BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 46
·期 7
·883-892
·
IF 2
Xiaoyu Yu,Chun Du,Yifei Cui,Yang Jiang,Di Feng
Ovarian cancer (OC) is one of the most common tumors in female reproductive organs with a five-year survival rate of less than 45%. Metastasis is a crucial contributor to OC development. ETS transcription factor (ELK3), as a transcriptional factor, have been involved in multiple tumor development. However, its role in OC remains elusive. In this study, we observed high expression of ELK3 and AEG1 in human OC tissues. OVCAR-3 and SKOV3 cells were treated with hypoxia to mimic tumor microenvironment in vivo. We found that the expression of ELK3 was significantly increased in cells under hypoxia compared with normoxia. ELK3 knockdown inhibited cell migration and invasion abilities under hypoxia. Moreover, ELK3 knockdown decreased β-catenin expression and inhibited the activation of Wnt/β-catenin pathway in SKOV3 cells under hypoxia. Astrocyte-elevated gene-1 (AEG1) has been reported to promote OC progression. Our results showed that the mRNA level of AEG1 was decreased when ELK3 knockdown under hypoxia. Dural luciferase assay confirmed that ELK3 bound to gene AEG1 promoter (−2005–+15) and enhanced its transcriptional activity under hypoxia. Overexpression of AEG1 increased the migration and invasion abilities of SKOV3 cell with ELK3 knockdown. In the absence of ELK3, the activation of β-catenin was recovered by AEG1 overexpression. To sum up, we conclude that ELK3 promotes AEG1 expression by binding to its promoter. ELK3 could promote migration and invasion of OC cells by targeting AEG1, which provides a potential basis for therapeutic approaches to OC.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
APOPTOSIS
·
2025
·
IF 8.1
Miao Jintian,Jiang Xinyan,Wang Siyun
Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
PATHOLOGY RESEARCH AND PRACTICE
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2025
·
IF 3.2
Ting-Ting Yang,Xin-Xin Ma,Xuan Zhang,Zhen-Qing Han,Shuang Zhang,Qi Wang,Hong-Wei Dong,Jia-Ren Liu
β-Ionone (BI) has shown the potent inhibitory malignant progression of multiple tumors including gastric cancer in vitro and in vivo. However, the mechanism by which BI inhibits gastric cancer remains to be clarified, especially in ferroptosis, which is a new form of programmed cell death. The aim of this study was to investigate whether BI could induce ferroptosis in gastric cancer and the underlying mechanisms. The results manifested that BI obviously inhibited cell viability and increased the Fe 2 + level, total reactive oxygen species (ROS) and lipid ROS levels and the malondialdehyde (MDA) concentrations, but reduced the mitochondrial membrane potential (MMP) and the expression of SLC7A11 and GPX4 in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Besides, BI also arrested cell cycle and decreased the expression of Cyclin D1 and CDK4 ( P < 0.05 or P < 0.01). Mechanistically, BI reduced the levels of β-catenin and pGSK-3β/GSK-3β in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Nevertheless, pretreatment with lithium chloride (LiCl), an inhibitor of GSK-3β, reversed BI-induced ferroptosis and cell cycle arrested in MKN45 cells ( P < 0.05). In addition, BI effectively inhibited the growth of gastric cancer xenografts and downregulated the levels of GPX4, SLC7A11, PCNA, β-catenin and pGSK-3β/GSK-3β ( P < 0.05 or P < 0.01). Collectively, our study reveals that BI inhibits proliferation of gastric cancer cells by induction ferroptosis via the Wnt/β-catenin signaling pathway and provides a novel therapy for gastric cancer.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
BMC Cardiovascular Disorders
·
2024
·Vol. 24
·期 1
·1-11
·
IF 2
Lin Wei,Hou Lianglei,Tang Jialyu,Huang Anwu,Jia Zhuyin
In this study, we sought to investigate the mechanisms of action of miR-195-5p in the osteogenic differentiation of vascular smooth muscle cells (VSMCs), and thereby provide novel insights and a reference for the targeted therapy of arterial media calcification. VSMC differentiation was induced using sodium β-glycerophosphate, and we investigated the effects of transfecting cells with miR-195-5p mimics, vectors overexpressing Smad7, and the Wnt/β-catenin pathway inhibitor (KYA1797K) on VSMC differentiation by determining cell viability and apoptosis, and the mRNA and protein expression of factors associated with osteogenic differentiation and the Wnt/β-catenin pathway. The results revealed that miR-195-5p mimics enhanced the osteogenic differentiation of VSMCs induced by β-glycerophosphate, whereas the overexpression of Smad7 reversed this phenomenon. In addition, KYA1797K was found to promote the effects of Smad7 overexpression. In conclusion, by targeting, Smad7, miR-195-5p promotes the Wnt/β-catenin pathway. and thus the osteogenic differentiation of VSMCs. These findings will provide a reference for elucidating the mechanisms whereby miR-195-5p regulates osteogenic differentiation.
