MATERIALS & DESIGN
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2026
·
IF 8.2
Yue Peng,Cuiman Tang,Mingcong Niu,Tianyi Xu,QingYu Meng,Xinran Li,Rongheng Ma,Huimin Yu
A traditional medicine-inspired strategy provides a logical framework for constructing carrier-free hybrids. • Precise structural modifications successfully circumvent the inherent bioaccessibility limitations of natural products. • The covalent integration of diverse functional modules enables synergistic therapeutic efficacy against arthritis. • The therapeutic action is closely associated with the modulation of protein kinase B and hypoxia-inducible factor signaling. Curcumin (Cur) possesses potent anti-inflammatory activity but faces clinical challenges due to poor aqueous dispersibility, insufficient membrane affinity, and low bioavailability. Borneol (Bor), a classic “envoy” component in Traditional Chinese Medicine (TCM), exhibits prominent membrane-penetrating properties. Inspired by the “monarch-envoy” compatibility theory, we rationally designed carrier-free hybrids by covalently conjugating Cur (“monarch”) with Bor (“envoy”). Systematic characterization confirmed the successful synthesis and controllable optimization of key properties, including enhanced dispersibility, improved cellular uptake, and favorable biocompatibility. Using rheumatoid arthritis (RA) as a disease model, we identified SCBMS as the optimal formulation owing to its superior dispersibility and uptake, which directly translated into the most potent anti-RA efficacy. The hybrids exerted synergistic multifunctional effects—including robust anti-inflammatory and antioxidant activities—effectively reducing the arthritis index and ameliorating synovial hyperplasia and joint destruction in vivo . Mechanistically, our results indicate a close correlation between the therapeutic effects and the downregulation of the AKT/mTOR/HIF-1α signaling pathway, supporting the involvement of this pathway in the observed anti-RA activity. This study provides a generalizable framework for developing functional hybrids guided by TCM principles and validates their translational potential. Download: Download high-res image (152KB) Download: Download full-size image
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DOI
高影响因子
Pharmaceutics
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2026
·Vol. 18
·期 7
·869
·
IF 6.9
Jiangtao Zhou,Yuhui Ge,Ran Li,Zhuoyang Cheng,Jianping Gao,Bin Zheng
Background: Skin photoaging, primarily induced by chronic ultraviolet (UV) radiation exposure, is characterized by dryness, wrinkle formation, pigmentation abnormalities, and reduced skin elasticity, resulting from oxidative stress, inflammation, and degradation of the extracellular matrix. Codonopsis pilosula , a traditional food–medicine homologous plant, is recognized for its anti-aging properties. However, its lipophilic components (designated as CP-L) remain insufficiently explored. Methods: Herein, we developed a thermosensitive nanogel encapsulating CP-L-loaded transferosomes (CP-L nanogel) to enhance topical delivery and evaluated its effects in both a UV-induced photoaging mouse model and UVB-irradiated HaCaT keratinocytes. Results: In UV-induced mice, topical application of the nanogel markedly reduced skin wrinkling and epidermal hyperplasia, with epidermal thickness decreased by 83.2% compared to the model group ( p < 0.01), and restored skin elasticity and collagen deposition, as evidenced by a 35.5% increase in collagen area fraction ( p < 0.01). Correspondingly, in UVB-irradiated HaCaT cells, it significantly increased cell viability from 53.0 ± 9.6% to 89.4 ± 1.0% ( p < 0.01) and suppressed apoptosis from 30.1 ± 0.48% to 12.4 ± 0.66% ( p < 0.01). Furthermore, the CP-L nanogel consistently attenuated oxidative stress, with SOD, CAT, and GSH-Px activities increased by 73.1%, 188.1%, and 18.2%, respectively ( p < 0.01), and MDA levels reduced by 71.0% ( p < 0.01), while inflammatory responses were suppressed, as TNF-α, IL-1α, IL-1β, and IL-6 levels decreased by 28.3%, 22.6%, 12.8% and 31.9%, respectively ( p < 0.01). Mechanistically, transcriptomic and molecular analyses revealed that the nanogel potently inhibited the UV-induced activation of the FGFR/PI3K/AKT/mTOR/p70S6K signaling cascade at both transcriptional and protein levels, with the phosphorylation levels of FGFR, PI3K, AKT, mTOR, and p70S6K significantly reduced by 43.9%, 30.9%, 38.8%, 34.9%, and 57.3%, respectively ( p < 0.01). Molecular docking and dynamics simulations identified isofuranodienone and aromadendrene oxide-(2) as key constituents with high-affinity, stable binding to FGFR1 and AKT1. The cytoprotective effect of the nanogel was completely abolished by co-treatment with the FGFR inhibitor PD173074 , confirming functional reliance on this pathway. Enhanced cellular delivery of the formulation was directly demonstrated by flow cytometry, showing an approximately 1.8-fold increase in cellular uptake compared to the free drug ( p < 0.01). Conclusions: Collectively, these results demonstrated that the CP-L nanogel alleviated skin photoaging through a multi-faceted mechanism involving enhanced cellular delivery, potent antioxidant and anti-inflammatory activities, and specific inhibition of the FGFR/PI3K/AKT/mTOR signaling cascade, highlighting its potential as a multitargeted topical agent derived from an edible plant.
