CELL BIOLOGY AND TOXICOLOGY
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2025
·Vol. 41
·期 1
·1-29
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IF 5.9
Tian Sirui,Yu Haiyang,Yang Ruoxuan,Wang Heshi,Zhao Baohong,Wang Danning
Soft tissue injury (STI) is a prevalent condition that requires effective therapeutic approaches. The focus of this investigation was to elucidate the molecular mechanisms linked to the IGFBP3 protein in adipose-derived stem cells (ADSCs) for STI repair, utilizing single-cell multiomics technology and a 3D bioprinting model. Establishment of a mouse-based STI model facilitated the comparison of cellular compositions and communication variances between wounded and normal tissues through single-cell RNA sequencing (scRNA-seq). High-throughput transcriptomics and bioinformatics analysis pinpointed IGFBP3 as a key target in ADSCs related to STI repair. In vitro experiments assessed IGFBP3's effects on ADSCs' epithelial cell differentiation, proliferation, and migration using various assays and lentivirus transfection to manipulate IGFBP3 expression. A 3D bioprinting technique was used to create an ADSCs-IGFBP3 peptide self-assembling hydrogel scaffold, characterized by Fourier-transform infrared spectroscopy, X-ray diffraction, SEM, and TEM. The scaffold's efficacy was validated in an animal model. Results showed nine cell subtypes in both normal and injured tissues, with increased ADSCs in STI tissues exhibiting enhanced connectivity and interactions. RNA-seq analysis confirmed IGFBP3 as crucial for ADSCs and STI. In vitro and 3D bioprinting experiments, along with animal model validation, confirmed IGFBP3's role in STI repair. Upregulation of IGFBP3 in ADSCs promoted epithelial cell differentiation by enhancing ITGB1 expression, activating the ERK pathway to boost cell proliferation and migration. This study highlights IGFBP3's significant role in ADSCs for STI repair, providing potential molecular targets for developing new treatments. The findings offer valuable insights into IGFBP3's mechanisms, aiding in advancing STI therapeutic strategies. Graphical 1. IGFBP3 enhances ADSC function in STI repair by activating ITGB1 and ERK pathways. 2. High IGFBP3 expression promotes ADSC differentiation into epithelial cells, improving tissue regeneration. 3. Single-cell multiomics and 3D bioprinting validate IGFBP3’s role in advancing STI treatment. 4. Findings present IGFBP3 as a promising molecular target for clinical STI therapy.
研究领域:
再生医学
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分子生物学
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生物材料学
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Yuwen Song,Tingting Xu,Hao Li,Jing Liu,Shumin Cao,Yichen Yang,Nianlu Li,Peiwen Lv,Min Han,Haohan Sun,Guangfu Dang,Jianxin Li,Hao Sun,Tao Xin,Huitang Xia,CanWei Zhang
Corneal neovascularization (CoNV) is a leading cause of visual impairment worldwide. However, CoNV remains challenging to cure clinically because of the limitations of current drugs. New and more effective therapeutic formulations for CoNV treatment are therefore urgently needed. Antisense oligonucleotide drugs hold great promise for the treatment of neovascular diseases, and ionizable cationic lipid nanoparticles (icLNPs) have shown excellent performance for nucleic acid delivery, with high encapsulation, good cellular uptake, and effective endosomal escape. In the present study, we identified integrin β1 ( Itgb1 ) as a key gene involved in angiogenesis and revealed the significant upregulation of Flt1 in vascular endothelial cells and pericytes in CoNV using single-cell sequencing. Itgb1 knockdown significantly inhibited the proliferation and migration of vascular endothelial cells and CoNV in mice. Based on these findings, we developed Itgb1 -small interfering RNA (siRNA)-loaded icLNPs, and conjugated anti-Flt1 peptide to their surface to improve CoNV targeting. Furthermore, because lipid nanoparticles reportedly trigger immune responses by upregulating pro-inflammatory cytokine expression, which may promote neovascularization, we modified triptolide (a compound with anti-inflammatory properties) into the icLNPs. The triptolide-modified, anti-Flt1 peptide-conjugated, and Itgb1 -siRNA-loaded icLNPs ( Itgb1 -siRNA@TPL) effectively inhibited the proliferation and migration of vascular endothelial cells in vitro and CoNV in mice after eye drop administration. These effects occurred via downregulation of the PI3K/AKT and NF-κB signaling pathways. Finally, the biosafety of Itgb1 -siRNA@TPL was tested, and the results revealed that it was not toxic to the cornea or major organs and had no impact on corneal epithelial healing. In conclusion, Itgb1 -siRNA@TPL represent a novel, noninvasive, and effective approach for the treatment of CoNV.
