Bioactive Materials
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2024
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IF 18
Lili Sun,Haoyi Niu,Yuqiong Wu,Shiyan Dong,Xuefeng Li,Betty Y.S. Kim,Changsheng Liu,Yifan Ma,Wen Jiang,Yuan Yuan
Repair of large bone defects caused by severe trauma, non-union fractures, or tumor resection remains challenging because of limited regenerative ability. Typically, these defects heal through mixed routines, including intramembranous ossification (IMO) and endochondral ossification (ECO), with ECO considered more efficient. Current strategies to promote large bone healing via ECO are unstable and require high-dose growth factors or complex cell therapy that cause side effects and raise expense while providing only limited benefit. Herein, we report a bio-integrated scaffold capable of initiating an early hypoxia microenvironment with controllable release of low-dose recombinant bone morphogenetic protein-2 (rhBMP-2), aiming to induce ECO-dominated repair. Specifically, we apply a mesoporous structure to accelerate iron chelation, this promoting early chondrogenesis via deferoxamine (DFO)-induced hypoxia-inducible factor-1α (HIF-1α). Through the delicate segmentation of click-crosslinked PEGylated Poly (glycerol sebacate) (PEGS) layers, we achieve programmed release of low-dose rhBMP-2, which can facilitate cartilage-to-bone transformation while reducing side effect risks. We demonstrate this system can strengthen the ECO healing and convert mixed or mixed or IMO-guided routes to ECO-dominated approach in large-size models with clinical relevance. Collectively, these findings demonstrate a biomaterial-based strategy for driving ECO-dominated healing, paving a promising pave towards its clinical use in addressing large bone defects.
研究领域:
组织工程
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骨再生
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生物材料
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骨科
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PubMed
高影响因子
TOXICOLOGY LETTERS
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2018
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IF 3.166
Yisen Cheng,Gaojian Chen,Li Wang,Jiamin Kong,Ji Pan,Yue Xi,Feihai Shen,Zhiying Huang
Triptolide is a major active ingredient of tripterygium glycosides, used for the therapy of immune and inflammatory diseases. However, its clinical applications are limited by severe male fertility toxicity associated with decreased sperm count, mobility and testicular injures. In this study, we determined that triptoide-induced mitochondrial dysfunction triggered reduction of lactate and dysregulation of fatty acid metabolism in mouse Sertoli cells. First, triptolide induced mitochondrial damage through the suppressing of proliferator-activated receptor coactivator-1 alpha (PGC-1α) activity and protein. Second, mitochondrial damage decreased lactate production and dysregulated fatty acid metabolism. Finally, mitochondrial dysfunction was initiated by the inhibition of sirtuin 1 (SIRT1) with the regulation of AMP-activated protein kinase (AMPK) in Sertoli cells after triptolide treatment. Meanwhile, triptolide induced mitochondrial fatty acid oxidation dysregulation by increasing AMPK phosphorylation. Taken together, we provide evidence that the mechanism of triptolide-induced testicular toxicity under mitochondrial injury may involve a metabolic change.