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2023
·
IF 3.9
Huaxiang Wang,Minyong Chen,Chengkai Yang,Huanzhang Hu,Yi Jiang,Fang Yang,Lizhi Lv
Background Small nuclear ribonucleoprotein Sm D1 (SNRPD1) has been reported as an oncogene in some solid cancers. Our previous study suggested that SNRPD1 has diagnostic and prognostic value in hepatocellular carcinoma (HCC), but its role in tumor growth and biological behavior remains unknown. In this study, we aimed to unravel the role and mechanism of SNRPD1 in HCC. Methods We investigated the SNRPD1 mRNA level in adjacent normal liver tissues and HCC tissues with different tumor stages in the UALCAN database. The associations between SNRPD1 mRNA expression and HCC prognosis were investigated in TCGA database. Then, 52 pairs of frozen HCC tissues and corresponding adjacent normal liver tissues were collected to perform qPCR and immunohistochemistry assay. Next, we carried out a series of experiments in vitro and in vivo to investigate the effects of SNRPD1 expression on cell invasion, migration, proliferation, autophagy, and the PI3K/AKT/mTOR pathway. Results The bioinformatics analysis and qPCR in our patient cohort demonstrated that the SNRPD1 mRNA level in HCC tissues was higher than in adjacent normal tissues. In addition, the immunohistochemistry assay exhibited an increased SNRPD1 protein level with the tumor stage increase. Survival analysis suggested that higher expression of SNRPD1 was significantly associated with unfavorable prognosis of patients with HCC. The functional experiments in vitro indicated that SNRPD1 knockdown suppressed the cellular proliferation , migration, and invasion capacities. Furthermore, SNRPD1 inhibition induced cellular apoptosis and arrested the HCC cells at the G0/G1 phase of the cell cycle. Mechanistic analyses demonstrated that SNRPD1 knockdown induced the increase of autophagic vacuoles and the expression of autophagy-related genes (ATG5, ATG7 , and ATG12) and blocked the PI3K/AKT/mTOR/4EBP1 pathway in vitro. Moreover, SNRPD1 inhibition suppressed tumor growth and expression of the Ki67 protein in vivo. Conclusions SNRPD1 may serve as an oncogene in HCC and promote tumor proliferation via inhibiting autophagy induced through the PI3K/Akt/mTOR/4EBP1 pathway.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Xin Xie,Yan Zhu,Huimin Cheng,Haili Li,Yadi Zhang,Rong Wang,Wenyong Li,Fengrui Wu
Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo . The results showed that BPA (10 μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10 μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo ; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
FOOD SCIENCE AND BIOTECHNOLOGY
·
2022
·Vol. 31
·期 13
·1741-1751
·
IF 3.231
Ding Haomiao,Zhang Yuzhe,Zha Yue,Zhou Sijia,Cao Chaoqing,Zhu Huajian,Xu Feng,Zhang Xiuqiang,Wang Caisheng
The cytoprotective and potential molecular mechanisms of Hylocereus polyrhizus protein (RFPP) were investigated on the hydrogen peroxide (H 2 O 2 )-triggered damage in normal human embryonic lung (MRC-5) cells. An MTT assay was conducted to assess the MRC-5 cell viability after exposure to H 2 O 2 or RFPP. Cell cycle distribution and apoptosis were explored via flow cytometry. The contents of related proteins were assessed via western blot. MRC-5 cells exhibited markedly decreased cellular viability after treatment with H 2 O 2 ; however, treatment with RFPP suppressed this decrease. Additionally, RFPP interference dampened H 2 O 2 -triggered intracellular apoptosis levels and increased H 2 O 2 -triggered intracellular S phase. In these processes, the contents of phosphorylated ( p )-AKT along with p -mTOR proteins were downregulated in 120 µM H 2 O 2 -treated cells compared with vehicle-treated cells. Nevertheless, in MRC-5 cells inoculated with RFPP, the levels expression of these proteins were reversed. To conclude, RFPP protected MRC-5 cells from H 2 O 2 -triggered damage via activation of the PI3K/AKT/mTOR cascade.
