ACS Omega
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2026
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IF 4.3
Xianghuai Zheng,Yue Zou,Qinkai Xie,Hao Dong,Jiating Lin,Xianxian Zhuang,Ruoting Xian,Shaobing Li
Oral squamous cell carcinoma (OSCC) presents significant therapeutic challenges due to chemoresistance and limited treatment modalities. Black phosphorus nanosheets (BPNSs), a novel two-dimensional nanomaterial, have shown promising antitumor effects. However, their role in inducing ferroptosis in OSCC and the underlying mechanisms remain to be elucidated. In this study, BPNSs were prepared via liquid-phase exfoliation, and their effects on the OSCC CAL-27 cells were subsequently evaluated. In vitro, BPNSs dose-dependently inhibited CAL-27 cell proliferation, induced G2/M phase arrest, and triggered ferroptosis, indicated by increased intracellular Fe2+, ROS, and lipid peroxidation, along with decreased glutathione (GSH) levels and altered expression of ferroptosis-related proteins (ACSL4, NCOA4, and GPX4). These effects were attenuated by ferroptosis inhibitor ferrostatin-1. In vivo, BPNSs suppressed CAL-27 xenograft growth without systemic toxicity, with elevated tumor malondialdehyde (MDA) and Fe2+ confirming ferroptosis. Mechanistic studies indicated that BPNSs inhibited the PI3K-AKT pathway, leading to the downregulation of SREBP1. Overexpression of SREBP1 attenuated BPNS-induced ferroptosis, confirming its critical role. These findings suggest that BPNSs induce ferroptosis in OSCC via the PI3K-AKT-SREBP1 signaling pathway, providing a novel therapeutic strategy for OSCC treatment.
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JOURNAL OF MOLECULAR HISTOLOGY
·
2026
·Vol. 57
·期 1
·30
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IF 2.2
Xiang Shouyu,Liu Wei,Tang Cheng,Xie Chuhai,Hu Hailan,Zhou Jianhui,Cao Yanming,Ling Long
Bone marrow mesenchymal stem cells (BMSCs) play a significant role in bone defect repair. Currently, the limited survival and function of transplanted BMSCs pose major obstacles to tissue repair mediated by these cells. Therefore, the exploration of BMSCs transplantation activity has become an urgent clinical problem. In this experiment, we constructed lentiviral vectors with overexpression and silencing of miR-19b-3p and utilized a rat fracture model. The effects of BMSCs proliferation were examined using CCK-8, the Annexin V-FITC apoptosis kit and TUNEL assay, the effects of BMSCs osteogenic differentiation were detected using ALP and Alizarin red staining. Furthermore, Western blotting and qRT-PCR were employed to examine the expression of key proteins in the PTEN/Akt/mTOR signaling pathway and autophagy-related proteins. Moreover, the impact of miR-19b-3p on bone microstructure was assessed using Micro CT, HE, Safranin O/Fast Green, as well as Masson staining, and Immunohistochemistry analysis examined PTEN, p62 and Runx2 expression levels on fracture site. By constructing lentiviral vectors with overexpression and silencing of miR-19b-3p, we found that silencing miR-19b-3p significantly promoted the proliferation as well as the osteogenic differentiation of BMSCs under hypoxia. Western blotting and qRT-PCR results showed that silencing miR-19b-3p significantly increased PTEN, LC3, and Beclin1 expression while decreasing p-Akt, p-mTOR, and p62 expression. Furthermore, by constructing the fracture rats and administering hypoxia-treated BMSCs transfected with miR-19b-3p via tail vein injection, we found that silencing miR-19b-3p obviously increased the formation of trabecular and promoted the healing of the fractures. Immunohistochemistry analysis showed that silencing miR-19b-3p upregulated PTEN and Runx2 expression levels and suppressed p62 expression with statistical significance. In summary, these findings suggest that miR-19b-3p may regulate BMSCs’ autophagy and osteogenic differentiation under hypoxia via the PTEN/Akt/mTOR signaling pathway, thereby promoting fracture healing and providing a potential target for the treatment of fractures.
