PHYTOMEDICINE
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2025
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IF 8.3
Meng Zhang,Rui Liu,Ting Zhou,Yuxin Guo,Hui Li,Wei Wu
Background Chronic fatigue syndrome (CFS) is a crippling illness with limited effective treatment options. Recent findings have suggested that ginseng stem and leaf saponins (GSLS) possess anti-fatigue effects. However, the detailed mechanisms by which GSLS impact CFS have yet to be fully elucidated. Purpose This study aimed to explore the efficacy and underlying mechanisms of GSLS in the treatment of peripheral and central fatigue in mice with CFS. Methods A CFS model was established in male C57BL/6 mice, which were then subjected to prolonged swimming tests. The validity of this model and the efficacy of GSLS were verified using the forced exhaustion swimming test and the Morris water maze test. The anti-fatigue mechanism of GSLS was verified using pathological section observations, biochemical index tests, neurotransmitter analysis, and Ultra-high performance liquid chromatography–high-resolution mass spectrometry (UHPLC-MS) metabolomics analysis. Results GSLS prolonged the swim time-to-exhaustion in CFS mice and reduced escape latency in the water maze, revealing their anti-fatigue and memory-improving effects. GSLS significantly protected both peripheral (liver) and central (hippocampus) tissues, as shown in pathological sections. Biochemical indices suggested that GSLS mitigate peripheral fatigue by reducing energy expenditure and oxidative damage and inhibiting the production of harmful metabolites. Furthermore, GSLS altered the abnormal levels of 14 neurotransmitters in the brains of CFS mice, including seven upregulated and seven downregulated neurotransmitters, highlighting their role in mitigating central fatigue through neurotransmitter regulation. Serum metabolomics analysis identified alterations in 19 metabolites across 11 metabolic pathways, thereby elucidating the potential mechanisms by which GSLS treat CFS. Conclusion GSLS ameliorate damage caused by both peripheral and central fatigue. They also act on multiple pathogenic mechanisms by modulating neurotransmitters and serum biomarkers, making them a potential therapeutic agent for CFS.
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BMC Oral Health
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2024
·Vol. 24
·期 1
·1-15
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IF 2.6
Zou Yin,Mei Xue,Wang Xinhe,Zhang Xuan,Wang Xun,Xiang Wen,Lu Naiyan
Background Effective treatments for the alveolar bone defect remain a major concern in dental therapy. The objectives of this study were to develop a fibrin and konjac glucomannan (KGM) composite hydrogel as scaffolds for the osteogenesis of nasal mucosa-derived ectodermal mesenchymal stem cells (EMSCs) for the regeneration of alveolar bone defect, and to investigate the osteogenesis-accelerating effects of black phosphorus nanoparticles (BPNs) embedded in the hydrogels.Methods Primary EMSCs were isolated from rat nasal mucosa and used for the alveolar bone recovery. Fibrin and KGM were prepared in different ratios for osteomimetic hydrogel scaffolds, and the optimal ratio was determined by mechanical properties and biocompatibility analysis. Then, the optimal hydrogels were integrated with BPNs to obtain BPNs/fibrin-KGM hydrogels, and the effects on osteogenic EMSCs in vitro were evaluated. To explore the osteogenesis-enhancing effects of hydrogels in vivo, the BPNs/fibrin-KGM scaffolds combined with EMSCs were implanted to a rat model of alveolar bone defect. Micro-computed tomography (CT), histological examination, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were conducted to evaluate the bone morphology and expression of osteogenesis-related genes of the bone regeneration.Results
The addition of KGM improved the mechanical properties and biodegradation characteristics of the fibrin hydrogels. In vitro, the BPNs-containing compound hydrogel was proved to be biocompatible and capable of enhancing the osteogenesis of EMSCs by upregulating the mineralization and the activity of alkaline phosphatase. In vivo, the micro-CT analysis and histological evaluation demonstrated that rats implanted EMSCs-BPNs/fibrin-KGM hydrogels exhibited the best bone reconstruction. And compared to the model group, the expression of osteogenesis genes including osteopontin (Opn, p < 0.0001), osteocalcin (Ocn, p < 0.0001), type collagen (Col , p < 0.0001), bone morphogenetic protein-2 (Bmp2, p < 0.0001), Smad1 (p = 0.0006), and runt-related transcription factor 2 (Runx2, p < 0.0001) were all significantly upregulated.Conclusion s
EMSCs/BPNs-containing fibrin-KGM hydrogels accelerated the recovery of the alveolar bone defect in rats by effectively up-regulating the expression of osteogenesis-related genes, promoting the formation and mineralisation of bone matrix.
