FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Shenghui Zhang,Qin Liu,Bo Chen,Hui Chang,Ying Pan,Yanli Liu,Xin Zhao,Juntang Lin
MenSC-EVs alleviate STZ-induced ovarian dysfunction in diabetic mice. • MenSC-EVs suppress high-glucose-induced ferroptosis in granulosa cells. • EV-associated HSPA5 mediates protection via AKT/mTOR–BECN1/SLC7A11 signaling. Type 1 diabetes mellitus (T1DM) is associated with ovarian dysfunction, including menstrual irregularities, impaired ovarian reserve, and premature reproductive aging, yet effective therapeutic strategies to safeguard ovarian function against metabolic stress remain limited. Mesenchymal stem cells (MSCs) have emerged as pivotal regulators of tissue homeostasis, with their paracrine effects largely mediated by extracellular vesicles (EVs). Here, we demonstrate that menstrual blood-derived endometrial stem cell-EVs (MenSC-EVs) alleviate streptozotocin (STZ)-induced ovarian dysfunction and inhibit granulosa cells (GCs) ferroptosis by delivering HSPA5. Mechanistically, EV-associated HSPA5 restored AKT/mTOR signaling and was accompanied by reduced BECN1 phosphorylation, thereby preserving the SLC7A11/GPX4-associated antioxidant pathway. We further show that BECN1 directly interacts with SLC7A11, linking BECN1 signaling to regulation of the system Xc−/GPX4 antioxidant axis. MenSC-EVs preserved this antioxidant pathway and reduced lipid peroxidation in injured GCs. Collectively, these findings identify an HSPA5-dependent anti-ferroptotic mechanism through which MenSC-EVs ameliorate T1DM-associated ovarian dysfunction, supporting their potential as an ovarian-protective strategy under diabetic conditions. Download: Download high-res image (241KB) Download: Download full-size image
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高影响因子
EXPERIMENTAL ANIMALS
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2026
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IF 2
Yang LI,Xinchang FENG,Lingpeng ZHENG
Insulin resistance (IR) and hepatic steatosis are key pathological features of type 2 diabetes mellitus (T2DM). Fraxin, a natural flavonoid with potential metabolic regulatory properties, has been proposed to modulate metabolic disorders. This study aimed to investigate whether fraxin protects against IR and steatosis via Sirt1/AMPK/mTOR-mediated autophagy activation. A T2DM rat model was established using high-fat diet (HFD) feeding combined with streptozotocin (STZ) injection. Rats were treated with fraxin (25 or 50 mg/kg) for 4 weeks, followed by assessment of fasting blood glucose (FBG), insulin (FINS), HOMA-IR index, serum lipid profiles and liver function. Histopathological examination (H&E and Oil Red O staining) evaluated hepatic steatosis. BRL 3A cells exposed to palmitic acid (PA) were treated with fraxin (40 or 80 μM), and glucose uptake, lipid accumulation, and protein expression (IRS-1 phosphorylation, GLUT-2 translocation, autophagy markers and Sirt1/AMPK/mTOR pathway components) were analyzed. The specific autophagy inhibitor chloroquine (CQ) was used to verify whether the regulatory effects of fraxin were dependent on autophagy activation. Fraxin significantly reduced FBG, FINS, HOMA-IR, and dyslipidemia in diabetic rats. In PA-treated BRL 3A cells, fraxin enhanced glucose uptake, reduced lipid droplets, and restored IRS-1 phosphorylation and GLUT-2 membrane localization. Mechanistically, fraxin activated autophagy and modulated the Sirt1/AMPK/mTOR pathway, which were abolished by the Sirt1 inhibitor EX527. In conclusion, fraxin alleviates IR and hepatic steatosis in HFD/STZ-induced diabetic rats by activating autophagy through Sirt1/AMPK/mTOR pathway, suggesting its potential as a therapeutic agent for diabetes-associated metabolic disorders.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2026
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IF 4
Liu Hengxu,Xiong Rui,Zhang Shipeng,Zheng Quanyou,Lai Xiaodan