研究领域:
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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PubMed
高影响因子
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
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2025
·
IF 3.1
Qing Su,Jia Chen
Steroid-induced osteonecrosis of the femoral head (SIONFH) is a debilitating orthopedic condition. This study investigated the mechanism of Tanshinone I (TsI) in SIONFH modulating apoptosis in SIONFH via the PI3K/AKT/mTOR pathway. A SIONFH rat model was treated with TsI and a PI3K activator. Bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were determined by microCT. Empty lacunae count, Osteopontin, and apoptosis of the femoral head tissues were assessed. Levels of Bax, cleaved-caspase-3, Bcl-2, and AKT, PI3K, and mTOR phosphorylation in femoral head tissues were determined by Western blot. SIONFH rats exhibited decreased BMD, BV/TV, Tb.N, and Tb.Th, increased Tb.Sp, reduced Osteopontin-positive cells, increased empty lacunae rate, and TUNEL and Osteopontin co-positive cells, elevated Bax and cleaved-caspase-3 protein levels, and diminished Bcl-2 protein expression. TsI promoted osteogenesis, attenuated SIONFH, and reduced apoptosis in SIONFH rats. TsI inhibited AKT, PI3K, and mTOR phosphorylation levels in the femoral head tissues of SIONFH rats, thereby repressing the PI3K/AKT/mTOR pathway activation. Activating the PI3K/AKT/mTOR pathway partially reversed TsI's effect in rats. Collectively, TsI limited the PI3K/AKT/mTOR pathway activation to reduce osteocyte apoptosis in SIONFH rats, which provided potential therapeutic insights for SIONFH treatment.
研究领域:
骨科学
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分子药理学
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细胞生物学
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信号转导
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中医药学
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PubMed
高影响因子
Heliyon
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2024
·
IF 3.4
Changhong Wu,Jie Yang,Chenxiao Ye,Hui Wu,Wenxi Shu,Rongrong Li,Sihan Wang,Yi Lu,Haitao Chen,Zewei Zhang,Qinghua Yao
Background 5-Fluorouracil (5-Fu), a prominent chemotherapeutic agent for colorectal cancer (CRC) treatment, is often associated with gastrointestinal toxicities, particularly diarrhea. Our previous study demonstrated that berberine (BBR) ameliorates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota in rats. Nevertheless, the precise molecular mechanism underlying BBR's protective effect on intestinal mucosa remains elusive, and its impact on the anti-tumor efficacy of 5-Fu warrants further investigation. Methods The effect of BBR on 5-Fu-induced intestinal mucosal injury was investigated using a tumor-bearing murine model, employing H&E staining, 16 S rDNA sequencing, transcriptome sequencing, Western blot analysis, cell experiments and constructing a pseudo-germ-free tumor xenograft model. Result Our findings demonstrate that BBR alleviates intestinal mucosal damage, reduces the levels of inflammatory factors (IL-6, TNF-α, and IL-1β), and inhibits epithelial cell apoptosis in 5-Fu-treated mice without compromising 5-Fu's anti-tumor efficacy. Moreover, 16 S rDNA sequencing indicated that BBR significantly increases the abundance of Akkermansia and decreases the abundance of pathogenic bacteria Escherichia/Shigella at the genus level. Mechanistically, transcriptome sequencing and Western blot analysis confirmed that BBR upregulates PI3K/AKT/mTOR expression in the intestinal mucosa. However, this effect was not observed in tumor tissues. Notably, BBR did not demonstrate a direct protective effect on 5-Fu-treated CCD841 and SW480 cells. Additionally, BBR had no effect on the PI3K/AKT/mTOR pathway in the intestinal tissue of the 5-Fu-treated mouse model with a depleted gut microbiota. Conclusion This study indicates that BBR alleviates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota and regulating the PI3K/AKT/mTOR signaling pathway without compromising the anti-tumor efficacy of 5-Fu.
研究领域:
肿瘤学
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微生物学
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药理学
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分子生物学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Lingli Jiang,Rui Liang,Qing Luo,Zhe Chen,Guanbin Song
Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.
研究领域:
癌症生物学
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分子生物学
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药理学
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PubMed
高影响因子
Oncotarget
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2015
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IF 6.359
Ping Song,Li Ye,Jiajun Fan,Yubin Li,Xian Zeng,Ziyu Wang,Shaofei Wang,Guoping Zhang,Ping Yang,Zhonglian Cao,Dianwen Ju
The antitumor enzyme asparaginase, which targets essential amino acid L-asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase-treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML.
