JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Zheng-Jiong Zhao,Mei-Yan Jiang,Meng-Xing Huang,Yi-Yi Yang,Ling-Ling Feng,Chen Zhang,Yi-You Huang,Hai-Bin Luo,Yinuo Wu
Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.
研究领域:
药理学
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药物化学
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肝病学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
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IF 4.8
Tangfei Guan,Xin Yang,Canhui Hong,Jiali Zhu,Peiyun Xiao,Yongshou Yang,Chenggui Zhang,Zhengchun He
Introduction: Alopecia areata (AA), an autoimmune hair-loss disease due to follicular inflammatory cell infiltration, lacks an ideal cure. The Periplaneta Americana (PA) extract (PA-011), a traditional Chinese medicine with anti-inflammatory, antioxidant, tissue-repair-promoting, and immune-regulating properties, was studied for its AA-treating effects.Methods: Guided by network pharmacology, AA model mice were treated with PA-011. Hair growth, skin tissue, inflammatory factors, and Wnt protein levels were examined. Transcriptomics, metabolomics, and 16S rRNA sequencing explored the hair-growth-promoting mechanisms.Results: Network pharmacology showed PA-011 could regulate AA-related targets and pathways. PA-011 intervention promoted hair follicle cell proliferation and hair growth in AA mice, reduced skin TNF-α, IL-23, and VCAM-1 expression. Transcriptomics and WB analysis indicated PA-011 downregulated inflammatory genes, activated Wnt3a, and modulated the TGF-β pathway. Metabolomics found PA-011 regulated metabolic pathways. 16S rRNA analysis showed it reversed AA-induced skin microbiota changes, inhibiting pathogens and promoting probiotics. Multi-omics analysis revealed PA-011 regulated skin microbiota and metabolic balance for hair growth.Discussion: In conclusion, PA-011 alleviates AA by reducing skin inflammation and modulating skin microbiota, suggesting its potential as an AA therapeutic.
研究领域:
药理学
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皮肤病学
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免疫学
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微生物学
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中医药学
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系统生物学
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PubMed
高影响因子
JOURNAL OF MOLECULAR HISTOLOGY
·
2025
·Vol. 56
·期 1
·1-14
·
IF 2.2
Ma Jinjie,Yan Jing,Su Nan,Qiu Zhengjun,Hou Huailong,Sun Jingxuan,Sun Xiangyu,Niu Yumei,He Lina
Facial nerve injuries lead to significant functional impairments and psychological distress for affected patients. Effective repair of these injuries remains a challenge. For longer nerve gaps, the regeneration outcomes after nerve grafting remain suboptimal due to limited sources and postoperative immune responses. Tissue engineering techniques are conventional methods for repairing peripheral nerve defects. This study explores the potential of dental pulp cells (DPCs) combined with stem cell factor (SCF) to enhance neurogenic differentiation and improve facial nerve regeneration. DPCs were isolated from rabbit dental pulp, the pluripotency of the cells was identified from three perspectives: osteogenic differentiation, adipogenic differentiation, and neurogenic differentiation. In vivo experiments involved injuring the buccal branch of the facial nerve in New Zealand white rabbits, followed by treatment with PBS, DPCs, SCF, or SCF + DPCs. Functional recovery was assessed over 12 weeks, with SCF + DPCs demonstrating the most significant improvement in whisker movement scores. Histomorphological evaluations revealed enhanced myelinated fiber density and axonal morphology in the SCF + DPCs group. RNA sequencing identified 608 differentially expressed genes, with enrichment in the TGF-β signaling pathway. In in vitro experiments, we demonstrated from multiple angles using Western blot analysis, Real-time quantitative polymerase chain reaction (QPCR) analysis, and immunofluorescence staining that SCF can promote the neurogenic differentiation of DPCs through the TGF-β1 signaling pathway. Our findings indicate that the combination of SCF and DPCs offers a promising strategy for enhancing facial nerve repair.