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Molecular Pain
·
2025
·
IF 2.8
Yu-Na Cheng,Ming-Zhu Zhang,Cui-Qing Xie,Zhi-Qi Li,You-Feng Ge,Zhao-Hui Jin,Zhi-Hua Luo,Chen-Yang Zheng,Liang Chen,dong fang,Chen-Guang Niu,Jin-Jin He
Bone cancer pain (BCP), one of the most intractable symptoms in patients with cancer, remains poorly understood and lacks effective therapeutic interventions. In this study, we employed an established rat model of BCP induced by intratibial injection of MRMT-1 mammary carcinoma cells. Transcriptomic profiling of the L4-L6 dorsal root ganglia (DRGs) revealed an upregulation of the amino acid transporter SLC38A3. This finding was further confirmed by time-dependent increases in both its mRNA and protein levels. Immunofluorescence co-localization indicated that SLC38A3 was expressed in NF200-, CGRP-, and IB4-positive neurons within the L4-L6 DRGs, and its expression was upregulated in the BCP model. Concomitantly, the transient receptor potential vanilloid 1 (TRPV1) expression in BCP rat DRGs was dynamically upregulated at both the mRNA and protein levels, aligning temporally with pain hypersensitivity. Lentivirus-mediated overexpression or knockdown of SLC38A3 in the DRGs led to a corresponding upregulation or downregulation of TRPV1-expression. Activation of the PI3K/AKT signaling pathway corresponds with BCP-related pain behaviors and expression patterns of SLC38A3 and TRPV1. Bexarotene alleviates BCP in rats by suppressing the aberrant overexpression of SLC38A3, thereby blocking the PI3K/AKT signaling pathway-mediated upregulation of TRPV1. These findings indicate that SLC38A3, through its downstream PI3K/AKT-TRPV1 axis, may serve as a potential molecular mechanism for analgesia in BCP.
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EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Hai-Tao Yang,Guan Wang,Peng-Cheng Zhu,Zhao-Yang Xiao
Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation , and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro . EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo . In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.
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Experimental and Therapeutic Medicine
·
2023
·Vol. 25
·期 4
·1-11
·
IF 2.7
Chun-Lian Liang,Xiu-Li Li,Xiao-Juan Quan,Lin Zhang
Idiopathic pulmonary fibrosis (IPF) is a heterogeneous lung disease associated with high mortality. Disabled‑2 (DAB2), an adapter protein, regulates cell‑fibrinogen adhesion and fibrinogen uptake. DAB2 is differentially expressed in mouse fibrotic lungs induced by bleomycin according to a genome microarray analysis based on Gene Expression Omnibus database. However, the role of DAB2 in IPF has not been revealed. A bleomycin‑induced mouse model of pulmonary fibrosis was constructed in the present study. It found that the expression of DAB2 was upregulated in bleomycin‑induced fibrotic lung tissue with collagen fiber deposition and pulmonary interstitium thickening. Colocalization of DAB2 with α‑smooth muscle actin (SMA) was observed in lung tissue sections. In vitro, human lung fibroblast MRC‑5 cells were treated with TGF‑β1 and the expression of DAB2 was increased. Knockdown of DAB2 suppressed cell proliferation and the expression of α‑SMA, collagen I, collagen IV and fibronectin in TGF‑β1‑treated MRC‑5 cells. The phosphorylation levels of PI3K and AKT were suppressed in DAB2‑knockdown cells. IGF‑1/IGF‑1R has been reported to promote pulmonary fibrosis and activate the PI3K/Akt signaling. In the present study, the activation of IGF‑1/IGF‑1R signaling pathways in bleomycin‑induced fibrotic lung tissues were positively associated with DAB2 expression. The phosphorylation level of IGF‑1R was increased in MRC‑5 cells with TGF‑β1 treatment, and DAB2 expression was decreased by silencing of IGF‑1R. This suggested that DAB2 might be a downstream target of the IGF‑1R pathway and thus induced PI3K/AKT signaling activation and fibrogenesis. The current study demonstrated the importance of DAB2 in pulmonary fibrosis and suggested the potential of IGF‑1R/DAB2/PI3K in the pathogenesis of IPF.