Fatigue is a widespread health problem, and abnormal autophagy in skeletal muscle cells is a key mechanism driving fatigue progression. The purpose of this study was to evaluate the effect of ginsenoside Rg3 (Rg3) on fatigue in ammonium chloride (NH 4 Cl)-induced C2C12 myoblasts cells and to elucidate its potential molecular mechanism. The potential anti-fatigue mechanism of Rg3 was predicted by network pharmacology and molecular dynamics simulations. C2C12 cells were treated with NH 4 Cl to construct an in vitro fatigue model and then treated with Rg3. CCK-8, live/dead staining, Giemsa staining, autolysosome staining, and Western blot were used to evaluate cell viability, myotube morphology, autophagic flow, and key protein expression. Network pharmacology analysis indicated that the anti-fatigue effect of Rg3 was associated with the PI3K/AKT/mTOR pathway-regulated autophagy. Molecular docking and molecular dynamics simulations confirmed that Rg3 binds strongly to PI3K. Cell experiments showed that Rg3 significantly attenuated cell death, myotube injury and abnormal autophagy in NH 4 Cl-induced C2C12 cells. Moreover, Rg3 effectively activated the PI3K/AKT/mTOR pathway. Our results indicated that the anti-fatigue effect of Rg3 may be associated with the attenuation of autophagy through activation of the PI3K/AKT/mTOR pathway. This provides a potential therapeutic candidate for fatigue intervention.
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高影响因子
Journal of Integrative Neuroscience
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2026
·Vol. 25
·期 7
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IF 3.3
Zhihui Li,Qian Wang,Kaixuan Ma,Mengna Yu,Yanyan Wang,Zhongqiao Ge,Peng Lin,Hui Wang,Lexun Lin,Yang Chen,Lina Jia,Heming Li,Zhongqiu Fu,Zhaohua Zhong,Guangtian Wang
Background: Stroke is a major cause of morbidity and mortality, characterized by neuronal damage and complex cell death pathways. This study aimed to investigate the protective role of spermine oxidase (Smox) in ischemic stroke and its effect on neuronal autophagy. Methods: We employed transient middle cerebral artery occlusion (tMCAO) models and oxygen-glucose deprivation/reoxygenation (OGD/R) experiments in HT22 cells to explore the protective effects of Smox knockdown against ischemic injury and to evaluate changes in autophagy. Results: Smox levels were significantly elevated following stroke, and correlated with increased autophagic activity and neuronal apoptosis. In contrast, knockdown of Smox reduced neuronal death and improved neurological function while decreasing autophagy activation. Mechanistically, Smox may regulate autophagy via the phosphorylation of protein kinase B (AKT),AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR); Smox knockdown increased AKT and mTOR phosphorylation, while reducing AMPK phosphorylation, suggesting a potential shift in the regulation of neuronal autophagy. Conclusions: Our findings suggest a dual role for Smox in stroke pathology, indicating that it may influence autophagy via the AKT/AMPK/mTOR signaling, which could be critical for neuronal survival after ischemic injury. Targeting Smox may offer a therapeutic strategy for neuronal protection and recovery in stroke management, suggesting the potential importance of autophagy modulation in ischemic brain injury.
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Journal of Inflammation Research
·
2025
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IF 4.1
Jing Ma,Lu Ding,Xiaoyu Zang,Yingying Yang,Wei Zhang,Xiangyan Li,Daqing Zhao,Zepeng Zhang,Zeyu Wang,Linhua Zhao,Xiaolin Tong
Purpose Pulmonary Fibrosis (PF) is a severe interstitial lung disease currently lacking effective prevention strategies. Endothelial mesenchymal transition (EndMT), a novel mechanism for fibroblast production, is closely associated with PF. The precise mechanisms underlying the contribution of EndMT-derived fibroblasts to PF, however, remain unclear.Methods Using network pharmacology, molecular docking, and molecular dynamics, we identified the key targets and pathways through which Qimai Feiluoping decoction (QM) combats PF. EndMT and autophagy proteins were quantified in bleomycin (BLM) -induced C57BL/6 mice, human umbilical vein endothelial cells (HUVECs), and zebrafish using Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), immunofluorescence (IF), Transwell migration assays, and transmission electron microscopy (TEM), revealing the targets and pathways through which QM mitigates PF.Results Network pharmacology, molecular docking, and molecular dynamics suggest that QM combats PF by modulating the PI3K/AKT/mTOR pathway. Observations from the study indicated that QM was found to alleviate EndMT by restoring autophagy, primarily through inhibition of the PI3K/AKT/mTOR signaling pathway in both BLM-induced C57 mice and HUVECs. Supporting evidence from zebrafish models demonstrated that QM not only counteracts EndMT but also improves a range of vascular functional disorders and remodeling issues following EndMT.Conclusion Our research validates the active compounds, core targets, and signaling pathways through which QM counters PF, providing valuable insights for its therapeutic application in PF management.