研究领域:
医学
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分子生物学
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药剂学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Deyu Zuo,Dingyi Lv,Guozhi Zhao,Yanliang Chen,Zhesheng Chen,Lili Pu,Minghao Luo,Ming Tang,Ming Wang,An He,Weijian Xiong,Xunjia Li
Background Vascular endothelial dysfunction is a core pathological feature of diabetes-associated vascular complications, primarily driven by impaired nitric oxide (NO) bioavailability due to dysregulated endothelial nitric oxide synthase (eNOS) activity. While pharmacological strategies targeting the eNOS pathway have shown promise, the discovery of natural compounds capable of restoring endothelial function through novel molecular targets remains an important research direction. Purpose The aim of this study was to investigate the targets and molecular mechanisms of Chikusetsusaponin V (CsV) in regulating vascular endothelial function in diabetes mellitus (DM). Methods The DM models were constructed using db/db mice and high-glucose cultured human aortic endothelial cells (HAECs). The vasodilatory function was investigated using techniques such as metal wire microvascular tension measurement and ultrasonography after intervention with CsV. Modern techniques such as affinity chromatography, mass spectrometry, molecular docking and microscale thermophoresis (MST) test were used to identify the direct targets of CsV. The key pathways and downstream transcription factors involved in the improvement of vasodilatory function of CsV were screened using RNA-Seq. Subsequent validation was performed using a dual luciferase assay. Knockdown adenoviral vectors, quantitative polymerase chain reaction (qPCR), and Western blot (WB) were used to elucidate the molecular mechanism of CsV in regulating the vasodilatory function in DM. Results The results showed that CsV down-regulated blood glucose and increased the expression of eNOS and p-eNOS (S1177), which improved vasodilatation and reduced vascular stiffness in DM mice. Additionally, CsV increased NO release and tube-forming capacity of HAECs. CsV can directly bind to the membrane protein ITGB1. In vivo and in vitro experiments showed that administration of CsV after knockdown of ITGB1 or inhibiting PI3K significantly down-regulated the expression of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, NR4A3, PURA, and p-eNOS (S1177)/eNOS, decreased NO levels, and affected angiogenesis and endothelial cell function. In contrast, overexpression of ITGB1 produced the opposite results. Moreover, knockdown NR4A3 inhibited NR4A3/PURA/eNOS expression and affected endothelial function, whereas overexpression produced the opposite result. Conclusions CsV improves endothelial function in DM vasculature by targeting ITGB1, enhancing eNOS phosphorylation via the PI3K/AKT pathway, and promoting PURA/eNOS expression through PI3K/AKT/mTOR/NR4A3. These findings support CsV's potential use for improving diabetes vascular function. CsV Targets ITGB1 to Improve Endothelial Function via activating PI3K/AKT/mTOR/NR4A3/eNOS Pathway - present study vs. previous study. Download: Download high-res image (224KB) Download: Download full-size image
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DOI
PubMed
高影响因子
Regenerative Biomaterials
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2025
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IF 8.1
Wen Zhuohao,Li Shuyi,Qiu Huiguo,Liu Xueyan,You Zhiying,Yan Yuhan,Che Yuejuan,Zhou Miao
Periosteum plays an indispensable role in bone regeneration by providing osteogenic and angiogenic cues essential for tissue repair. In cases of severe bone defects or nonunion, autologous vascularized periosteum transplantation remains a highly effective clinical solution. However, its application is restricted by donor site morbidity and limited tissue availability, thereby underscoring the urgent need for artificial periosteum that mimics both the composition and structure of the native counterpart. Among these properties, the topological morphology of the periosteum is believed to be critical, yet its influence on bone regeneration remains insufficiently understood. In this study, biomimetic periosteum membranes composed of coaxially electrospun poly(ε-caprolactone) (PCL) and periosteal extracellular matrix (pECM) were fabricated with either random or aligned nanofiber architectures. Their osteogenic potential was systematically evaluated in vitro and in vivo. Compared to the randomly arranged structure, aligned pECM (aPEC) significantly enhanced the adhesion, alignment, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by activating the ITGB1/PI3K/AKT signaling pathway, whereas these effects were not observed in pure PCL membranes. These findings demonstrate that aligned topological morphology in biomimetic periosteum plays a pivotal role in directing stem cell behavior and promoting bone regeneration. This work provides mechanistic insight and technical guidance for the future design of functionally enhanced artificial periosteum for bone tissue engineering applications.
