CURRENT PHARMACEUTICAL BIOTECHNOLOGY
·
2021
·Vol. 22
·期 5
·609-621
·
IF 2.837
Zheng Jing,Changyuan Wang,Shijie Wen,Yue Jin,Qiang Meng,Qi Liu,Jingjing Wu,Huijun Sun,Mozhen Liu
Background: Osteoporosis, characterized by bone loss, usually occurs with the increased bone resorption and decreased bone formation. H2O2-induced MC3T3-E1 cells are commonly used for the study of osteoblastic activities, which play a crucial role in bone formation. Objective: This study aimed to investigate the effects of Phosphocreatine (PCr) on the osteoblastic activities in H2O2-induced MC3T3-E1 cells and elaborate on the possible molecular mechanism. Methods: The Osteoprotegerin (OPG)/Receptor Activator of NF-ΚB Ligand (RANKL) ratio and osteogenic markers were detected to investigate the effects of PCr on osteoblastic activities, and the osteoblastic apoptosis was detected using Hochest staining. Moreover, oxidative stress, Adenosine Triphosphate (ATP) generation and the expression of Sirtuin 1 (SIRT1), Forkhead Box O 1 (FOXO1) and Peroxisome Proliferator-Activated Receptor Γ Coactivator-1α (PGC-1α) were also examined to uncover the possible molecular mechanism in H2O2-induced MC3T3-E1 cells. Result: The results showed that PCr promoted the osteoblastic differentiation by increasing the expression levels of osteogenic markers of Alkaline Phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as increased the OPG/RANKL ratio and suppressed the osteoblastic apoptosis in H2O2-induced MC3T3-E1 cells. Moreover, treatment with PCr suppressed reactive oxygen species (ROS) over-generation and promoted the ATP production as well as increased the PGC-1α, FOXO1 and SIRT1 protein expression levels in H2O2-induced MC3T3-E1 cells. Conclusion: PCr treatment could promote osteoblastic activities via suppressing oxidative stress and increasing the ATP generation in H2O2-induced MC3T3-E1 cells. In addition, the positive effects of PCr on osteoblasts might be regulated by SIRT1/FOXO1/ PGC-1α signaling pathway.
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PLoS One
·
2026
·Vol. 21
·期 4
·e0348261
·
IF 2.8
Yating Lv,Yanfei Meng,Haiying Rui,Tongqin Li,Jing Zhang,Jie Liu,Xin Ma,Jiaqi Wang,Yamin Yuan,Yujing Jiang,Xiaoxi Yan,Miaobo Li,Xiaorong Dong,Bei Zhang,Li Ma
Sepsis-associated acute lung injury (SALI) is characterized by endothelial barrier dysfunction and capillary leakage. Ulinastatin (UTI), a serine protease inhibitor with recognized clinical benefits in sepsis, has been reported to protect endothelial function, but the underlying mechanisms remain incompletely defined. This study investigated the protective effects of UTI against SALI and its specific mechanism of action. We found that UTI attenuated lung injury and endothelial dysfunction in both cecal ligation and puncture (CLP)-induced septic rats and LPS-stimulated human umbilical vein endothelial cells (HUVECs). UTI treatment reduced the expression of angiopoietin-2 (Ang-2), a key mediator of vascular destabilization, and exerted similar protective effects on endothelial function as dexamethasone (DEX). Mechanistically, UTI was demonstrated to have a stable interaction and favorable binding affinity to PI3K by docking and activating the PI3K/Akt signaling pathway. This led to phosphorylation and subsequent nuclear export of the transcription factor FoxO1, thereby suppressing FoxO1-dependent Ang-2 transcription. The protective effects of UTI on capillary leakage and junctional protein integrity were abolished by the PI3K inhibitor wortmannin. In conclusion, our findings demonstrate that UTI alleviates SALI by disrupting an Ang-2-mediated vicious cycle via the PI3K/Akt/FoxO1 pathway, revealing a novel mechanistic insight into its therapeutic action against sepsis-induced vascular leakage.
