INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Shuo Wei,Feng Xiong,Haonan Gu,Zhuojun Zhang,Hongyun Xuan,Yan Jin,Ye Xue,Biyun Li,Wei Feng,Huihua Yuan
This study investigates the efficacy of a novel tissue-engineered scaffold for nerve repair and functional reconstruction following injury. Utilizing stable jet electrospinning, we fabricated aligned ultrafine fibers from dopamine and poly(L-lactic acid) (PLLA), further developing a biomimetic, oriented, and electroactive scaffold comprising poly(pyrrole) (PPy), polydopamine (PDA), and PLLA through dual in situ polymerizations. The scaffold demonstrated enhanced cell adhesion and reactive oxygen species (ROS) scavenging capabilities and promoted the differentiation of mesenchymal stem cells (MSCs) into Schwann-like cells, essential for nerve regeneration. In vivo assessments revealed significant peripheral nerve regeneration in 10 mm sciatic nerve defects in rats, with observations made 12 weeks post-transplantation. This included facilitated myelination and increased muscle density on the injured side, leading to improved motor function recovery. Our results suggest that the aligned PPy/PDA/PLLA fibrous scaffold offers a promising approach for promoting the differentiation of MSCs into Schwann-like cells conducive to nerve regeneration and represents a significant advancement in nerve repair technologies. This study provides a foundational basis for future research into tissue-engineered solutions for nerve damage, potentially impacting clinical strategies for nerve reconstruction.
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Research
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2024
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IF 8.5
Chen Xiao,Jiayuan Li,Ao Hua,Xing Wang,Shiyou Li,Zheng Li,Chen Xu,Zhijie Zhang,Xiangliang Yang,Zifu Li
Cuproptosis-based cancer nanomedicine has received widespread attention recently. However, cuproptosis nanomedicine against pancreatic ductal adenocarcinoma (PDAC) is severely limited by cancer stem cells (CSCs), which reside in the hypoxic stroma and adopt glycolysis metabolism accordingly to resist cuproptosis-induced mitochondria damage. Here, we leverage hyperbaric oxygen (HBO) to regulate CSC metabolism by overcoming tumor hypoxia and to augment CSC elimination efficacy of polydopamine and hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@PH NPs). Mechanistically, while HBO and CuET@PH NPs inhibit glycolysis and oxidative phosphorylation, respectively, the combination of HBO and CuET@PH NPs potently suppresses energy metabolism of CSCs, thereby achieving robust tumor inhibition of PDAC and elongating mice survival importantly. This study reveals novel insights into the effects of cuproptosis nanomedicine on PDAC CSC metabolism and suggests that the combination of HBO with cuproptosis nanomedicine holds significant clinical translation potential for PDAC patients.
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Advanced Healthcare Materials
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2024
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IF 10
Jiahao Wang,Liang Zhang,Lingjun Wang,Jincheng Tang,Wei Wang,Yichang Xu,Ziang Li,Zhouye Ding,Xinzhao Jiang,Kun Xi,Liang Chen,Yong Gu
Targeting macrophages can facilitate the site-specific repair of critical bone defects. Herein, a composite hydrogel, gelatin- Bletilla striata polysaccharide-mesoporous bioactive glass hydrogel (GBM gel ), is constructed via the self-assembly of mesoporous bioactive glass on polysaccharide structures, through the Schiff base reaction. GBM gel can efficiently capture macrophages and drive the recruitment of seed stem cells and vascular budding required for regeneration in the early stages of bone injury, and the observed sustained release of inorganic silicon ions further enhances bone matrix deposition, mineralization, and vascular maturation. Moreover, the use of macrophage-depleted rat calvarial defect models further confirms that GBM gel , with ligand-selective macrophage targeting, increases the bone regeneration area and the proportion of mature bone. Mechanistic studies reveal that GBM gel upregulates the TLR4/NF-κB and MAPK macrophage pathways in the early stages and the JAK/STAT3 pathway in the later stages; thus initiating macrophage polarization at different time points. In conclusion, this study is based on the endogenous self-healing properties of bone macrophages, which enhances stem cell homing, and provides a research and theoretical basis upon which bone tissue can be reshaped and regenerated using the body's immune power, providing a new strategy for the treatment of critical bone defects.