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MATERIALS & DESIGN
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2026
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IF 8.2
Jiali Deng,Xiaoqiong Huang,Yang Yang,Linjuan Li,Jiaqi Shen,Wenyi Zeng,Xiaolin Yu,Feilong Deng,Ruogu Xu,Zhengchuan Zhang
Ti‑preconditioned exosomes suppress macrophage inflammation via autophagy activation. • Lyophilized exosome–loaded biomimetic periosteum was successfully constructed. • The delivery system promotes M2 macrophage polarization to facilitate angiogenic osteogenesis. Critical-sized bone defects remain a clinical challenge due to dysregulated inflammation that impairs angiogenesis. Here, we developed a cell-free biomaterial system consisting of a decellularized biomimetic periosteum (DBP) loaded with engineered exosomes derived from nanoporous titanium–preconditioned mesenchymal stem cells (Ti–Exos). We further demonstrated that Ti-Exos significantly attenuated LPS-induced macrophage inflammation by enhancing autophagy through the inhibition of the PI3K/AKT/mTOR pathway, thereby promoting M1-to-M2 macrophage polarization and anti‑inflammatory cytokine secretion. The bilayer DBP scaffold enabled sustained release of Ti-Exos and mimicked key functions of natural periosteum. In a rat critical-sized calvarial defect model, DBP/Ti-Exos facilitated the early macrophage transition from the M1 to M2 phenotype, reduced inflammatory infiltration, stimulated angiogenesis, and ultimately enhanced the formation of mature and mineralized bone. Collectively, this study demonstrates that the engineered exosomes integrated within a biomimetic periosteum can synergistically orchestrate immunomodulation and angiogenesis, offering a promising cell–free therapeutic strategy for vascularized bone regeneration of critical-sized bone defects. This study introduces an engineered exosome–based cell–free strategy that orchestrates the local immune microenvironment to accelerate vascularized bone repair. Specifically, nanoporous Ti-preconditioned exosomes (Ti-Exos) were fabricated and proven to attenuate LPS-induced macrophage inflammation by inhibiting PI3K/AKT/mTOR to activate autophagy. Lyophilized Ti-Exos-loaded decellularized biomimetic periosteum (DBP/Ti-Exos) was constructed and exhibited uniform distribution of Ti-Exos. DBP/Ti-Exos was demonstrated to drive M1-to-M2 macrophage polarization, and promote angiogenic osteogenesis in rat calvarial defects. Download: Download high-res image (182KB) Download: Download full-size image
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高影响因子
EXPERIMENTAL ANIMALS
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2023
·
IF 2.4
Ce XU,Jiahui HAN,Di JIA,Jimin CAI,Jianming YUAN,Xin GE
Increasing studies have suggested that oxidative stress and inflammation play momentous roles in acute pulmonary embolism (APE). Honokiol, a bioactive biphenolic phytochemical substance, is known for its strong anti-oxidative and anti-inflammatory effects and here serves as an activator of sirtuin3 (SIRT3). The purposes of the study are to explore the effects of Honokiol on APE rats, and investigate whether the function of Honokiol is mediated by SIRT3 activation. In this study, the rats received a right femoral vein injection with dextran gel G-50 particles (12 mg/kg) to establish the APE model, which were administrated with Honokiol and/or selective SIRT3 inhibitor 3- (1H-1, 2, 3-triazol-4-yl) pyridine (3-TYP; 5 mg/kg) intraperitoneally. The data showed that SIRT3 activation by Honokiol attenuated the loss in lung function, ameliorated inflammatory response and oxidative damage as well as inhibited apoptosis in lung tissues of the rats with APE, which was reversed by 3-TYP. In addition, we found AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway might be activated by Honokiol but restrained by 3-TYP. These results indicated that Honokiol was capable of suppressing APE’s adverse effects, which was diminished by SIRT3 suppression, implying that activation of SIRT3 might serve as a therapeutic method for APE.