研究领域:
药理学
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毒理学
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生殖生物学
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细胞代谢
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PubMed
高影响因子
ACS Biomaterials Science & Engineering
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2019
·
IF 4.511
Lingna Deng,Fang Zhang,Yanlin Wu,Jiahao Luo,Xuhong Mao,Lingli Long,Maling Gou,Liqun Yang,David Y. B. Deng
Studies have shown that the use of proangiogenic genes can improve the prognosis of ischemic stroke by promoting angiogenesis at the injury site. For example, within this study, hypoxia-inducible factor 1-α (HIF-1α) has exhibited an angiogenic effect. Our previous study reported a more stable HIF-1α mutant form (HIF-1α-AA), which was transfected into mesenchymal stem cells to provide neuroprotective effects against ischemic stroke. The safety of nonviral gene vectors has attracted researchers’ attention. This study encapsulated the HIF-1α-AA plasmid DNA into a newly synthesized effective nonviral gene vector, a hyperbranched cationic amylopectin derivative (DMAPA-Amyp) nanocarrier. In addition, a targeting strategy was applied to select the RGD peptides and bind to the designed nanocarrier as a molecule targeting endothelial cells. The targeting strategy is used to directly deliver the nanocarriers to the vascular endothelial cells of the brain peri-infarct site. This study emphasizes the targeting ability of nanocarrier and its therapeutic effect on cerebral ischemia. The results showed that RGD-DMAPA-Amyp had good biocompatibility and a high cell uptake rate, indicating that it is a safe nonviral gene vector that can be endocytosed by human cells. In rat models of ischemic stroke, compared with the nontargeted nanocarrier group, more RGD-DMAPA-Amyp nanoparticles aggregated in vascular endothelial cells of the peri-infarct region and significantly improved the recovery of neurological function. It is indicated that the RGD-modified nanomedicine promotes the recovery of nerve function more efficiently. Further study on the mechanism of RGD-DMAPA-Amyp/HIF-1α-AA in the treatment of cerebral ischemia displayed potential to significantly promote the formation of new blood vessels in vivo. Our findings suggest that the RGD-modified nonviral gene vector containing HIF-1α-AA appears to be a safe and promising therapeutic strategy for ischemic stroke gene therapy.
研究领域:
神经科学
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分子生物学
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基因治疗
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药学
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PubMed
高影响因子
Theranostics
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2018
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IF 8.537
Feng Zhang,Shuai Lu,Jianlin He,Huanhuan Jin,Feixia Wang,Li Wu,Jiangjuan Shao,Anping Chen,Shizhong Zheng
Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl 4 for evaluating ligustrazine's effects in vivo . Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl 4 -induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Sheng Ding,Siyu Liu,Shaoyang Kang,Shuwei Wang,Nan Jiang,Yuwei Li,Chunxiao Zhou,Hantao Lou,Chuangnian Zhang,Pingsheng Huang,Wenshuai Liu,Zujian Feng,Weiwei Wang,Deling Kong,Ningbei Yin
Diabetic wound healing poses a major clinical challenge. One of the promising therapy, the flap transplantation surgery exhibited unsatisfactorily low flap survival due to the intertwined pathological barriers: impaired angiogenesis, excessive oxidative stress, and persistent inflammation, leading to poor tissue repair. While the therapeutic platforms based on extracellular vesicles (EVs) emerges as a promising treatment, its efficacy is often limited by the inadequate yield and rapid in vivo clearance. To address this challenge, this study developed a strategy centered on preconditioning human umbilical vein endothelial cells (HUVECs) with high glucose (HG) stress to produce HG-preconditioned extracellular vesicles (hEVs), which significantly improve production, enrich regenerative cargoes (e.g., HIF-1α, VEGF), and enhance homologous cellular internalization. The hEVs derived from HUVECs were encapsulated by microfluidically fabricated gelatin methacryloyl (GelMA) microgels to create GelMA@hEVs. The biodegradable and biocompatible GelMA microgels enabled a sustained hEVs release profile. Therefore, GelMA@hEVs exhibited significant efficacy improvement in promoting endothelial cell proliferation, migration, and tube formation critical for vascularization, mitigating reactive oxygen species, and modulating macrophage polarization toward a pro-reparative phenotype. Mechanistically, these therapeutic effects relied on activating the HIF-1α/VEGF pathway, a core axis for angiogenesis dysregulated in diabetes. In diabetic ischaemic flap models, GelMA@hEVs significantly improved flap survival, restored vascular perfusion, and facilitated tissue regeneration without systemic toxicity. Altogether, this work provides a generalizable strategy for diabetic ischaemic flap repair by combining engineered EVs as bioactive cargo with a microgel scaffold for sustained delivery, offering a promising in situ tissue engineering solution.