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Pharmacognosy Magazine
·
2023
·
IF 0.7
Jiang-Long Shi,Li-Yun Liu,Yu-Ting Dong,Tao Shen
BackgroundSeveral studies have demonstrated the anti-inflammatory properties of gastrodin. However, its specific role and mechanism in the context of osteoarthritis (OA) remain unclear.ObjectivesThe objective of this study was to explore the function and mechanism of gastrodin in both in vivo and in vitro OA models.Materials and MethodsIn this study, the targets of gastrodin against osteoarthritis were analyzed using bioinformatics methods. The effect of gastrodin on neutrophil infiltration and inflammatory cytokines in OA synovial tissue was evaluated using H&E staining. The levels of inflammatory cytokines were determined using ELISA and Q-PCR. The extracellular matrix degradation-related proteins and PI3K/AKT/FoxO1 signaling pathway were tested using western blotting.ResultsBioinformatics analysis predicted that the target of gastrodin against OA might act on the FoxO pathway. The use of gastrodin resulted in a significant reduction in the infiltration of neutrophils in the synovial tissue of rats, as observed through H&E staining. Additionally, gastrodin was found to attenuate IL-1β-induced inhibition of chondrocyte viability, pro-inflammatory cytokine production, and extracellular matrix degradation. This effect can be attributed to the suppression of PI3K/AKT/FoxO1 by gastrodin.ConclusionThese findings indicate that gastrodin is a treatment for OA.
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JOURNAL OF BIOLOGICAL CHEMISTRY
·
2025
·
IF 3.9
Yijun Yang,Nengyi Wang,Yuankun Chen,Tianpeng Ma,Minhua Weng,Haifeng Wu,Qiuping Wu,Yiqiang Xie,Chuanwu Zhu,Wenting Li
Nonalcoholic fatty liver disease (NAFLD) has posed a huge threat to public health globally, but there are currently no approved drugs available. Growing evidence has proved the close association between increased Th17 cells and NAFLD progression. Interleukin-4 induced protein 1 (IL4I1), an amino acid oxidase secreted by immune cells, was reported to regulate the Th17 cells, but its exact role in NAFLD progression has not been fully explained yet. We found that IL4I1 was highly expressed in the liver of C57BL/6J mice with NAFLD induced by an 8-weeks western diet. To explore the IL4I1’s effect, mice were injected with AAV8 encoding IL4I1 1 week before western diet administration. The results showed that IL4I1 overexpression inhibited the NAFLD progression, demonstrated by relieved liver damage and lipid accumulation. The underlying mechanism in which IL4I1 acts on NAFLD might be attributed to the inactivated AKT/forkhead box protein O1 (FOXO1) signaling pathway–mediated decrease of Th17 cells in liver tissues. Subsequently, by culturing naive CD4 + T cells isolated from the spleen of mice in Th17 cell-polarizing conditions, we determined that IL4I1 overexpression inhibited Th17 cell differentiation by inactivating the AKT/FOXO1 pathway, whereas its knockdown exhibited opposite effects. Further, the AKT activator SC79 reversed the effect of IL4I1 overexpression on Th17 cell differentiation. Collectively, our study supports that compensatory upregulation of IL4I1 protects against liver damage and lipid accumulation in NAFLD progression, partially by inhibiting the activated AKT/FOXO1 signaling pathway-induced Th17 cell differentiation.
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Science of Advanced Materials
·
2022
·Vol. 14
·期 7
·1175-1184
·
IF 1.067
Mei Qing,Shou Diwen,Quan Ying,Cheng Jiemin,Pan Pan,Chen Huiting,Huang Hongli,Li Yongqiang,Xia Yu,Zhou Yongjian
Lipid deposition is a key predisposing factor of nonalcoholic fatty liver disease (NAFLD). FOXO1 is obviously expressed in polarized M1 macrophages and may cause liver cell steatosis. Thus, silencing FOXO1 during M1 macrophage polarization using small interfering RNA (siRNA) technology
may alleviate lipid deposition in liver cells. However, a lack of effective and biocompatible carriers is challenging for such siRNA-delivery to macrophages. To improve this, RGDfC peptide-modified selenium nanoparticles (RGDfC-Se NPs) were fabricated as a siFOXO1 delivery carrier system.