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Meng Chen,Qilan Hu,Shengquan Wang,Ling Tao,Xiaoxia Hu,Xiangchun Shen
Our previous data confirmed that 1,8-Cineole had an antihypertensive effect in animal models. However, it is unclear whether antihypertension is dependent on the protective effect of 1,8-Cineole on endothelial function and structure. At present, the purpose was to investigate the protective effects of 1,8-Cineole on vascular endothelial tissue in hypertensive rats and human umbilical vein endothelial cells (HUVECs). Our results showed that 1,8-Cineole significantly reduced the blood pressure and improved the vascular endothelial lesion , attenuated vascular oxidative stress and inflammation induced by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) in rats. Pretreatment with 1,8-Cineole was able to inhibit the increase in malondialdehyde (MDA) and reactive oxygen species (ROS) induced by L-NAME, and increased the release and expression of superoxide dismutase (SOD) and nitric oxide (NO). In addition, 1,8-Cineole also reversed the increase of autophagy-associated protein LC3Ⅱ/LC3Ⅰ and the decrease of P62 in vivo and in vitro respectively. There was a synergistic effect between PI3K agonists and drugs, while PI3K inhibitors blocked the efficacy of 1,8-Cineole. The addition of autophagy inhibitor chloroquine increases the expression of eNOS. Taken together, our results indicate that 1,8-Cineole has potential beneficial promising antihypertension depending on the integrity of vascular endothelial structure and function induced by L-NAME, and the mechanism involves ameliorating autophagy by regulating of PI3K/mTOR.
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BIOORGANIC CHEMISTRY
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2023
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IF 5.1
Ren-Fen Ma,Hu Liu,Xue-Chun Zhao,Peipei Shan,Ping Sun,Jun-Juan Xue,Guodong Wei,Hua Zhang
Phytochemical investigation into the leaves and branches of Daphne genkwa afforded 25 meroterpenoids ( 1 – 16 ) including nine pairs of enantiomers ( 1a / 1b − 8a / 8b and 12a / 12b ), among which 20 compounds have been reported in the present work for the first time. The structures with absolute configurations of the new molecules (excluding 10 – 13 ) were established via comprehensive spectroscopic analyses especially electronic circular dichroism (ECD) and Mosher’s methods. A preliminary in vitro cell viability assay revealed remarkable cytotoxicities of selective compounds against A549 (lung), Hela (cervical), MDA-MB231 (breast) and MCF-7 (breast) cancer cells, and compound 8a showed the best inhibitory activity with IC 50 values in the range of 3.12–4.67 μM toward the four cell lines. Subsequent in vitro antitumor evaluation of 8a disclosed that it could inhibit the proliferation and metastasis, as well as induce significant apoptosis and cycle arrest, of A549 cells. Further mechanistic investigations revealed that 8a could exert its antitumor activity via inhibiting the PI3K/Akt/mTOR signaling pathway.