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Advanced Healthcare Materials
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2024
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IF 10
Bo Ma,Fangye Chen,Xin Liu,Yang Zhang,Shuangquan Gou,Qianxiang Meng,Peng Liu,Kaiyong Cai
The application of titanium (Ti) implants for patients with diabetes mellitus (DM) is still facing a significant challenge due to obstacles such as hyperglycemia, reactive oxygen species (ROS), and chronic inflammation, which hinders osseointegration. To address this issue, a Ti implant with dual functions of regulating polarization of macrophages and facilitating osseointergration is developed via hydrothermal reaction and hydrogel coating. The reactive oxygen species (ROS) and glucose (Glu) responsive hydrogel coating can locally deliver adenosine (ADO) in the early stage of implantation. The controlled release of ADO regulated the phenotype of macrophages, restored oxidative balance, and enhanced mitochondrial function during the early stages of implantation. Subsequently, strontium (Sr) ions will be released to promote osteogenic differentiation and proliferation of mesenchymal stem cells (MSCs), as the hydrogel coating degraded. It eventually leads to bone reconstruction during the late stages, aligning with the biological cascade of bone healing. The modified Ti implants showed effective osteogenesis for bone defects in DM patients, shedding light on the design and biological mechanisms of surface modification. This research offers promising potential for improving the treatment of bone-related complications in diabetic patients.
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Cell Death & Disease
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2018
·Vol. 9
·期 3
·1-15
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IF 5.638
Ding Yue,Liang Xiaoting,Zhang Yuelin,Yi Li,Shum Ho Cheung,Chen Qiulan,Chan Barbara P.,Fan Huimin,Liu Zhongmin,Tergaonkar Vinay,Qi Zhongquan,Tse Hung-fat,Lian Qizhou
Immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. Our previous studies showed that activation of nuclear factor-kappa B (NF-κB) regulates cytokine/growth factor secretion by MSCs. This study aimed to elucidate the role of Rap1 (repressor/activator protein), a novel modulator involved in the NF-κB pathway, in regulating the immunomodulatory potency of MSCs in acute allograft rejection of heart transplantation. The immunosuppressive potency of wild-type MSCs (WT-MSCs) or Rap1-deficient MSCs (Rap1 −/− -MSCs) was examined in mice with acute allograft rejection following heart transplantation. With a combination of immunosuppressant rapamycin at a dose of 1 mg/kg/d, WT-MSCs notably prolonged the survival of the transplanted heart compared with Rap1 −/− -MSCs. Rap1 −/− -MSCs displayed a marked insensitivity to inhibit the mixed lymphocyte reaction (MLR) due to impaired cytokine production and a significantly reduced activity of NF-κB signaling in vitro . Finally, transplantation of encapsulated WT-MSCs greatly prolonged the survival of the heart allograft compared with encapsulated Rap1 −/− -MSCs. Our results indicate that Rap1 is essential to maintain the immunomodulatory function of MSCs. Deletion of Rap1 results in impaired immunomodulatory function of MSCs.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Qingyu Yu,Huizhong Hao,Weitong Wang,Linhua Zhang,Chenlu Huang,Jianying Hao,Xinyu Yang,Dunwan Zhu,Junjie Li,Hong Sun
Due to the utilization of well-defined artificial niches, stem cell culture in a three-dimensional hydrogel matrix has been a promising method for obtaining sufficient seed cells. Although various hydrogels can support desirable cell proliferation, establishing a normalized hydrogel that adequately mimics the extracellular matrix (ECM), maintains stemness and allows for controlled release of stem cells remains a significant challenge. Herein, we report a hydrogel composed of sulfobetaine-modified dextran and gelatin to maintain stemness and enable the rapid release of adipose-derived stem cells (ADSCs). Dextran can effectively maintain multipotent