研究领域:
分子生物学
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细胞生物学
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心血管研究
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Jieyi Zuo,Juan Liao,Lilin Zhu,Shuang Chen,Wenxin Wen,Ying Li,Dawei Sun,Lei Xu
Osteoporosis is one of the most prevalent age-related diseases worldwide. It is characterized by a systemic deterioration in bone strength (bone density and bone mass), leading to an increase in fragility fractures. The complex pathological environment of osteoporosis presents a significant challenge to the induction of bone regeneration under osteoporotic conditions. Therefore, the development of a system for local delivery of active substances with osteoinductive effects is of practical significance in the clinical treatment of osteoporosis. In this study, we successfully loaded the anti-osteoporotic small molecule drug zoledronate (ZOL) into calcium alginate to prepare a biologically functional hydrogel, designated as ALG-ZOL-Ca. The prepared ALG-ZOL-Ca hydrogel gels quickly, making the hydrogel easy to inject and adapt to irregularly shaped bone defects, and simultaneously exhibits good bioactivity and osteoconductivity. The RT-qPCR results suggested that this hydrogel effectively promoted the expression levels of β-catenin and Axin2, which indicating a stimulative effect on the Wnt/β-catenin pathway in vitro. Moreover, ALG-ZOL-Ca hydrogel effectively promoted the expression of the OCN and SP7 genes. Therefore, this study proposes a new functional composite hydrogel that provides a potential treatment strategy for osteoporosis.
研究领域:
药理学
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材料科学
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生物医学工程
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骨科
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Wenli Cai,Keneng Cai,Zeyu Li,Xiaoru Zhang,Shuqing Gong,Lingling liao,Jiaying Gao,Quangang Xu,Ergang Liu,Jianming Liang,Yongzhuo Huang
The pathogenesis of androgenetic alopecia (AGA) is driven by heightened androgen receptor signaling, alongside contributing factors of oxidative stress, follicular inflammation, and impaired perifollicular angiogenesis. Existing treatments such as minoxidil and finasteride suffer from limited efficacy, systemic side effects, and high relapse rates. In this study, we developed a rosemary oil (RO)-based microemulsion (QAR ME) for the co-delivery of quercetin (QT) and adenosine (AD) to synergistically target multiple pathological pathways of AGA. Here, RO can not only serve as a component of the oil phase but also function as a functional excipient with inherent antioxidant activity. The optimized QAR ME formulation demonstrated high stability, a small uniform particle size (24.98 ± 0.41 nm). It not only improved the solubility of QT but also enhanced the skin penetration of each active component. In vitro and in vivo evaluations revealed that QAR ME effectively attenuated oxidative stress, suppressed inflammatory responses, promoted angiogenesis, and activated the Wnt/β-catenin pathway, leading to enhanced hair follicle regeneration. It is worth noting that during the 28-day continuous treatment, QAR ME did not show any adverse reactions, which indicates that this therapy has the potential for long-term treatment of AGA. These findings indicate that QAR ME is a promising topical nanotherapy for the safe and effective treatment of AGA.