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MOLECULAR BIOLOGY REPORTS
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2024
·Vol. 51
·期 1
·1-15
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IF 2.6
Wumiti Taxi,Wang Lining,Xu Bin,Ma Yong,Zhu Yihua,Zuo Xinchen,Qian Weiqing,Chu Xudong,Sun Haitao
Background Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. Methods The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. Results The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. Conclusion lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.
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Asian Journal of Pharmaceutical Sciences
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2024
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IF 10.7
Yuan Ding,Ruohan Chen,Jianfen Zhou,Yanning Bao,Nana Meng,Xudong Zheng,Shengmin Yang,Jiasheng Lu,Zhixuan Jiang,Yu Liu,Cao Xie,Linwei Lu,Weiyue Lu
There remain several intractable challenges for chemotherapy in glioma treatment, including the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. Here, we established a nano strategy to kill glioma cells and CSCs, combining carfilzomib and bis(diethyldithiocarbamate)copper. The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis. The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site. This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.
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Materials Today Bio
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2025
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IF 10.2
Yiwen Chen,Zhen Qin,Yujia Wang,Baoxin Gu,Jing Wang,Yunfei Zheng,Yuting Niu,Lingfei Jia
Cancer stem cells (CSCs) play critical roles in tumor growth, metastasis, and chemoresistance. Although several small-molecule inhibitors designed to inhibit CSCs have been investigated in clinical trials, their inadequate tumor targeting and potential off-target side effects have led to poor outcomes. A CD44-targeted virus-mimicking nanomedicine encapsulating the BMI1 inhibitor PTC209 (PTC209@VNP-HA) was designed to treat head and neck squamous cell carcinoma (HNSCC). We used a dendritic mesoporous silica nanoparticle (MSN) as the core for virus-mimicking nanoparticle (VNP) formation after adding shell particles to the MSN surface. The VNP surface was then modified with hyaluronic acid (HA), and PTC209 was adsorbed by mesopores to form PTC209@VNP-HA. In this system, HA is used to target CD44 + CSCs. The rough surface of VNP-HA provided better drug delivery efficiency than smooth nanoparticles modified with HA. VNP-HA enhanced the cancer inhibitory effect of PTC209 12-fold compared to the administration of free PTC209, leading to significantly higher bioavailability of PTC209. Both in vitro and in vivo assays showed that PTC209@VNP-HA inhibited cancer stemness, proliferation, and metastasis in HNSCC. Mechanistically, this inhibitory effect is closely associated with DNA damage/apoptosis signaling. Using a series of preclinical models in murine systems, we confirmed that PTC209@VNP-HA eliminated BMI1 + CSCs, and greatly inhibited the proliferation and metastasis of HNSCC when combined with cisplatin.This study investigated PTC209@VNP-HA as a novel and potentially transformative HNSCC treatment option that eliminates CSCs, prevents metastasis, and overcomes cisplatin resistance.
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ACS Measurement Science Au
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2025
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IF 9
Jiafeng Wang,Xiaozhang Qu,Zhimin Zhang,Xiuping Meng,Guohua Qi
Stem cells are a class of multipotential cells with the capability of self-replication, which can differentiate into multiple functional cells under extra stimulus. The differentiation of stem cells has important implications for tissue regeneration. Therefore, controllable regulation of dental pulp stem cell (DPSC) behaviors is critical for repairment and regeneration of damaged teeth tissues. Rapid promotion of DPSCs, directed differentiation, and revealing molecular events within the organelle level during the cell differentiation process are in great demand for regeneration of teeth, which remains a great challenge. Herein, we developed a highly effective and uncomplicated stimulation platform to promote the DPSCs for odontogenic differentiation based on impulse electrical stimulation and revealed the molecular stress response of mitochondria during cell differentiation based on fluorescence imaging combined with surface-enhanced Raman spectroscopy (SERS). Our approach can greatly shorten the DPSC differentiation time from usually more than 20 days to only about 3 days under 0.8 V for 5 min every day than drug stimulation. Notably, the glycogen and adenosine triphosphate levels within mitochondria were apparently elevated, which is conducive to improving the progression of cell differentiation. Simultaneously, the expression of mitofusin1 and mitofusin2 within mitochondria was significantly down-regulated during the differentiation process. Mechanistically, the molecular insights into mitochondria within DPSCs were clearly revealed through SERS spectra. It demonstrated that the expression of phenylalanine was significantly reduced, whereas the contents of tryptophan within mitochondria were promoted during the cell differentiation process. This study provides a comprehensive and clinically feasible strategy for the rapid promotion of DPSCs-directed differentiation and reveals the molecular dynamic changes within mitochondria, which broadens the biomedical cognition of electrical stimulation for dental pulp stem cell differentiation and provides a potential application for teeth tissue regeneration in the future.