phenotype of ADSCs by grafting zwitterionic groups. Gelatin can significantly improve the proliferation of ADSCs. The hydrogel network they form effectively mimics the ECM microenvironment, providing an advantage when used as a three-dimensional niche to promote cell proliferation. Most importantly, the disulfide-crosslinked hydrogels show specific photodegradation capability, which precisely enables the system to achieve controlled release and efficient harvest of ADSCs. The cell viability (90 %) and harvest ratio (64 %) were well maintained by light degradation compared with GSH and collagenase degradation. Overall, this study offers a universal stem cell niche based on photodegradable hydrogel that shows great promise in the field of ADSCs proliferation and harvest.
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Discover Oncology
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2024
·Vol. 15
·期 1
·1-15
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IF 2.8
Li Weinan,Fu Yuhan,Sun Jialin,Gong Hexin,Yan Ru,Wang Yanhong
Breast cancer is a major threat to safety and health of women. The breast cancer stem cells (BCSCs) have multi-drug resistance to chemotherapy drugs, which leads to chemotherapy failure. We proposed a strategy of delivery of tumor-killing drugs and a resistance reversal agent, to enhance inhibition of BCSCs. Here, schisandrin B (SchB)/AP NPs are constructed using acid-grafted-poly (β-amino ester) (ATRA-g-PBAE, AP) grafted polymer nanoparticle encapsulated SchB, with pH-sensitive release function. This drug delivery system has good pharmacological properties and can increase the SchB release with the decrease of pH. The NPs showed cytotoxic effects in reversing ATRA resistance to BCSCs. Lysosomal escape was achieved when the nanoparticles were taken up by BCSCs. In addition, we found that NPs may reverse MDR by inhibiting the expression of P-glycoprotein (P-gp) and affecting the energy supply of drug efflux. This study provides a nanodelivery therapy strategy that reverses BCSCs multidrug resistance (MDR) and demonstrates that it did so by interfering with cancer cell energy metabolism. Therefore, the co-delivery strategy of ATRA and SchB provides a new option for the treatment of breast cancer.
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Liuxin Yang,Fengya Jing,Dandan Wei,Xiaocong Zhao,Yinghua Tao,Tao Liu,Tianzhu Zhang
Abdominal wall defects caused by trauma, congenital rupture, and intra-abdominal infection remain challenging due to the large wound area and complex complications. Herein, an assembled mesenchymal stem cell (MSCs)-laden granular hydrogel (termed assembled GSD@FPs), loaded with basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF), is developed. This hydrogel is constructed through dynamic covalent cross-linking ( via borate ester bonds) among dopamine-grafted gelatin methacrylamide (GelMA-DA), phenylborate-modified hyaluronic acid (HA-PBA), and epigallocatechin-3-gallate (EGCG), serving as multifunctional bulk building blocks for cell delivery and abdominal wall repair. The designed assembled granular hydrogels possess good rheological properties, self-healing, injectability, and tissue-adhesion properties. Detailed in vitro cell experiments are conducted, revealing that the GSD@FPs granular hydrogels can effectively promote cell proliferation, cell migration and angiogenesis. Furthermore, in abdominal wall defects, assembled GSD@FPs significantly accelerates the tissue healing process by simultaneously inhibiting the inflammatory response, promoting collagen deposition, and promoting cell proliferation and angiogenesis. Importantly, the assembled GSD@FPs granular hydrogels can also provide mechanical support and increase the thickness of regenerated tissue (1727.8 ± 169.6 μm for the control group, 3204.2 ± 278.5 μm for the assembled GSD@FPs group at 14 d). Eventually, the GSD granular hydrogels biodegraded, facilitating tissue remodeling and generating new muscle tissues. Therefore, this study provides a promising strategy with great potential for application in abdominal wall repair.