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高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Xiaochen Su,Xunan Jing,Wanting Jiang,Meng Li,Kai Liu,Menghao Teng,Daquan Wang,Lingjie Meng,Yingang Zhang,Wenchen Ji
The microenvironment of excessive inflammation and the activation of apoptotic signals are primary barriers to neurological recovery following spinal cord injury (SCI). Thus, long-lasting anti-inflammation has become an effective strategy to navigate SCI. Herein, a curcumin (CUR)-containing nanosystem (FCTHPC) with high drug loading efficiency was reported via assembling hydrophobic CUR into cross-linked polyphosphazene (PPZ), and simultaneous loading and coordinating with porous bimetallic polymers for greatly enhanced the water-solubility and biocompatibility of CUR. The nanosystem is noncytotoxic when directing its biological activities. By inhibiting the expression of pro-inflammatory factors (IL-1β, TNF-α and IL-6) and apoptotic proteins (C-caspase-3 and Bax/Bcl-2), which may be accomplished by activating the Wnt/β-catenin pathway, the versatile FCTHPC can significantly alleviate the damage to tissues and cells caused by inflammation and apoptosis in the early stage of SCI. In addition, the long-term in vivo studies had demonstrated that FCTHPC could effectively inhibit the formation of glial scars, and simultaneously promote nerve regeneration and myelination, leading to significant recovery of spinal cord function. This study emphasises the promise of the biocompatible CUR-based nanosystem and provides a fresh approach to effectively treat SCI.
研究领域:
药理学
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神经科学
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
Chinese Journal of Integrative Medicine
·
2023
·
IF 2.9
Qian Xiao-li,Meng Di,Liu Heng,Liu Chao-he,Zhou Ping,Yang Yin-he,Wang Jia-peng,Xiao Huai,Ding Zhong-tao
Objective To explore the proliferation inhibitory effect of quinones from Blaps rynchopetera defense secretion on colorectal tumor cell lines. Methods Human colorectal cancer cell HT-29, human colorectal adenocarcinoma cell Caco-2 and normal human colon epithelial cell CCD841 were chosen for the evaluation of inhibitory activity of the main quinones of B. rynchopetera defense secretion, including methyl p-benzoquinone (MBQ), ethyl p-benzoquinone (EBQ), and methyl hydroquinone (MHQ), through methyl thiazolyl tetrazolium assay. The tumor-related factors, cell cycles, related gene expressions and protein levels were detected by enzyme-linked immunosorbent assy, flow cytometry, RT-polymerase chain reaction and Western blot, respectively. Results MBQ, EBQ, and MHQ could significantly inhibit the proliferation of Caco-2, with half maximal inhibitory concentration (IC 50 ) values of 7.04 ± 0.88, 10.92 ± 0.32, 9.35 ± 0.83, HT-29, with IC 50 values of 14.90 ± 2.71, 20.50 ± 6.37, 13.90 ± 1.30, and CCD841, with IC 50 values of 11.40 ± 0.68, 7.02 ± 0.44 and 7.83 ± 0.05 µg/mL, respectively. Tested quinones can reduce the expression of tumor-related factors tumor necrosis factor α, interleukin (IL)-10, and IL-6 in HT-29 cells, selectively promote apoptosis, and regulate the cell cycle which can reduce the proportion of cells in the G 1 phase and increase the proportion of the S phase. Meanwhile, tested quinones could up-regulate mRNA and protein expression of GSK-3β and APC, while down-regulate that of β-catenin, Frizzled1, c-Myc, and CyclinD1 in the Wnt/β-catenin pathway of HT-29 cells. Conclusion Quinones from B. rynchopetera defense secretion could inhibit the proliferation of colorectal tumor cells and reduce the expression of related factors, which would be functioned by regulating cell cycle, selectively promoting apoptosis, and affecting Wnt/β-catenin pathway-related mRNA and protein expressions.
研究领域:
肿瘤学
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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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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Xuepeng Wang,Chunchun Zou,Changju Hou,Zhenyu Bian,Wu Jiang,Maoqiang Li,Liulong Zhu
Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have emerged as promising tools for promoting bone regeneration. This study investigates the functions of EVs derived from bone marrow-derived MSCs (BMSCs) in osteoporosis (OP) and the molecular mechanism. EVs were isolated from primary BMSCs in mice. A mouse model with OP was induced by ovariectomy. Treatment with EVs restored bone mass and strength, attenuated trabecular bone loss and cartilage damage, and increased osteogenesis while suppressing osteoclastogenesis in ovariectomized mice. In vitro , the EVs treatment improved the osteogenic differentiation of MC-3T3 while inhibiting osteoclastic differentiation of RAW264.7 cells. Microarray analysis revealed a significant upregulation of ubiquitin specific peptidase 7 (USP7) expression in mouse bone tissues following EV treatment. USP7 was found to interact with Yes1 associated transcriptional regulator (YAP1) and stabilize YAP1 protein through deubiquitination modification. YAP1-related genes were enriched in the Wnt/β-catenin signaling, and overexpression of YAP1 promoted the nuclear translocation of β-catenin. Functional experiments underscored the critical role of maintaining USP7, YAP1, and β-catenin levels in the pro-osteogenic and anti-osteoclastogenic properties of the BMSC-EVs. In conclusion, this study demonstrates that USP7, delivered by BMSC-derived EVs, stabilizes YAP1 protein, thereby ameliorating bone formation in OP through the Wnt/β-catenin activation.