研究领域:
神经科学
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组织工程
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再生医学
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分子生物学
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
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IF 6.8
Yin Zhuang,Xiangying Sun,Siting Deng,Ya Wen,Qiujin Xu,Quanquan Guan
Background Bisphenol A (BPA) is known to exhibit endocrine disrupting activities and is associated with adiposity. We examined the obesogenic effect of prenatal BPA exposure in the present study. Methods Pregnant ICR mice were exposed to vehicle or BPA via the drinking water at a dose of 0.5 μg/kg·d throughout the gestation. Obesity-related indexes were investigated in the 12-wk-old offspring. Primary mouse embryonic fibroblasts (MEFs) collected from treated embryos were used to test effects of BPA on adipocyte differentiation. Results Offspring presented a significantly higher rate of weight gain than the control, with impaired insulin sensitivity and increased adipocyte size. Differentiation of MEFs from BPA-treated mice showed a higher propensity for the adipocyte commitment as well as up-regulation of genes enriched in lipid biosynthesis. TGF-β signaling pathway was found to modulate obesogenic effect of BPA in MEF model, but estrogen signaling pathway had no effect. Conclusions The present study provides strong evidence of the association between prenatal exposure to low dose of BPA and a significant increase in body weight in the offspring mice with a critical role played by TGF-β signaling pathway. The potential interactions modulating the binding of BPA and TGF-β that activate its obesogenic effects need to be examined.
研究领域:
毒理学
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内分泌学
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发育生物学
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PubMed
高影响因子
Cell Regeneration
·
2021
·Vol. 10
·期 1
·1-18
·
IF 0
Zhao Zixian,Wang Yujia,Wu Yingchuan,Li Dandan,Zhang Ting,Ma Yu,Teng Xiaoming,Zuo Wei
Information about the dynamic change and post-injury regeneration of cervical epithelium is relatively rare, even though it is tightly related to gynecologic malignancy. Here, using a feeder cell-based culturing system, we stably cloned mouse and human P63 and KRT5 expressing cells from the adult cervix as putative cervical stem/progenitor cells (CVSCs). When subjected to differentiation, the cultured cells gave rise to mature cervical epithelium by differentiating into squamous or glandular cells. The ability of endogenous mouse CVSCs to reconstitute cervical epithelium after injury was also evident from the genetic lineage tracing experiments. Single-cell transcriptomic analysis further classified the CVSCs into three subtypes and delineated their bi-lineage differentiation roadmap by pseudo-time analysis. We also tracked the real-time differentiation routes of two representing single CVSC lines in vitro and found that they recapitulated the predicted roadmap in pseudo-time analysis. Signaling pathways including Wnt, TGF-beta, Notch and EGFR were found to regulate the cervical epithelial hierarchy and implicated the different roles of distinct types of cells in tissue homeostasis and tumorigenesis. Collectively, the above data provide a cloning system to achieve stable in vitro culture of a bi-lineage stem/progenitor cell population in the cervix, which has profound implications for our understanding of the cervix stem/progenitor cell function in homeostasis, regeneration, and disease and could be helpful for developing stem cell-based therapies in future.
研究领域:
细胞生物学
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干细胞研究
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癌症生物学
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再生医学
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DOI
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Jiaying Yang,Mengyu Lai,Yuhang Ma,Jingzhu Wu,Chuan Zhang,Huiwen Yuan,Guiling Liang,Chuchen Meng,Yanmei Su,Bing Luan,Liping Gu,Yufan Wang
Uncontrolled programmed polarization of macrophages plays an important role in chronic diabetic wound healing. Therefore, correcting programmed macrophage polarization while inducing new tissue remodelling through materials and preventing scar formation is desirable. Herein, a composite hydrogel brake that enables spatiotemporal regulation of the immune microenvironment was constructed to promote skin tissue regeneration. The system was based on thiolated hyaluronic acid to reshape the programmed polarization of macrophages, methacrylate gelatin as a mechanical support, and poly (L-lactic acid) nanoparticles loaded with TGF-β receptor antagonists to inhibit scar formation. Notably, the composite hydrogel acts as a double brake: in the early stage, self-induced M2-type polarization is achieved with the help of thiols; the TNF and NLRP signalling pathways are downregulated; and the immune microenvironment is regulated. During tissue remodeling, the long-term biological effect of TGF-β secretion by M2-type macrophages is interrupted by the slow release of antagonists, which inhibits excessive collagen deposition and prevents scar formation. The dual effect of restraint on reprogramming macrophage polarization and inhibiting scar formation was further confirmed in a diabetic rat skin defect model. Therefore, based on the immunological mechanism, a composite hydrogel brake was specifically designed to regulate the immune microenvironment, induce new tissue remodelling, and provide a promising clinical strategy for treating chronic diabetic wounds.
