Powder (SJP) in the context of chronic gastritis. Methods A rat model of gastric mucosal injury was induced by 1-methyl-3-nitroso-1-nitrosoguanidine (MNNG) and a 10% NaCl solution, followed by treatment with either Vitacoenzyme or SJP. Histopathological changes in gastric tissues were evaluated using hematoxylin-eosin staining. Serum IL-6 levels were measured by enzyme-linked immunosorbent assay. Western blot (WB) analysis was performed to detect COX-2 expression. Immunohistochemistry was used to assess TFF1 and TFF2 expression. Serum metabolomics was conducted to identify differential metabolites and enriched pathways, while proteins related to the FOXO signaling pathway were further examined in vivo . WB analysis was used to detect SIRT1, FOXO1, and STAT3. CAT and SOD2 activities were measured using biochemical assays. Multiplex immunohistochemistry was used to examine SIRT1-FOXO1 co-localization and FOXO1 nuclear localization. For the in vitro experiments, normal human gastric epithelial cells were treated with MNNG to induce inflammatory injury, followed by SJP administration in the presence or absence of the SIRT1 inhibitor EX-527. Results SJP alleviated gastric mucosal injury, reduced serum IL-6 levels and COX-2 expression, and significantly increased TFF1 and TFF2 expression. Metabolomics analysis identified 13 differential metabolites. The targets of these metabolites were intersected with gastritis-related targets, yielding 522 overlapping targets that were significantly enriched in the FOXO signaling pathway. In vivo and in vitro experiments showed that SJP upregulated SIRT1 and FOXO1 expression, increased CAT and SOD2 activities, inhibited STAT3 expression, and promoted FOXO1 nuclear localization. EX-527 blocked the restorative effects of SJP on FOXO1 expression and antioxidant enzyme activities. Conclusion SJP ameliorates gastric mucosal injury and inflammation, potentially through modulation of the SIRT1/FOXO1 axis.
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PubMed
高影响因子
npj Science of Food
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2026
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IF 9.7
Wang Xiaoran,Song Yagang,Zhao Wenyu,Liu Yuting,Fu Yiping,Zhang Yu,Zhao Quanyou,Miao Mingsan,Zhao Wenxia,Wang Xianbo,Li Zhanzhan
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health burden with limited therapeutic options. Cinnamomum cassia , a medicinal-food homologous plant, contains principal bioactive cinnamaldehyde (CA), whose anti-MASLD mechanisms require clarification. This study employed both a high-fat diet (HFD)-induced MASLD model and a free fatty acid (FFA)-stimulated cell model. CA administration attenuated intracellular lipid accumulation in vitro and ameliorated both hepatic steatosis and systemic hyperlipidemia in vivo, while inhibiting hepatic lipid peroxidation. Mechanistically, integrated RNA-seq, network pharmacology, siRNA, immunofluorescence, and transmission electron microscopy analyses identified the SIRT1/FOXO1–autophagy axis as CA’s key regulatory pathway. Gut microbiome profiling revealed CA’s capacity to ameliorate HFD-induced dysbiosis, particularly enriching Lachnospiraceae_NK4A136 . Fecal microbiota transplantation (FMT) and Spearman correlations link serum lipids and hepatic injury factors to gut microbiota, indicating partially microbiota-mediated metabolic modulation by CA. Collectively, CA ameliorates MASLD through coordinated autophagy enhancement and microbial homeostasis restoration, holding promise as a functional food ingredient for metabolic liver disease prevention.
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DOI
PubMed
高影响因子
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