We showed that RGDfC-Se NPs effectively increased siFOXO1 cellular uptake and silenced FOXO1 expression in human peripheral blood monocyte-like macrophages (THP-1 cells). Additionally, RGDfC-Se@siFOXO1 blocked M1 polarization in these cells. Also, FOXO-1-suppressed cell supernatants extenuated
lipid deposition in LO2 liver cells probably by down-regulating the expression of lipid deposition-related fat metabolic enzymes acetyl-CoA carboxylase 1 and fatty acid synthase. Furthermore, our in vivo analyses showed that RGDfC-Se@siFOXO1 attenuated hepatic steatosis by inhibiting
M1 macrophage polarization in mouse liver tissue. Our studies represent a new strategy and clinic treatment target for NAFLD.
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ADVANCED MATERIALS
·
2026
·
IF 29.1
Jiacheng Lei,Ruihao Xue,Qingqing Liang,Ge Yang,Xiaokai Pan,Tianxiang Ren,Kaikai Zheng,Qiang Wei,Ze Gong,Xiaojing Liu
Stem cell aging critically limits the efficacy of regenerative biomaterials, yet how mechanical cues within the microenvironment modulate this process remains insufficiently understood. Here, we reveal that the nanoscale spacing of adhesive ligands imposes stiffness-dependent effects on mesenchymal stem cell (MSC) senescence. Wider spacing (distance 150 nm) accelerates aging on stiff hydrogels (50 kPa) but mitigates it on soft hydrogels (5 kPa), relative to dense spacing (distance 30 nm). Using a molecular clutch-based theoretical model, we demonstrate that ligand spacing and matrix stiffness cooperatively regulate cell behaviors through focal adhesion assembly. Enhanced focal adhesion formation amplifies stress fiber-generated traction forces and nuclear envelope tension, leading to increased chromatin accessibility and transcriptional activation of FOXO1, a central regulator of cellular senescence. These mechanistic insights are further validated in vivo. Collectively, these findings delineate a mechanotransduction mechanism through which nanoscale adhesive architecture and matrix stiffness cooperatively govern stem cell aging.
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Foods
·
2023
·Vol. 12
·期 13
·2471
·
IF 5.2
Jinjie Li,Yi Li,Xiangying Suo,Jiangtao Li,Da Huang,Guangning Kou
Bayberry is known to be a rich source of natural flavonoids and has been reported to have various health-promoting abilities. However, its function on regulating skeletal muscle fiber type remains unclear. This study examined whether bayberry extract affects skeletal muscle fiber type by promoting fast myofiber formation, as well as the potential molecular mechanism. After eight weeks, the “Biqi” bayberry extract (BBE) groups mice displayed markedly enhanced grip strength and improved metabolic rate compared to the control group mice. BBE also significantly increased myofibers size, LDH activity, MyHC-IIb (fast-twitch mRNA) expression, and the percentage of fast-twitch myofibers, while decreasing SDH activity, MyHC-I (slow-twitch mRNA) expression, and slow-twitch myofibers percentage in the skeletal muscle of the mice. The effect of BBE on regulating skeletal muscle fiber type remodeling is likely attributed to its activation of the Akt-FoxO1 pathway. Our findings indicated that BBE can effectively regulate the expression and proportion of fast-twitch fibers, making it a potential therapy for improving glucose homeostasis of skeletal muscle.Keywords:bayberry extract;skeletal muscle;fast-twitch fibers;myofiber type;FoxO1
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Journal of Genetics and Genomics
·
2021
·
IF 4.275
Feifei Chen,Lei Guo,Jiehui Di,Man Li,Dong Dong,Dongsheng Pei
Numerous circular RNAs (circRNAs) have been identified as vital regulators in various cancers. The newly reported circular RNA ubiquitin-associated protein 2 (circUBAP2) is a critical player in cell growth and metastasis in various types of cancers, although its role in colorectal cancer (CRC) has yet to be fully elucidated. We find that circUBAP2 is upregulated in CRC tissues and cell lines to induce autophagy both in vitro and in vivo . The effects of circUBAP2 on migration, invasion, and proliferation may be partially related to autophagy. Mechanistically, we uncover that circUBAP2 can directly interact with miR-582-5p and subsequently act as a microRNA sponge to regulate the expression of the miR-582-5p target gene forkhead box protein O1 ( FOXO1 ) and downstream signaling molecules, which collectively advance the progression and metastasis of CRC. These results suggest that circUBAP2 acts as an oncogene via a novel circUBAP2/miR-582-5p/FOXO1 axis, providing a potential biomarker and therapeutic target for CRC management.