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ACS Applied Materials & Interfaces
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2026
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IF 7.8
Xin Zhang,Zutong Cui,Wenming Liang,Zihan Zhang,Jianming Sun,Liming Gao,Ming Shi,Zhiwei Liu,Kun Li,Jian Li
Phototherapy not only targets tumor cells for destruction but also triggers immunogenic cell death (ICD), thereby activating systemic immunity. Traditional photothermal therapy (PTT), however, damages adjacent normal tissues, and photodynamic therapy (PDT) creates severe hypoxia within tumor tissues, which promotes immune evasion and reduces the effectiveness of immunotherapy. In this study, we developed a biomimetic nanomodulators-cell membrane-coated gambogic acid/indocyanine green micelles loaded with HIF-1α siRNA (CM-IGM/siRNA) to achieve mild photothermal therapy (mPTT), enhance photodynamic therapy (PDT), and modulate the tumor microenvironment (TME). This platform utilizes gambogic acid (GA) to inhibit HSP90 expression and synergizes with HIF-1α siRNA to suppress HIF-1α expression, thereby ameliorating hypoxic and immunosuppressive TME. HSP90 inhibition further reduces tumor cell thermotolerance, enabling effective tumor cell ablation at mild hyperthermia temperatures (42−45 °C) characteristic of mPTT. Furthermore, we found that π–π stacking of GA with indocyanine green (ICG) enhances ICG photostability and boosts reactive oxygen species (ROS) generation. The elevated ROS production significantly improves PDT efficacy and, in combination with mPTT, potentiates the ICD of tumor cells. Overall, this strategy offers a significant advancement in cancer immunotherapy by improving the tumor microenvironment and enhancing immune activation.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Xiaohui Jin,Leilei Zhu,Shuaifei Lu,Caiyin Li,Ming Bai,Erping Xu,Jiduo Shen,Yucheng Li
Mitochondrial dysfunction has been reported to be involved in the pathogenesis of depression, and mitophagy is a key pathway for mitochondrial quality control. This study aimed to investigate the effect of baicalin on mitophagy in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS) and explore its potential mechanism. After exposure to CUMS for 6 weeks, mice were given baicalin (20 mg/kg) or fluoxetine (20 mg/kg) by oral gavage for 4 weeks, and HT22 cells were injured by corticosterone (CORT) in vitro. Depression-like behaviors were assessed by sucrose preference test and tail suspension test . The mitochondrial structure was observed by transmission electron microscopy . Detection of mitophagy and mitophagy-related protein by mitophagy kit and Western blot . The results showed that baicalin improved depressive-like behaviors in CUMS mice, and ameliorated mitochondrial structural impairment in the hippocampus neuron. Baicalin significantly down-regulated light chain 3(LC3)II/I, protein sequestosome 1 (P62), and translocase of the outer membrane 20 (TOM20), and up-regulated Nip-like protein (NIX), Adenylate activated protein kinase (AMPK), and Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α. Furthermore, molecular docking showed that baicalin interacts with AMPK through hydrogen bonding. Baicalin increased NIX and AMPK, and improved mitophagy level and mitochondrial function in HT22 cells. Treatment with Phorbol 12-Myristate 13-acetate demonstrated that up-regulation of NIX ameliorated CORT-induced mitochondrial dysfunction in HT22 cells. In conclusion, the present study suggested that the antidepressant effect of baicalin may be related to the enhancement of NIX-mediated mitophagy through activating the AMPK/PGC-1α pathway by directly binding to AMPK.