研究领域:
干细胞生物学
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骨生物学
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分子生物学
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再生医学
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DOI
PubMed
高影响因子
Dermatologica Sinica
·
2025
·
IF 2.2
Peng Yan,He Ling,Yang Xiaoqiong,Zhao Aijie
Background: Androgenetic alopecia (AGA), a kind of nonscarring baldness, is an androgen-dependent autosomal dominant polymorphism. Compound glycyrrhizin (CG), a compound preparation-containing glycyrrhizin, aminoacetic, and methionine, has been used to treat alopecia areata. Objectives: Our study aimed to explore the role of CG in hair regrowth in testosterone-induced AGA mouse model and the proliferation of human hair dermal papilla cells (HDPCs) and the related molecular mechanisms. Methods: The AGA mouse model was established through the injection of testosterone. The in vivo therapeutic effects of CG on AGA were assessed by detecting skin color changes, hair growth time, average hair length, and histological score. Human HDPCs after CG treatment were subjected to CCK-8 assay to evaluate cell proliferation. The impacts of CG on growth factor expression and the Wnt/β-catenin signaling in mouse dorsal skins and HDPCs were determined by undertaking western blotting, reverse transcription-quantitative polymerase chain reaction, and immunofluorescence staining. The Wnt/β-catenin pathway inhibitor XAV939 was used to validate the beneficial role of Wnt/β-catenin pathway activation in CG-mediated hair growth. Results: Our results showed that CG facilitated new hair growth and increased hair follicle numbers on the depilated dorsal area of the model mice. Furthermore, CG administration upregulated p-GSK-3β, β-catenin, cyclin D1, Axin2, LEF1, fibronectin, and survivin levels in the dorsal skins of model mice. In vitro assays revealed that CG promoted cell proliferation, elevated the mRNA levels of growth factors-related genes (insulin-like growth factors-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF)), and increased p-GSK-3β, β-catenin, cyclin D1, Axin2, LEF1, fibronectin, and survivin protein levels in HDPCs. Importantly, XAV939 treatment debilitated the promotion of CG on hair regrowth in model mice and human hair dermal papilla cell (HPDC) proliferation. Conclusion: The beneficial role of CG in hair regrowth in AGA mice and HDPC cell proliferation depends on the Wnt/β-catenin pathway activation and the subsequent growth factor production in hair follicles. These results imply the potential of CG in the treatment of AGA.
研究领域:
皮肤病学
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药理学
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分子生物学
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细胞生物学
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内分泌学
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DOI
高影响因子
Biology-Basel
·
2025
·Vol. 14
·期 7
·831
·
IF 3.5
Tangfei Guan,Xin Yang,Canhui Hong,Peiyun Xiao,Yongshou Yang,Chenggui Zhang,Zhengchun He
Androgenetic alopecia (AGA), the most prevalent form of hair loss, faces challenges such as high costs and limited efficacy in current treatments. This study demonstrates that PA-011, a derivative of Periplaneta americana (L.), exhibits promising therapeutic potential in AGA mouse models. Using a DHT-induced AGA mouse model combined with multi-omics approaches (LC-MS/MS, transcriptomics, metabolomics) and 16S rRNA microbiome analysis, we found that PA-011 promotes hair follicle stem cell proliferation (via upregulated Ki67 expression) by activating the Wnt/β-catenin pathway while suppressing oxidative stress and inflammation. Mechanistic studies revealed its ability to regulate the PI3K-Akt/MAPK signaling pathways, improve pentose phosphate metabolism and amino acid biosynthesis, and maintain skin microbial homeostasis. Safety assessments confirmed no toxicity with topical application. This preclinical study highlights PA-011 as a multi-target therapeutic candidate for AGA, offering a novel strategy for future treatment development. Androgenetic alopecia (AGA), the most prevalent form of hair loss worldwide, faces significant therapeutic challenges due to high costs and limited efficacy of current interventions, necessitating safer and more effective solutions. Periplaneta americana (L.)-derived PA-011, endowed with anti-inflammatory and antioxidant properties, has demonstrated notable hair growth-promoting effects in AGA mouse models. This study employed LC-MS/MS, peptidomics, and network pharmacology to characterize PA-011’s chemical composition and predict its potential targets in AGA pathogenesis. Using Western blot and RT-qPCR, PA-011 intervention significantly inhibited inflammatory responses and oxidative stress levels in mouse skin tissues. Concurrently, PA-011 activated the proliferative potential of hair follicle stem cells, as demonstrated by upregulated expression of the cell proliferation marker Ki67, and activated the Wnt/β-catenin signaling pathway in DHT-induced AGA mice. Transcriptomic and metabolomic analyses revealed multi-target effects of PA-011, including modulation of PI3K-Akt/MAPK pathways, pentose phosphate metabolism, and amino acid biosynthesis. 16S rRNA sequencing and metagenomic analysis showed that AGA disrupts skin microbial homeostasis, while PA-011 intervention normalized the microbiota composition. Topical application of PA-011 promoted robust hair regrowth without detectable toxicity in safety assessments. This preclinical study establishes PA-011 as a promising candidate for AGA therapy, warranting further translational investigation.