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Acta Biomaterialia
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2024
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IF 9.4
Jintao Zhong,Wenhua Li,Hetong Li,Jin Zhang,Zuoxu Hou,Xiao Wang,Enhui Zhou,Ke Lu,Weida Zhuang,Hongxun Sang
The periosteum, a highly specialized thin tissue, is instrumental in contributing to as much as 70% of early bone formation. Recognizing the periosteum's vital physiological roles, the fabrication of a biomimetic periosteum has risen as an auspicious strategy for addressing extensive bone defects. In the study, we obtained such biomimetic periosteum by utilizing periosteum-derived stem cells (PDSCs) spheroids. These spheroids are induced to spontaneously generate a bioactive membrane on a delicate 3D-printed polycaprolactone (PCL) substrate. This process yields a biomimetic periosteum rich in the resources needed for bone repair. The in vitro evaluations demonstrated that this membrane can act as a repository for growth factors and stem cells. The release kinetics confirmed a sustained delivery of BMP-2 and VEGF, which promoted enhanced osteogenesis and angiogenesis in vitro , respectively. The in vivo results further highlighted robust bone regeneration from critical cranial defects upon the application of this biomimetic periosteum. The biomimetic periosteum, easily harvested and potent in bioactivity, presents substantial clinical potential, particularly for the treatment of critical-sized bone defects. Statement of Significance PDSC theoretically demonstrates substantial potential in membrane construction, a value we've harnessed in this pioneering application. By employing cell spheroids, we've successfully integrated a substantial number of cells into the membrane framework. PDSC spheroids exhibit the remarkable ability to self-assemble into functional membranes, endowing them with robust biological capabilities that enhance their performance in biological systems. The in vitro evaluations demonstrated that this membrane can act as a repository for growth factors and stem cells. The in vivo bone repair facilitated by this membrane is notably effective, characterized by superior bone quality and accelerated formation rates. This process mirrors the natural intramembrane ossification, offering a promising approach to bone integration and regeneration.
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Stem Cell Research & Therapy
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2024
·Vol. 15
·期 1
·1-15
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IF 7.1
Zhu Yufan,Liu Xu,Chen Xihang,Liao Yunjun
Background Chronic radiation dermatitis (CRD) is a late consequence of radiation with high incidence in patients receiving radiotherapy. Conventional therapies often yield unsatisfactory results. Therefore, this study aimed to explore the therapeutic potential and mechanism of adipose-derived stem cells (ADSCs) for CRD, paving the way for novel regenerative therapies in clinical practice.Methods Clinical CRD skin biopsies were analyzed to character the pathological changes of CRD skin and guided the animal modeling scheme. Subsequently, an in vivo analysisusing mouse CRD models was conducted to explore their effects of ADSCs on CRD, monitoring therapeutic impact for up to 8 weeks. Transcriptome sequencing and histologic sections analysis were performed to explore the potential therapeutic mechanism of ADSCs. Following observing extensive apoptosis of transplanted ADSCs, the therapeutic effect of ADSCs were compared with those of apoptosis-inhibited ADSCs. Multiphoton imaging and analysis of collagen morphologic features were employed to explain how translated ADSCs promote collagen remodeling at the microscopic level based on the contrast of morphology of collagen fibers.Results Following injection into CRD-afflicted skin, ADSCs therapy effectively mitigated symptoms of CRD, including acanthosis of the epidermis, fibrosis, and irregular collagen deposition, consistent with the possible therapeutic mechanism suggested by transcriptome sequencing. Notably, in vivo tracking revealed a significant reduction in ADSCs number due to extensive apoptosis. Inhibiting apoptosis in ADSCs partially tempered their therapeutic effects. Mechanically, analysis of collagen morphologic features indicated that translated ADSCs might promote dermal extracellular matrix remodeling through enlarging, lengthening, crimping, and evening collagen, counteracting the atrophy and rupture caused by irradiation.Conclusion sThis study demonstrated that ADSCs underwent substantial apoptosis upon local skin transplantation, and paradoxically, this apoptosis is essential for their efficacy in promoting the regeneration of late radiation-impaired skin. Mechanically, transplanted ADSCs could promote the remodeling and rearrangement of radiation-damaged dermal collagen matrix.