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Scientific Reports
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2024
·Vol. 14
·期 1
·1-13
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IF 3.8
Zhu Dongsheng,Chen Feng,Qiang Hongjia,Qi Han
To clarify the impact of SETD2 on macrophage function in pediatric patients with acute suppurative osteomyelitis and to elucidate the precise underlying mechanism. To gain insights into the potential functions of SETD2, a comprehensive study was conducted utilizing a co-culture model of human bone mesenchymal stem cells (hBMSCs) and bone marrow-derived macrophages (THP-1). A range of techniques were employed, including quantitative polymerase chain reaction, western blotting, ELISA, alkaline phosphatase activity assays, alizarin red S staining, luciferase reporter gene assays, and chromatin immunoprecipitation, to unravel the intricate interactions and molecular mechanisms involving SETD2 in this system. It was observed that SETD2 expression was reduced in THP-1 cells stimulated by staphylococcal protein A (SPA). Furthermore, the downregulation of SETD2 resulted in elevated M1 macrophage polarization and glycolysis, effects that were mitigated by SPA stimulation. Notably, SPA-stimulated THP-1 cells exhibited an increase in HIF-1α expression, which exhibited an inverse correlation with SETD2 levels. Moreover, it was discovered that SETD2 functioned as a catalyst for H3K36me3 and bound to the HIF-1α gene, which, in turn, regulated HIF-1α expression. Furthermore, the suppression of HIF-1α abrogated the consequences of SETD2 downregulation on glycolysis and M1 macrophage polarization. Lastly, the study demonstrated that M1 macrophage polarization serves as a mediator for BMP4’s inhibitory effect on osteogenic differentiation of hBMSCs. This research has uncovered a previously unknown role of SETD2 in macrophages during osteomyelitis, revealing its significance in the pathogenesis of this condition. These findings suggest SETD2 as a novel target for the treatment of osteomyelitis.
研究领域:
免疫学
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分子生物学
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细胞生物学
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骨科
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PubMed
高影响因子
Molecular Medicine Reports
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2019
·Vol. 19
·期 4
·2758-2766
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IF 1.851
Ya Hou,Xiaobo Wang,Xiaorui Chen,Jing Zhang,Xiaopeng Ai,Yusheng Liang,Yangyang Yu,Yi Zhang,Xianli Meng,Tingting Kuang,Yao Hu
This study was conducted to establish a stable hypobaric hypoxia brain injury model. SD rats were randomly separated into control and model groups, and placed outside or inside of a hypobaric chamber, respectively. Subsequent to 24 h anoxic exposure, plasma superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG) and lactate dehydrogenase (LDH) were measured using commercial biochemical kits. Hematoxylin‑eosin (H&E), Nissl's and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to observe the morphology of neurons in the hippocampus. The protein expression levels of apoptotic protease activating factor‑1 (Apaf‑1), hypoxia inducible factor‑1α (HIF‑1α), caspase‑3, cleaved caspase‑3, Bcl‑2‑associated X protein (Bax) and cytochrome c (cyto‑c) were detected using western blot and immunohistochemistry analyses. Hypoxic substantially induced morphological lesions in the hippocampus concomitant with the physical behavioral performance deficit. Furthermore, hypoxia markedly exacerbated the levels of MDA, LDH and GSSG, and restrained GSH (P<0.01) and SOD (P<0.05) levels compared with the control group. In addition, hypoxia significantly induced the protein expression of Apaf‑1, HIF‑1α, caspase‑3, cleaved caspase‑3, Bax and Cyto‑c (P<0.01) compared with the control group. Finally, a lower number and volume of Nissl bodies were verified in the hypoxic group. TUNEL results demonstrated a greater number of apoptotic cells in the hypoxic group. The present study demonstrates a model of rat hypoxic brain injuries induced by a hypobaric chamber at 9,000 m for 24 h. Furthermore, the redox enzyme, HIF‑1α and mitochondrial apoptosis‑associated protein, along with H&E and Nissl's staining, may be applied to evaluate the degree of injury.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
Biology-Basel
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2026
·Vol. 15
·期 13
·999