研究领域:
生物医学工程
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组织工程
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免疫学
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糖尿病研究
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材料科学
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高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 13
·e18527
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IF 4.3
Maomao Miao,Mengying Li,Yunjie Sheng,Peijian Tong,Yang Zhang,Dan Shou
Infected bone defects (IBDs) are the common condition in the clinical practice of orthopaedics. Although surgery and anti-infective medicine are the firstly chosen treatments, in many cases, patients experience a prolonged bone union process after anti-infective treatment. Epimedium-Curculigo herb pair (ECP) has been proved to be effective for bone repair. However, the mechanisms of ECP in IBDs are insufficiency. In this study, Effect of ECP in IBDs was verified by micro-CT and histological examination. Qualitative and quantitative analysis of the main components in ECP containing medicated serum (ECP-CS) were performed. The network pharmacological approaches were then applied to predict potential pathways for ECP associated with bone repair. In addition, the mechanism of ECP regulating LncRNA MALAT1/miRNA-34a-5p/SMAD2 signalling axis was evaluated by molecular biology experiments. In vivo experiments indicated that ECP could significantly promote bone repair. The results of the chemical components analysis and the pathway identification revealed that TGF-β signalling pathway was related to ECP. The results of in vitro experiments indicated that ECP-CS could reverse the damage caused by LPS through inhibiting the expressions of LncRNA MALAT1 and SMAD2, and improving the expressions of miR-34a-5p, ALP, RUNX2 and Collagen type І in osteoblasts significantly. This research showed that ECP could regulate the TGF-β/SMADs signalling pathway to promote bone repair. Meanwhile, ECP could alleviate LPS-induced bone loss by modulating the signalling axis of LncRNA MALAT1/miRNA-34a-5p/ SMAD2 in IBDs.
研究领域:
骨科
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药理学
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分子生物学
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信号转导
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DOI
PubMed
高影响因子
EXPERIMENTAL LUNG RESEARCH
·
2023
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IF 1.7
Ting Yang,Chang Xu,Niu Ding,Shujuan Luo,Bichen Wu,Shijie Jin,Yanping Chen
Background To investigate the protective effect of p14ARF in a nitric acid (NA) aerosol inhalation-induced bronchiolitis obliterans (BO) mouse model and its potential regulatory mechanism.Methods A BO mouse model was established by NA aerosol inhalation. The expressions of p14ARF, phosphatidylinositol-3-kinase (PI3K), and protein kinase B (AKT) were detected by quantitative reverse transcription PCR (qRT-PCR) and western blot (WB). Hematoxylin (HE) staining, Masson staining, and periodic acid-Schiff (PAS) staining observed pulmonary histological changes. TdT-mediated dUTP nick end labeling (TUNEL) staining detected pulmonary cell apoptosis, and enzyme-linked immunosorbent assay (ELISA) measured matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), interleukon-6 (IL-6), and transforminh growth factor-β (TGF-β) levels in lung tissue and bronchoalveolar lavage fluid (BALF).Results The expressions of p14ARF, PI3K, and AKT showed a time gradient change, with a decrease trend (*P < 0.05 and **P < 0.01). Severe inflammatory infiltration and tracheal fibrosis were found in lung tissue in the modeling group (BO group) compared with the control group (Con group). The pH, PaO2, and PaO2/FiO2 values significantly reduced, while the PaCO2 value and the number of TUNEL-positive cells increased in BO group (P < 0.05). In addition, MMP-2, MMP-9, IL-6, and TGF-β levels remarkably increased, with an increase in the number of white blood cells, neutrophils, and lymphocytes in BO group (P < 0.05). Furthermore, p14ARF up-regulation reversed the trend of the aforementioned indexes in BO mice.Conclusions p14ARF ameliorated the inflammatory response and airway remodeling in a BO mouse model via the PI3K/AKT pathway.