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Frontiers in Pharmacology
·
2023
·
IF 5.6
Xiu Yanghui,Su Yu,Gao Lihua,Yuan Hui,Xu Sennan,Liu Ying,Qiu Yan,Liu Zhen,Li Yuhang
Introduction: Chronic non-healing wound is a considerable clinical challenge and research into the discovery of novel pro-healing agents is underway as existing therapeutic approaches cannot sufficiently meet current needs.Method: We studied the effects of corylin in cell line fibroblasts and macrophages by Western blots, PCR, Flow cytometry assay, Immunofluorescence.Results: We showed that corylin, a main flavonoid extracted from Psoralea corylifolia L, reduced inflammatory responses, promoted collagen deposition, and accelerated the healing of full-thickness skin wounds in mice. Exploration of the underlying mechanisms showed that corylin activated the PI3K/AKT signaling, leading to fibroblasts’ migration, proliferation, and scratch healing. Corylin also activated sirtuin 1 (SIRT1) signaling, enhanced the deacetylation and cytoplasmic translocation of NF-κB p65, and therefore reduced lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Furthermore, inhibition of PI3K/AKT and sirtuin 1 pathway with LY294002 and EX527 prevent the therapeutic potency of corylin against chronic wounds.Conclusion: In summary, our results suggested that corylin may be a candidate for the development of novel pro-healing agents.
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Aging and Disease
·
2023
·
IF 7.4
Guoxiang Liu,Xiaoxia Li,Fanghao Yang,Jingyu Qi,Lipeng Shang,Huhu Zhang,Shuang Li,Fenghua Xu,Lingne Li,Huaxin Yu,Yang Li,Xiaolei Dong,Qinghang Song,Feng Zhu,Guang Chen,Can Cao,Liangqian Jiang,Junzhe Su,Lina Yang,Xiaohui Xu,Zhe Zhang,Robert Chunhua Zhao,Bing Li
The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.
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Chemical Biology & Drug Design
·
2022
·Vol. 101
·期 1
·24-39
·
IF 2.873
Donglin Zhang,Aiqin Pan,Jianke Gu,Renfeng Liao,Xueyu Chen,Zhaozhu Xu
MicroRNAs (miRs) are implicated in heart failure (HF). Thereby, we aim to uncover the role of miR-144-3p in HF. Doxorubicin (Dox)-induced HF model was constructed in rats and cardiomyocytes H9C2, and the cardiac function was determined using ultrasound cardiogram. Morphology of cardiac tissue was observed using hematoxylin–eosin (H&E) staining. The viability and apoptosis of Dox-treated and transfected cardiomyocytes were determined using Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Relative expressions of the HF-associated miRs (including miR-144-3p), suppressor of cytokine signaling 2 (SOCS2), apoptosis- and phosphoinositide 3-kinase (PI3K)/AKT pathway-related factors (B-cell lymphoma 2, Bcl-2; Bcl-2 associated X protein, Bax; cleaved [C] capsase-3; phosphoinositide 3-kinase, PI3K; phosphorylated-PI3K, p-PI3K; p-AKT; AKT) were measured with quantitative real-time polymerase chain reaction or Western blot. Target gene of miR-144-3p was predicted by Starbase and TargetScan and confirmed with dual-luciferase reporter assay. Dox caused rat cardiac dysfunction, aggravated cardiac injury, decreased cardiomyocytes viability, and the expression of miR-144-3p, Bcl-2, and phosphorylation of both PI3K and AKT yet the upregulated those of Bax and C caspase-3, which was reversed by upregulating miR-144-3p, whereas downregulating miR-144-3p did oppositely. SOCS2 was the target gene of miR-144-3p, Dox promoted SOCS2 expression, which was reversed by upregulating miR-144-3p, while downregulating miR-144-3p did conversely. In addition, silencing SOCS2 reversed the effects of miR-144-3p downregulation in Dox-treated cardiomyocytes. Upregulating miR-144-3p alleviated Dox-induced cardiac dysfunction and cell apoptosis via targeting SOCS2, providing a novel evidence of miR-144-3p in HF.
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MOLECULAR BIOTECHNOLOGY
·
2023
·
IF 2.6
Chang Ruijing,Su Yuan,Kong Hongfang,Wang Fang,Xing Ying,Jiang Lei,Xin Hong
Disturbance of extravillous trophoblast infiltration is associated with preeclampsia (PE), a severe condition of pregnancy characterized by hypertension and proteinuria. Senescence-associated epithelial membrane protein 1 (SEMP1), an integral membrane protein, is a vital component of tight junction strands in epithelial or endothelial cells, with no clear function reported in PE. Gene Expression Omnibus (GEO) datasets showed that SEMP1 expression was downregulated in the placental tissues of PE patients, which was confirmed by assessing SEMP1 levels in placental samples collected in our hospital. Furthermore, less SEMP1 was detected in cytokeratin 7 positive trophoblast cells in the spiral arteries of rat placentas post L-arginine methyl ester hydrochloride (L-NAME) treatment. Trophoblast cells acquired robust ability of proliferation, migration, and invasion when SEMP1 was overexpressed. Such capability was weakened in SEMP1-silenced cells. Trophoblast cells overexpressing SEMP1 secreted more vascular endothelial growth factor A (VEGFA), which facilitated the tube formation of human umbilical vein endothelial cells. Blockade of PI3K/AKT signaling transduction with LY294002 dampened the effects of SEMP1 on trophoblast cells. Collectively, we firstly indicated that SEMP1 inhibition is a potential driver for PE, which may be associated with the deactivation of the PI3K/AKT pathway. Graphical Abstract SEMP1 was involved in PE progression by regulating cell growth, migration, invasion, and tube formation via PI3K/AKT signaling pathway in trophoblast cells and endothelial cells.