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IF 4.3
Xiang Li,Bo Tian,Yuxin Chen,Huili Tong,Xiaoming Chen,Zhifeng Cheng
Simple SummaryType 2 diabetes (T2DM) often leads to skeletal muscle loss and weakness, a condition called sarcopenia, which worsens human health. This study explored whether carnosine, a natural dipeptide found in meat and present in human muscle, can help protect against muscle wasting. Using a T2DM sarcopenia mouse model and a high-glucose-treated C2C12 myotube in vitro model, the researchers found that carnosine levels were reduced in T2DM sarcopenia muscles. Oral carnosine supplementation in the mice helped alleviate skeletal muscle atrophy. Carnosine works by activating a cellular signaling pathway that boosts the number of mitochondria (the energy powerhouses of cells) and shifts muscle fibers toward a more oxidative type, leading to stronger and healthier muscles in T2DM sarcopenia mice. These findings suggest that carnosine supplementation could be a simple and promising nutritional strategy to help manage skeletal muscle loss in people with type 2 diabetes, though further studies in humans are needed to confirm its effectiveness.Type 2 diabetes mellitus (T2DM) accounts for over 90% of diabetes cases, and T2DM-related sarcopenia is a growing concern. Carnosine, abundant in human skeletal muscle, helps maintain muscle quality and function. This study investigated whether carnosine deficiency contributes to T2DM-related sarcopenia and whether exogenous carnosine supplementation alleviates muscle atrophy. A mouse model of T2DM sarcopenia was established using streptozotocin combined with a high-fat diet. LC-MS metabolomics revealed a significant reduction in carnosine content in the gastrocnemius muscle of model mice. A C2C12 myotube atrophy model was induced by high-glucose (HG), and qRT-PCR showed altered expression of carnosine metabolism-related enzymes, suggesting disrupted carnosine homeostasis under T2DM conditions. Mechanistic investigations using immunofluorescence, Western blotting, transcriptome sequencing, mitochondrial staining, and molecular docking indicated that carnosine may alleviate high-glucose-induced myotube atrophy through the PI3K/AMPK/PGC-1α signaling pathway. In vivo, carnosine supplementation increased the number of mitochondria and the proportion of slow muscle fibers in gastrocnemius muscle, ameliorating the atrophic phenotype. These findings suggest that carnosine has potential as a candidate for intervention in T2DM-related sarcopenia, though further validation of its direct molecular targets is required.
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PHYTOMEDICINE
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2026
·
IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Yangwei Xiang,Qin Wang,Ke Zhou,Weili Han
Phthalate esters (PAEs), widely used as plastic additives in consumer products such as food packaging, can be metabolized to phthalic acid (PTA) in vivo . However, the potential contribution of PTA to respiratory fibrotic processes remains poorly understood. In this study, we investigated the effects and underlying mechanisms of PTA on pulmonary fibrogenesis using human lung fibroblast IMR-90 cells chronically exposed to environmentally relevant concentrations of PTA (0–60 μg/L) for 14 days. PTA exposure promoted pro-fibrotic responses and cellular senescence, as evidenced by increased expression of fibrosis-associated markers, enhanced senescence-associated β-galactosidase activity, and upregulation of CDKN2A . Proteomic profiling and functional perturbation experiments further implicated the IL-1α/NF-κB/SASP signaling axis in these responses. PTA-induced senescence and pro-fibrotic effects were attenuated by inhibition of NF-κB signaling and IL-1 signaling, supporting the functional involvement of this pathway. In a bleomycin-induced progressive pulmonary fibrosis model, subsequent PTA exposure further aggravated collagen deposition and increased the pulmonary expression of fibrosis-, senescence-, and Il-1a/Nf-κb -associated genes, providing in vivo support for the biological relevance of the pathway identified in vitro . Molecular docking additionally predicted a potential interaction between PTA and IL-1α. Therefore, these findings offer novel mechanistic insights into environmental pollutant-induced fibrogenesis. Download: Download high-res image (131KB) Download: Download full-size image
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