研究领域:
呼吸医学
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分子生物学
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免疫学
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PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Hong-Lin Qian,Sheng-Yu Chen,Fan Jia,Wei-Pin Huang,Jing Wang,Ke-Feng Ren,Guo-Sheng Fu,Jian Ji
The valid management of inflammation and precise inhibition of smooth muscle cells (SMCs) is regarded as a promising strategy for regulating vascular responses after stent implantation , yet posing huge challenges to current coating constructions. Herein, we proposed a spongy cardiovascular stent for the protective delivery of 4-octyl itaconate (OI) based on a “spongy skin” approach, and revealed the dual-regulation effects of OI for improving vascular remolding. We first constructed a “spongy skin” onto poly-l-lactic acid (PLLA) substrates, and realized the protective loading of OI with the highest dosage of 47.9 μg/cm 2 . Then, we verified the remarkable inflammation mediation of OI, and surprisingly revealed that the OI incorporation specifically inhibited SMC proliferation and phenotype switching, which contributed to the competitive growth of endothelial cells (EC/SMC ratio ∼ 5.1). We further demonstrated that OI at a concentration of 25 μg/mL showed significant suppression of the TGF-β/Smad pathway of SMCs, leading to the promotion of contractile phenotype and reduction of extracellular matrix. In vivo evaluation indicated that the successful delivery of OI fulfilled the inflammation regulation and SMCs inhibition, therefore suppressing the in-stent restenosis. This “spongy skin” based OI eluting system may serve as a new strategy for improving vascular remolding, and provides a potential concept for the treatment of cardiovascular diseases.
研究领域:
心血管工程
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生物材料
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药物递送系统
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血管生物学
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组织工程
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Mengmeng Yang,Chao Qin,Linlin Tao,Gang Cheng,Jingjing Li,Fangnan Lv,Nan Yang,Zuhang Xing,Xinyu Chu,Xiaopeng Han,Meirong Huo,Lifang Yin
The poor permeability of therapeutic drugs, limited T-cell infiltration, and strong immunosuppressive tumor microenvironment of triple-negative breast cancer (TNBC) acts as a prominent barrier to the delivery of drugs and immunotherapy including programmed cell death ligand-1 antibody (anti-PD-L1). Transforming growth factor (TGF)- β , an important cytokine produced by cancer-associated fibroblasts (CAFs) and tumor cells contributes to the pathological vasculature, dense tumor stroma and strong immunosuppressive tumor microenvironment (TME). Herein, a nanomedicine platform (HA-LSL/siTGF- β ) employing dual-targeting, alongside hyaluronidase (HAase) and glutathione (GSH) triggered release was elaborately constructed to efficiently deliver TGF- β small interference RNA (siTGF- β ). It was determined that this system was able to improve the efficacy of anti-PD-L1. The siTGF- β nanosystem efficiently silenced TGF- β -related signaling pathways in both activated NIH 3T3 cells and 4T1 cells in vitro and in vivo. This occurred firstly, through CD44-mediated uptake, followed by rapid escape mediated by HAase in endo/lysosomes and release of siRNA mediated by high GSH concentrations in the cytoplasm. By simultaneous silencing of TGF- β in stromal and tumor cells, HA-LSL/siTGF- β dramatically reduced stroma deposition, promoted the penetration of nanomedicines for deep remodeling of the TME, improved oxygenation, T cells infiltration and subsequent anti-PD-L1 deep penetration. The double suppression of TGF- β has been demonstrated to promote blood vessel normalization, inhibit an epithelial-to-mesenchymal transition (EMT), and further modify the immunosuppressive TME, which was supported by an overall increase in the proportion of dendritic cells and cytotoxic T cells. Further, a reduction in the proportion of immunosuppression cells such as regulatory T cells and myeloid-derived suppressor cells was also observed in the TME. Based on the comprehensive remodeling of the tumor microenvironment by this nanosystem, subsequent anti-PD-L1 therapy elicited robust antitumor immunity. Specifically, this system was able to suppress the growth of both primary and distant tumor while preventing tumor metastasis to the lung. Therefore, the combination of the dual-targeted siTGF- β nanosystem, alongside anti-PD-L1 may serve as a novel method to enhance antitumor immunotherapy against stroma-rich TNBC.