研究领域:
组织工程
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生物材料学
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分子生物学
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再生医学
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生物医学工程
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DOI
PubMed
高影响因子
Metabolites
·
2024
·Vol. 14
·期 4
·224
·
IF 3.4
Jianing Ren,Jing Dai,Yue Chen,Zhenzhen Wang,Ruyi Sha,Jianwei Mao,Yangchen Mao
Rice (Oryza sativaL.) is one of the primary sources of energy and nutrients needed by the body, and rice resistant starch (RRS) has been found to have hypoglycemic effects. However, its biological activity and specific mechanisms still need to be further elucidated. In the present study, 52 RRS differential metabolites were obtained from mouse liver, rat serum, canine feces, and human urine, and 246 potential targets were identified through a literature review and database analysis. A total of 151 common targets were identified by intersecting them with the targets of type 2 diabetes mellitus (T2DM). After network pharmacology analysis, 11 core metabolites were identified, including linolenic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, lithocholic acid, lithocholylglycine, glycoursodeoxycholic acid, phenylalanine, norepinephrine, cholic acid, and L-glutamic acid, and 16 core targets were identified, including MAPK3, MAPK1, EGFR, ESR1, PRKCA, FYN, LCK, DLG4, ITGB1, IL6, PTPN11, RARA, NR3C1, PTPN6, PPARA, and ITGAV. The core pathways included the neuroactive ligand–receptor interaction, cancer, and arachidonic acid metabolism pathways. The molecular docking results showed that bile acids such as glycoursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, deoxycholic acid, and cholic acid exhibited strong docking effects with EGFR, ITGAV, ITGB1, MAPK3, NR3C1, α-glucosidase, and α-amylase. In vitro hypoglycemic experiments further suggested that bile acids showed significant inhibitory effects on α-glucosidase and α-amylase, with CDCA and UDCA having the most prominent inhibitory effect. In summary, this study reveals a possible hypoglycemic pathway of RRS metabolites and provides new research perspectives to further explore the therapeutic mechanism of bile acids in T2DM.
研究领域:
药理学
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生物化学
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分子生物学
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糖尿病研究
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营养学
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PubMed
高影响因子
GENOMICS
·
2024
·
IF 3.4
Jiongxue Chen,Jiatian Xie,Fuyin Deng,Jinhua Cai,Sitai Chen,Xingrong Song,Shangzhou Xia,Qingyu Shen,Xinying Guo,Yamei Tang
The significance of the adaptive immune response in Alzheimer's disease (AD) is increasingly recognized. We analyzed scRNA-Seq data from AD patients, revealing a notable rise in CD4 cytotoxic T cells (CD4-CTLs) in peripheral blood mononuclear cells (PBMCs), validated in vivo and in vitro. This rise correlates with cognitive decline in AD patients. We also identified transcription factors TBX21 and MYBL1 as key drivers of CD4-CTL expansion. Further analyses indicate these cells are terminally differentiated, showing clonal expansion, metabolic changes, and unique communication patterns. Mendelian randomization identified risk genes SRGN and ITGB1, suggesting their genetic regulation in CD4-CTLs may contribute to AD. To summarize, our findings characterize the expansion of CD4-CTLs in the PBMCs of AD patients, providing valuable understanding into the possible mechanisms involved in the expansion of CD4-CTLs in AD.
研究领域:
神经科学
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免疫学
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基因组学
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转化医学
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DOI
PubMed
高影响因子
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