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Drug Design Development and Therapy
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2025
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IF 5.1
Xuehui Deng,Bingfeng Lin,Wenlong Xiao,Fang Wang,Pingcui Xu,Nani Wang
Background Specnuezhenide (SPN) is an iridoid glycoside isolated from Fructus Ligustri Lucidi, an herb prescribed for the treatment of senile osteoporosis. However, the direct role of SPN on bone metabolism remains unclear. In this study, the effects of SPN on d-galactose (d-gal)-induced mice, bone marrow mesenchymal stem cells (BMSCs), and nuclear factor-κB ligand-induced osteoclasts were examined.Methods Micro-computed tomography was used to observe the bone microstructure. Osteogenesis was examined using Western blotting and alkaline phosphatase staining. Osteoclastogenesis was examined using Western blotting and F-actin ring staining. Senescence-associated β-galactosidase was used to detect cell senescence. In addition, the expression of Takeda G protein-coupled receptor 5 (TGR5)/farnesoid X receptor (FXR) signaling pathway-related genes and proteins was determined through quantitative real-time polymerase chain reaction and immunofluorescence.Results Oral administration of SPN improved the bone microstructure in d-gal-induced mice and increased bone mineral density, bone volume, trabecular thickness, and trabecular number. SPN also upregulated the expression of the osteogenesis markers osteocalcin, bone morphogenetic protein 2, and runt-related transcription factor 2 and downregulated the expression of the osteoclasis markers tartrate-resistant acid phosphatase, nuclear factor-κB, and nuclear factor of activated T-cells in the d-gal-induced bone. Furthermore, SPN increased alkaline phosphatase staining, inhibited F-actin ring formation, and reduced the activity of senescence-associated β-galactosidase in vitro. Mechanistically, SPN activated the TGR5/FXR pathway in d-gal-induced BMSCs and osteoclasts. The protective effects of SPN were abolished after addition of the TGR5 inhibitor SBI-115 or FXR inhibitor DY268. Moreover, SPN could elevate the protein and mRNA levels of TGR5, FXR, and the downstream small heterodimer partner in d-gal-induced bone.Conclusion SPN alleviated senile osteoporosis and cell senescence by activating the TGR5/FXR pathway.
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DEVELOPMENTAL CELL
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2024
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IF 10.7
Xiaoxin Guo,Juanyu Zhou,La Yan,Xingzhu Liu,Yu Yuan,Jinbao Ye,Zehong Zhang,Haiou Chen,Yongxin Ma,Zhendong Zhong,Guanzheng Luo,Haiyang Chen
Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.
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ACS Central Science
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2025
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IF 10.4
Qifang Wu,Yingna Li,Yunyun Zhao,Ruifen Zhang,Jingyang Tong,Chunlei Ji,Yiming Zhao,Mingjiang Wu,Xiaosheng Jin,Dandan Wang,Haibin Tong,Liwei Sun,Fangbing Liu
Excessive fructose intake drives intestinal aging and impairs intestinal stem cell (ISC) function, yet effective therapeutic interventions remain elusive. Astragaloside IV (AS-IV), a natural saponin from Astragalus membranaceus, has been widely recognized for its antiaging, anti-inflammatory, and gut-protective properties. Here, we revealed that AS-IV alleviates fructose-induced intestinal metabolic senescence via direct inhibition of ketohexokinase (KHK), the key rate-limiting enzyme in fructose metabolism. Molecular docking and site-directed mutagenesis identified Asn261 and Ala226 as distinct binding sites for AS-IV on KHK, with Asn261 also serving as a critical catalytic residue that is essential for KHK activity. Mutation at Asn261 abolished KHK enzymatic function, reduced the accumulation of fructose-derived metabolites such as palmitic acid and ceramide, and thereby prevented fructose-induced ISC cycle arrest. AS-IV’s therapeutic efficacy was validated across Drosophila, murine intestinal organoids, and mice, where treatment consistently reversed high-fructose-induced intestinal metabolic senescence phenotypes, restored ISC proliferation, and preserved ISC homeostasis. These findings indicate that KHK is a previously unrecognized molecular target of AS-IV and reveal a conserved mechanism by which AS-IV modulates fructose metabolism to interfere with gut aging. Our results highlight its therapeutic potential in treating fructose-driven intestinal aging and associated metabolic disorders.