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PubMed
高影响因子
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY
·
2023
·
IF 1.9
Wenchao Pan,Yadong Wang,Caiyan Zhao
Objective To explore the protective effect and related mechanism of miR-140-5p on liver fibrosis by interfering with TGF-β/Smad signaling pathway.Methods Liver fibrosis mice models were established by intraperitoneal injection of CCL4. Hematoxylin and eosin (HE) staining was used to detect the structural and morphological changes of the liver. Masson staining was used to detect collagen deposition. Human hepatic stellate cells (HSCs, LX-2) were transfected with miR-140-5p mimic or inhibitor then treated with TGF-β1. The qRT-PCR and Western blotting was used to detect the expression of related molecules. The luciferase reporter assay was used to identify the target of miR-140-5p.Results Our results indicated that miR-140-5p expression was downregulated in fibrotic liver tissues of model mice and LX-2 cells treated with TGF-β1. The overexpression of miR-140-5p decreased the expression of collagen1(COL1) and α-smooth muscle actin(α-SMA), inhibited the phosphorylation of Smad-2/3 (pSmad-2/3) in LX-2 cells. Conversely, the knockdown of miR-140-5p upregulated COL1 and α-SMA expression, increased Smad-2/3 phosphorylation. A dual-luciferase reporter assay showed that TGFβR1 was a target gene of miR-140-5p. The overexpression of miR-140-5p suppressed TGFβR1 expression in LX-2 cells. Additionally, knockdown of TGFβR1 decreased the expression of COL1 and α-SMA. Conversely, the overexpression of TGFβR1 reversed the inhibitory effect of miR-140-5p upregulation on expression of COL1 and α-SMA.Conclusion miR-140-5p bound to TGFβR1 mRNA 3′-untranslated region(3′UTR) and inhibited the expression of TGFβR1, pSmad-2/3, COL1 and α-SMA, thereby exerting a potential therapeutic effect on hepatic fibrosis.
研究领域:
分子生物学
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肝病学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·791
·
IF 12.6
Qiao Wenyu,Yang Luling,Liu Yu,Zhang Huaiyuan,Zheng Zhihuan,Gu Tianheng,Zhu Jiaxi,Hu Xinyi,Li Gangze,Zhang Yuxia,Xiao Meng,Zhang Lin
Excessive accumulation of reactive oxygen species (ROS) and dysbiosis of the gut microbiota are pivotal contributors to the pathogenesis of inflammatory bowel disease (IBD) and associated fibrosis. In this study, a microfluidic approach was utilized to fabricate a multifunctional therapeutic microsphere system by encapsulating hollow mesoporous cerium oxide nanoparticles (HCeO 2 ) loaded with KP1 short peptides-specific inhibitors of the TGF-β/Smad signaling pathway. The resulting composite formulation (KP1@HCeO₂@SAM) was designed to achieve synergistic antioxidant, anti-inflammatory, and antifibrotic effects. The developed microspheres exhibited prolonged intestinal retention and effectively modulated gut microbiota composition, increasing the relative abundance of probiotic species by over sevenfold. Moreover, they demonstrated remarkable reactive oxygen species (ROS) scavenging efficiency (> 95%) and significant inhibition of fibrotic signaling cascades. In dextran sulfate sodium (DSS)-induced murine colitis models, treatment with the microspheres led to a substantial reduction in Disease Activity Index (DAI) (> 76%), restoration of intestinal barrier integrity (> 90%), and mitigation of fibrotic progression, as indicated by a 66% decrease in α-SMA expression. These findings establish a novel and integrative therapeutic platform for the effective management of IBD. Graphical abstract
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高影响因子
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