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MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·1-14
·
IF 4.3
Cai Minghui,Guo Qi,Li Jiaxin,Dai Xiaoqi,Su Huiyu,Zhang Wenwen,Qiang Na,Li Geng,Jin Zihan,Zhu Hui
The factors influencing hippocampal aging are complex, and it remains challenging to identify effective anti-aging drugs and reveal pharmacological mechanisms. This study investigates the effects of autophagy mediated by the SIRT1/FoxO1 signaling pathway on resveratrol resistance to H 2 O 2 -induced aging and apoptosis in mouse hippocampal neurons. HT22 cells were treated with resveratrol and H 2 O 2 to evaluate the effects of resveratrol on H 2 O 2 -induced aging and apoptosis. The levels of P21, P53, BAX, Cleaved Caspase-3, and Bcl-2 were measured to estimate aging and apoptosis. Western blot, immunofluorescence assays, and transmission electron microscopy observation were used to detect the regulation of resveratrol on autophagy. 3-Methyladenine was used to block autophagy, and EX-527 was used to inhibit SIRT1. The changes of autophagy factors and the levels of SIRT1/FoxO1 signaling pathway were assayed. H 2 O 2 treatment induced aging in HT22 cells, manifesting increased levels of P21 and P53 and decreased cell viability. H 2 O 2 treatment aggravated apoptosis, showing increased levels of BAX and Cleaved Caspase-3, decreased levels of Bcl-2, and increased apoptotic cells. Resveratrol alleviated aging and apoptosis in H 2 O 2 -induced HT22 cells. Mechanically, resveratrol activated autophagy by up-regulating the levels of LC3B Ⅱ/Ⅰ and Beclin1 and down-regulating P62 against aging and apoptosis, which was abolished by 3-Methyladenine. Western blot results showed resveratrol activated SIRT1/FoxO1 signaling pathway which was related to regulation of autophagy. EX-527 treatment suggested resveratrol could not activate autophagy when the SIRT1/FoxO1 signaling pathway was blocked. These findings indicated that resveratrol activated autophagy via SIRT1/FoxO1 signaling pathway to protect against H 2 O 2 -induced aging and apoptosis in HT22 cells.
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PHYTOMEDICINE
·
2023
·
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.
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Food Bioscience
·
2026
·
IF 6.2
Qing Liu,Zengying Sui,Shiyi Li,Miaomiao Wan,Meilan Xue,Xia Qiu,Hui Liang,Lirui Sun
Fucoidan is a sulfated polysaccharide derived from brown algae ( Saccharina japonica ), and exhibits immunomodulatory properties. Emerging evidence suggests a strong correlation between the development of food allergy and intestinal dysfunction. The present study aimed to investigate the potential anti-food allergy activity of fucoidan and to elucidate its mechanism at the intestinal barrier function. The ovalbumin (OVA)-induced allergy mouse model was established, exhibiting increased OVA-specific IgE, histamine, Th2 inflammatory response, and intestinal damage. Oral administration of fucoidan markedly alleviated allergic symptoms by inhibiting mast cell activation and modulating intestinal immune responses. Furthermore, fucoidan significantly ameliorated intestinal immunological dysregulation, maintained barrier integrity, modulated gut microbiota composition, and enhanced short-chain fatty acid (SCFA) production. Mechanistically, the protective effects of fucoidan were closely associated with activation of the AMPK/SIRT1/FOXO1 pathway, which correlated with improved intestinal barrier function. Collectively, these results demonstrate that fucoidan may protect against food allergy by enhancing intestinal barrier function, highlighting the potential of natural biological substances in addressing food allergy.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
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.
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