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Materials Today Bio
·
2022
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IF 10.761
Lili Liu,Xianjing Li,Wenhuan Bu,Nianqiang Jin,Yuan Meng,Yi Wang,Duan Wang,Xiaowei Xu,Ding Zhou,Hongchen Sun
Pulp injury is one of the most common clinical diseases, and severe cases are usually associated with the functional loss of the tooth, while the current clinical treatment modality is only a cavity filling procedure without the regeneration of the dentin-pulp complex, thus leading to a devitalized and brittle tooth. In this study, carbon dots (CDots) with excellent biocompatibility are prepared from ascorbic acid and polyethyleneimine via a hydrothermal method. The as-prepared CDots can enhance extracellular matrix (ECM) secretion of human dental pulp stem cells (DPSCs), giving rise to increased cell adhesion on ECM and a stronger osteogenic/odontogenic differentiation capacity of DPSCs. Further, the mechanism underlying CDots-enhanced ECM secretion is revealed by the transcriptome analysis, Western blot assay and molecular dynamics simulation, identifying that the pharmacological activities of CDots are originated from a reasonable activation of the autophagy, which is mediated by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Based on the abundant CDots-induced ECM and thereby the reinforcement of the cell-ECM adhesion, an intact dental pulp stem cell sheet can be achieved, which in return promote in vivo the efficient regeneration of dentin-pulp complex as well as blood vessels.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Wang Xueqin,Xiong Tiandi,Cui Miao,Li Na,Li Qin,Zhu Li,Duan Shaofeng,Wang Yunlong,Guo Yuqi
Background Multidrug resistance (MDR) is the main challenge of successful chemotherapy for ovarian cancer patients, with 50% to 75% of ovarian cancer patients eventually relapsed due to it. One of the effective strategies for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed by using gold nanorods coated with functionalized mesoporous silica nanoparticles (HA-PTX/let-7a-GNR@MSN) for combined delivery of hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. Furthermore, we also analyzed the molecular mechanism of this nanotherapeutic system in the treatment of ovarian cancer.Results HA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3TR cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. The nanosystem realized the stable combination and protective transportation of PTX and miRs. Analysis of drug-resistant SKOV3TR cells and an SKOV3TR xenograft model in BALB/c-nude mice showed significant downregulation of P-glycoprotein in heterogeneous tumor sites, PTX release, and subsequent induction of apoptosis. More importantly, this nanosystem could synergistically inhibit the growth of ovarian tumors. Further studies suggest that mTOR-mediated signaling pathways play an important role in reversing drug resistance and inducing apoptosis.Conclusion sTo sum up, these data provide a model for overcoming PTX resistance in ovarian cancer.Graphical Abstract
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Journal of Animal Science and Biotechnology
·
2023
·Vol. 14
·期 1
·1-17
·
IF 7
He Zhaoqi,Zhao Caijun,He Yuhong,Liu Zhuoyu,Fan Guyue,Zhu Kun,Wang Yiqi,Zhang Naisheng,Fu Yunhe,Hu Xiaoyu
Background Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety. Our previous study found that the body has a gut/rumen-mammary gland axis and that disturbance of the gut/rumen microbiota could result in ‘gastroenterogenic mastitis’. However, the mechanism has not been fully clarified. Recently, we found that long-term feeding of a high-concentrate diet induced mastitis in dairy cows, and the abundance of Stenotrophomonas maltophilia (S. maltophilia) was significantly increased in both the rumen and milk microbiota. Accordingly, we hypothesized that ‘gastroenterogenic mastitis’ can be induced by the migration of endogenous gut bacteria to the mammary gland. Therefore, this study investigated the mechanism by which enterogenic S. maltophilia induces mastitis.Results First, S. maltophilia was labelled with superfolder GFP and administered to mice via gavage. The results showed that treatment with S. maltophilia promoted the occurrence of mastitis and increased the permeability of the blood-milk barrier, leading to intestinal inflammation and intestinal leakage. Furthermore, tracking of ingested S. maltophilia revealed that S. maltophilia could migrate from the gut to the mammary gland and induce mastitis. Subsequently, mammary gland transcriptome analysis showed that the calcium and AMPK signalling pathways were significantly upregulated in mice treated with S. maltophilia. Then, using mouse mammary epithelial cells (MMECs), we verified that S. maltophilia induces mastitis through activation of the calcium-ROS-AMPK-mTOR-autophagy pathway.Conclusion sIn conclusion, the results showed that enterogenic S. maltophilia could migrate from the gut to the mammary gland via the gut-mammary axis and activate the calcium-ROS-AMPK-mTOR-autophagy pathway to induce mastitis. Targeting the gut-mammary gland axis may also be an effective method to treat mastitis.
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