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REPRODUCTIVE TOXICOLOGY
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2025
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IF 2.8
Shiling Chen,Xiuying Lin,Lei Liu,Jianhua Fu,Xiaodan Lu,Chunxue Niu,Qilai Wang,HaiFeng Wei,Mengxue Wu,Munan Sun,Lixin Cao,Xuguang Mi,Yanqiu Fang
Estrogen plays a central role in promoting endometrial thickening during the menstrual cycle. In patients with a thin endometrium, endometrial cells exhibit reduced sensitivity to estrogen, contributing to female infertility. We established an endometrial stromal cell damage model using the estrogen antagonist raloxifene (RAL) and investigated the role and underlying mechanism of human umbilical cord mesenchymal stem cell–derived exosomes (hUCMSC-EXO) in repairing RAL-induced damage in human endometrial stromal cells (hEndoSCs). In this study, hEndoSCs were treated with RAL and subsequently cultured with hUCMSC-EXO. The results showed that hUCMSC-EXO restored the proliferative capacity of hEndoSCs, decreased endogenous reactive oxygen species production, and increased mitochondrial membrane potential. Mechanistic analysis indicated that hUCMSC-EXO activated intracellular autophagy, and that autophagy inhibition reversed the protective effects of hUCMSC-EXO on hEndoSCs. These findings suggest that hUCMSC-EXO may ameliorate endometrial injury associated with estrogen insensitivity.
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Journal of Materials Chemistry B
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2024
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IF 6.1
Fan Zhang,Liping Nan,Jia-Qi Fang,Lei Liu,Bo Xu,Xue-Han Jin,Shuhao Liu,Shengfu Liu,Kaihang Song,Zhijie Weng,Feng Chen,Jian-Guang Wang,Jun-Jian Liu
The Nerve Guide Conduit (NGC)offers a promising alternative to traditional methods for regenerating peripheral nerves. The efficacy of nerve regeneration and functional recovery is heavily dependent on the electrical, chemical, and physical properties of the NGC. A bionic Melt electrowriting (MEW) NGC loaded with Placental derived mesenchymal Stem Cells (PDMSCs) has been developed. Our study introduces a novel approach by utilizing Schwann cells induced from placental mesenchymal stem cells (PDMSCs), showcasing their potential in enhancing nerve regeneration when integrated with conductive nerve guidance conduits. Schwann cells (SCs) are crucial for nerve regeneration, and while various stem cells, including Bone Marrow Stromal Cells (BMSCs), have been investigated as sources of SCs for NGC loading, they are often limited by ethical concerns and restricted availability. PDMSCs, however, offer the advantages of widespread sourcing and the unique ability to differentiate into SCs, making them an attractive alternative for NGC applications. This NGC utilizes of an electrostatic direct writing technique employing Polycaprolactone (PCL) for the sheath and acrimped fiber scaffold made of polypyrrole (PPY) incorporating PDMSCs for itsinternal structure. The bionic PC-NGC loaded with PDMSCs, exhibits favorable characteristics including permeability, mechanical stability, and electrical conductivity. The PPY component effectively transmitsphysiological nerve signals, thereby promoting nerve regeneration, while the PDMSCs differentiateinto Schwann cells, creating a conducive environment for nerve regeneration. This research innovatively combines PDMSCs, known for their wide availability and SC differentiation potential, with a bionic NGC to enhance the treatment of peripheral nerve injuries (PNI). In vitro evaluations have confirmed the excellent biocompatibility of the materials used. Animal experiments usinga rat model with sciatic nerve injury demonstratedthat the PC-NGC significentlyfacilitated peripheral nerve regeneration. This was evidenced by improvements in axonal myelination, increased musclemass, enhanced sciatic nerve function index, and positive electrophysiologicalfindings. These outcomes arecomparable to those achieved through autologous transplantation. Characterized by its layered oriented fibers, the bionic PC-NGC integrates multi-scale and multifunctional biomaterials with PDMSCPDMSCs to effectively address peripheral nerve injuries (PNI). The useof thisprinted NGC stimulatesneuronal cell growth, thereby accelerating nerve regeneration. This innovative approach in tissue engineering presentsa promising clinical treatment strategy for PNI.
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