研究领域:
皮肤病学
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药理学
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系统生物学
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微生物学
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生物信息学
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分子生物学
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代谢通路
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干细胞研究
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
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IF 5.9
Xin Wei,Yuyan Guo,Jianyuan Lei,Na Chen
Introduction Microsatellite stable colorectal cancer (MSS-CRC) is referred to as an immune desert-type tumor. Emerging studies have demonstrated that inhibition of the Wnt/β-catenin pathway can enhance the anti-tumor immune response. This research focuses on synthesizing the human serum albumin (HSA) -based Wnt inhibitor GHSACA and assessing its internalization pathway and therapeutic effectiveness in conjunction with PD-1 antibody for treating MSS-CRC. Methods Glucosamine was covalently conjugated to HSA via EDC/NHS activation to generate GHSA, which was subsequently coupled with carnosic acid (CA) -Wnt pathway inhibitor, to synthesize GHSACA. For in vitro studies, LOX1- and CD44- deficient MC38 and CT26 colon cancer cell lines, validated by RT-qPCR, were used to investigate the cellular uptake mechanism and macropinocytic activity of GHSACA using flow cytometry. The effectiveness of GHSACA in targeting tumors in vivo was assessed in CT26 tumor-bearing BALB/c mice via fluorescence imaging. Therapeutic efficacy was assessed in MSS-CRC patient-derived xenograft (PDX). Results RT-qPCR confirmed efficient knockdown of LOX1 and CD44 in both MC38 and CT26 cell lines. Cellular uptake assay demonstrated that GHSACA internalization is predominantly mediated by the LOX1-dependent macropinocytosis pathway. In vivo fluorescence imaging revealed sustained accumulation of GHSACA in tumor and rapid clearance from normal organs. In the PDX model, GHSACA monotherapy significantly suppressed tumor growth (TGI = 59.3%). The combination with PD-1 antibody (G&P group) resulted in further enhancement of antitumor efficacy (TGI = 87.9%). TUNEL assays showed the most pronounced induction of tumor cell apoptosis in the G&P group. Immunohistochemical analysis demonstrated that GHSACA suppressed the Wnt/β-catenin signaling cascades, alongside with lower Ki67 expression. The G&P combination increased PD-L1 expression and significantly boosted Granzyme B-positive cytotoxic immune responses. Immunofluorescence double staining showed the highest infiltration of CD3 + /CD8 + cytotoxic T lymphocytes of the G&P group, with a concurrent decrease in CD4 + /CD25 + regulatory T cells. GHSACA was found to have favorable systemic biocompatibility and safety. Discussion GHSACA achieves efficient targeted cellular internalization via a macropinocytosis pathway regulated by the LOX1 receptor rather than the CD44 receptor, simultaneously inhibiting the Wnt/β-catenin signaling while activating anti-tumor immune responses. It provides a highly promising translational therapeutic approach for overcoming immune resistance in MSS-CRC.
研究领域:
肿瘤学
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纳米医学
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免疫治疗
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分子生物学
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药物递送
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癌症免疫学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）