研究领域:
肿瘤学
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血液学
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分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Qicheng Chen,Li Ye,Jiajun Fan,Xuyao Zhang,Huan Wang,Siyang Liao,Ping Song,Ziyu Wang,Shaofei Wang,Yubin Li,Jingyun Luan,Yichen Wang,Wei Chen,Wenjing Zai,Ping Yang,Zhonglian Cao,Dianwen Ju
Asparaginase has been reported to be effective in the treatment of various leukemia and several malignant solid cancers. However, the anti-tumor effect of asparaginase is always restricted due to complicated mechanisms. Herein, we investigated the mechanisms of how glioblastoma resisted asparaginase treatment and reported a novel approach to enhance the anti-glioblastoma effect of asparaginase. We found that asparaginase could induce growth inhibition and caspase-dependent apoptosis in U87MG/U251MG glioblastoma cells. Meanwhile, autophagy was activated as indicated by autophagosomes formation and upregulated expression of LC3-II. Importantly, abolishing autophagy using chloroquine (CQ) and LY294002 enhanced the cytotoxicity and apoptosis induced by asparaginase in U87MG/U251MG cells. Further study proved that Akt/mTOR and Erk signaling pathways participated in autophagy induction, while reactive oxygen species (ROS) served as an intracellular regulator for both cytotoxicity and autophagy in asparaginase-treated U87MG/U251MG cells. Moreover, combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model. Taken together, our results demonstrated that inhibition of autophagy potentiated the anti-tumor effect of asparagine depletion on glioblastoma, indicating that targeting autophagy and asparagine could be a potential approach for glioblastoma treatment.
研究领域:
肿瘤学
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药理学
·
细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
·
2014
·
IF 2.114
Jing Lu,Duanping Sun,Si Gao,Ying Gao,Jiantao Ye,Peiqing Liu
Autophagy is a highly regulated and multi-step biological process that serves to remove damaged cytoplasmic components and organelles. It has been suggested that the activation of autophagy may be a promising therapeutic strategy for cancer treatment by triggering cell death. In this study, we reported that cyclovirobuxine D (CVB-D), an alkaloid component in a traditional Chinese herb, could induce autophagy in the MCF-7 human breast cancer cell line. CVB-D inhibited the viability of MCF-7 cells in a concentration- and time-dependent manner. Activation of autophagy was characterized by transmission electron microscopy, monodansylcadaverine staining, and expression of autophagy marker microtubule-associated protein 1 light chain 3 (LC3). After CVB-D treatment, a clear accumulation of autophagosomes was observed accompanied with elevated LC3 fluorescent puncta. Western blot analysis revealed that CVB-D significantly promoted the conversion from LC3-I to LC3-II and the expression of autophagy-related protein 5 (ATG5), which are both essential for autophagosome formation. On the other hand, CVB-D–induced autophagy and decrease in cell viability could be blocked by 3-methyladenine, a well-established autophagy inhibitor. Moreover, CVB-D attenuated the phosphorylation of Akt and mTOR, two pivotal suppressors in autophagy pathways. These findings shed new light on the pharmacological actions and mechanism of CVB-D and may support the potential utility of autophagy inducers in cancer treatment.
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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DOI
PubMed
高影响因子
POULTRY SCIENCE
·
2026
·
IF 4.5
Yi Fang,Hongyu Fu,Xuehan Jiang,Hongxue Yang,Yishan Yin,Bo Li,Xiaoxiao Chen,Bendong Shi,Jingzeng Cai,Ziwei Zhang
Deoxynivalenol (DON), as the most prevalent mycotoxin, not only poses a significant threat to animal and human health but also exerts pronounced adverse effects on growth and development. Quercetin (QUE), a naturally occurring antioxidant, is known to promote muscle growth and differentiation. In this study, a DON-exposed broiler model with QUE intervention was established to investigate the protective mechanisms of QUE against DON-induced skeletal muscle toxicity. Eighty broilers were randomly divided into four groups: CON group, DON group, QUE group, and DON+QUE group. Each group received oral administration of 10 mg/kg DON and/or 4 mg/kg QUE. For in vitro experiments, myoblasts were used as experimental subjects to establish intervention models with LY294002, Z-VAD-FMK, and IBS008738. This study demonstrates that DON exposure induces oxidative stress and apoptosis (increased by 329%) in both in vivo muscle tissue and in vitro myoblasts, inhibits the expression of myogenic regulatory factors such as MYH2, and consequently leads to structural muscle damage and developmental impairment. Crucially, we identified that QUE effectively alleviated DON-induced oxidative stress (CAT activity increased by 45.1%), apoptosis (nearly completely inhibited), and muscle developmental disorders (MYH2 increased by 35.2%) by upregulating the transcription and phosphoprotein expression levels of genes associated with the PI3K/Akt/mTOR signaling pathway. The pivotal role of this pathway was further confirmed by the fact that the PI3K inhibitor LY294002 abolished the protective effects of QUE. Moreover, inhibition of apoptosis, but not promotion of myogenesis, directly alleviated DON-induced muscle defects, establishing apoptosis as the causative event. In conclusion, our data demonstrated that QUE alleviated DON-induced apoptosis via the PI3K/Akt/mTOR pathway, thereby mitigating muscle development disorders.
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高影响因子
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