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BIOMATERIALS
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2024
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IF 12.8
Chen Xiao,Xing Wang,Shiyou Li,Zhijie Zhang,Jiayuan Li,Qingyuan Deng,Xiang Chen,Xiangliang Yang,Zifu Li
Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.
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SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Hao Sun,Zhazheng He,Yao Gao,Yanhan Yang,Yachang Wang,Aihua Gu,Jin Xu,Yingyi Quan,Yang Yang
The early stage of heart development is highly susceptible to various environmental factors. While the use of animal models has aided in identifying numerous environmental risk factors, the variability between species and the low throughput limit their translational potential. Recently, a type of self-assembling cardiac structures, known as human heart organoids (hHOs), exhibits a remarkable biological consistency with human heart. However, the feasibility of hHOs for assessing cardiac developmental risk factors remains unexplored. Here, we focused on the cardiac developmental effects of core components of Glyphosate-based herbicides (GBHs), the most widely used herbicides, to evaluate the reliability of hHOs for the prediction of possible cardiogenesis toxicity. GBHs have been proven toxic to cardiac development based on multiple animal models, with the mechanism remaining unknown. We found that polyoxyethylene tallow amine (POEA), the most common surfactant in GBHs formulations, played a dominant role in GBHs' heart developmental toxicity. Though there were a few differences in transcriptive features, hHOs exposed to sole POEA and combined POEA and Glyphosate would suffer from both disruption of heart contraction and disturbance of commitment in cardiomyocyte isoforms. By contrast, Glyphosate only caused mild epicardial hyperplasia. This study not only sheds light on the toxic mechanism of GBHs, but also serves as a methodological demonstration, showcasing its effectiveness in recognizing and evaluating environmental risk factors, and deciphering toxic mechanisms.
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Jianhua Wang,Qiang Hou,Jie Qu,Xueping Huo,Huiting Li,Yangmeng Feng,Qiyu Wang,Le Chang,Cuixiang Xu
Gastric cancer is a prevalent malignant tumor worldwide, posing challenges due to its poor prognosis and limited treatment options. Cancer stem cells (CSCs) were demonstrated as a subset of cancer cells responsible for tumor initiation and progression, and their inherent resistance to conventional chemotherapy and radiotherapy critically contributes to tumor recurrence and metastasis. Promoting the eradication of cancer stem cells is crucial for enhancing the efficacy of cancer treatments. This study introduces a novel therapeutic strategy utilizing polyhedral magnetic nanoparticles (PMNPs) functionalized with CD44 antibodies and cell-penetrating peptides (CPPs) to improve uptake by gastric cancer stem cells (MCSCs). PMNPs, synthesized via thermal decomposition, exhibited a diameter of 90 nm ± 9 nm and a saturation magnetization of 79.9 emu/g. Functionalization enhanced their uptake capabilities. Under a rotating magnetic field (RMF) of 15 Hz, PMNPs disrupted cellular structure, leading to apoptosis and ferroptosis in MCSCs. The in vitro studies showed significant reduction in MCSCs viability , while in vivo studies demonstrated tumor growth suppression with minimal side effects and high biocompatibility . This work presents a novel strategy for designing magnetic nanoparticles to mechanically destroy cancer stem cells, offering a more efficient and safety treatment option for gastric cancer.
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