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FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Xin Xie,Yan Zhu,Huimin Cheng,Haili Li,Yadi Zhang,Rong Wang,Wenyong Li,Fengrui Wu
Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo . The results showed that BPA (10 μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10 μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo ; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.
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Aging-US
·
2023
·
IF 5.2
Huahua Li,Jin Zheng,Yacen Wu,Hong Zhou,Suli Zeng,Quanqing Li
Backgrounds: High glucose (HG) caused oxidative stress and mitochondrial dysfunction, resulting in insulin resistance in podocytes, a key mechanism of diabetic nephropathy. Dendrobium officinale polysaccharide (DOP) was able to improve insulin resistance and antioxidant capability. Objective: The purpose of this study is to explore the mechanism by which DOP decreases the podocyte injury induced by HG. Methods: MPC5 cells were treated with HG, DOP, and IRS-1/2 inhibitor NT157. Afterwards, glucose consumption, generations of ROS and MDA were measured using the detection kits. Mitophagy was monitored using both MtphagTracyker and LysoTracker. The mitochondrial membrane potential was evaluated by JC-1 staining. DOP was also used in a mouse model of diabetes, with the measurements of urine albumin, blood creatinine and blood urea nitrogen. Results: Treatment with DOP suppressed the HG-induced reduction of glucose consumption, the phosphorylation of IRS-1 (phospho Y632), AKT (phospho Ser473 and Thr308) and Nephrin. In addition, HG-induced augment of ROS and MDA, formation of γ-H2A.X foci and translocation of AKT to nucleus were inhibited by DOP. DOP enhanced mitophagy, which was associated with decreased mitochondrial membrane potential and ROS production. DOP conferred protective effect on podocyte in the diabetic mouse by reducing the albumin/creatinine ratio and blood urea nitrogen, and restoring Nephrin expression in podocytes. Conclusions: DOP alleviates HG-induced podocyte injuryby regulating IRS-1/AKT signal and promoting mitophagy.
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Advanced Healthcare Materials
·
2023
·
IF 10
Limin Fan,Xiaoyi Ma,Bingbing Liu,Yushan Yang,Yan Yang,Tianbin Ren,Yongyong Li
Inspired by the experience of relieving inflammation in infants with milk, we have developed antioxidant-engineered milk-derived extracellular vesicles (MEVs) to evaluate their potential for accelerating wound healing. In this work, we engineered MEVs with polydopamines (PDA) using the co-extrusion method. Subsequently, we incorporated them into a Schiff-based crosslink hydrogel, forming a skin dosage form that could facilitate the wound healing process. The antioxidant properties of PDA assist in the anti-inflammatory function of engineered MEVs, while the gel provides better skin residency. The PDA@MEVs+GEL formulation exhibited excellent biocompatibility, pro-angiogenic capacity, and antioxidant ability in vitro. Furthermore, in vivo, experiments demonstrated its efficacy in wound repair and inflammation inhibition. Mechanistically, PDA@MEVs+GEL simultaneously promoted the growth, migration, and anti-inflammation of 3T3 cells by activating PI3K-AKT pathway. Moreover, PDA@MEVs+GEL exhibited enhanced functionality in promoting wound healing in vivo, attributed to its ability to inhibit inflammation, stimulate angiogenesis, and promote collagen synthesis. In conclusion, this study delves into the mechanism of MEVs and underscores the improved efficacy of engineered extracellular vesicles. Additionally, the feasibility and prospect of engineered MEVs in treating skin wounds were verified, suggesting that antioxidant-engineered MEVs could be a promising therapeutic agent for wound healing applications. This article is protected by copyright. All rights reserved
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