Bioactive Materials
·
2024
·
IF 18
Changjiang Liu,Kun Liu,Dong Zhang,Yuting Liu,Yifeng Yu,Haifei Kang,Xianzhen Dong,Honglian Dai,Aixi Yu
Diabetic wounds present multiple functional impairments, including neurovascular dysregulation, oxidative imbalance, and immune dysfunction, making wound healing particularly challenging, while traditional therapeutical strategies fail to address these complex issues effectively. Herein, we propose a strategy utilizing dual-layer microneedles to deliver therapeutic gases by modulating neurovascular coupling and immune functions for diabetic wound treatment. The microneedle can respond to reactive oxygen species (ROS) in the diabetic microenvironment and subsequently generate oxygen (O 2 ) and nitric oxide (NO). These gases comprehensively promote neuro-vascular regeneration, reduce oxidative stress levels, and attenuate inflammation. In vivo studies demonstrate that the microneedle can accelerate diabetic wound healing by modulating neurovascular regeneration and inflammatory processes. Transcriptomic analyses further validate the involvement of related advantageous signaling pathways. The potential mechanism involves the activation of the PI3K-AKT-mTOR pathway to facilitate autophagy, ultimately accelerating the healing process. Thus, our multifunctional dual-layer microneedles provide an effective strategy for treating diabetic wounds.
研究领域:
生物医学工程
·
药理学
·
伤口愈合
·
糖尿病研究
·
神经科学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Guiqin Huang,Yawen Cai,Menghui Ren,Xiaoyu Zhang,Yu Fu,Run Cheng,Yingdi Wang,Mingxing Miao,Lingpeng Zhu,Tianhua Yan
Introduction Triple-negative breast cancer (TNBC) is the primary cause of breast cancer-induced death in women. Literature has confirmed the benefits of Salidroside (Sal) in treating TNBC. However, the study about potential therapeutic targets and mechanisms of Sal-anchored TNBC remains limited. Objective This study was designed to explore the main targets and potential mechanisms of Sal against TNBC. Methods Network pharmacology, bioinformatics, and machine learning algorithm strategies were integrated to examine the role, potential targets, and mechanisms of the Sal act in TNBC. MDA-MB-231 cells and tumor-bearing nude mice were chosen for in vitro and in vivo experimentation. Cell viability and cytotoxicity were determined using CCK-8, LDH test, and Calcein-AM/PI staining. Antioxidant defense, lipid peroxidation, and iron metabolism were explored using glutathione, glutathione peroxidase, malondialdehyde (MDA), C11-BODIPY 581/591 probe, and FerroOrange dye. Glutathione peroxidase 4 (GPX4) or stearoyl-CoA desaturase 1 (SCD1) overexpression or nuclear receptor co-activator 4 (NCOA4) deficiency was performed to demonstrate the mechanism of Sal on TNBC. Results The prediction results confirmed that 22 ferroptosis-related genes were identified in Sal and TNBC, revealing that the potential mechanism of the Sal act on TNBC was linked with ferroptosis. Besides, these genes were mainly involved in the mTOR, PI3K/AKT, and autophagy signaling pathway by functional enrichment analysis. The in vitro validation results confirmed that Sal inhibited TNBC cell proliferation by modulating ferroptosis via elevation of intracellular Fe 2+ and lipid peroxidation. Mechanistically, Sal sensitized TNBC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR axis, thereby suppressing SCD1-mediated lipogenesis of monounsaturated fatty acids to induce lipid peroxidation, additionally facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe 2+ content. The GPX4 or SCD1 overexpression or NCOA4 deficiency results further supported our mechanistic studies. In vivo experimentation confirmed that Sal is vital for slowing down tumor growth by inducing ferroptosis. Conclusions Overall, this study elucidates TNBC pathogenesis closely linked to ferroptosis and identifies potential biomarkers in TNBC. Meanwhile, the study elucidates that Sal sensitizes TNBC to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy, regulated by PI3K/AKT/mTOR signaling pathways. Our findings provide a theoretical basis for applying Sal to treat TNBC.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jianan Qiao,Shuhui Liu,Yanfeng Huang,Xiang Zhu,Chenyang Xue,Yan Wang,Hui Xiong,Jing Yao
Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo . Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.
研究领域:
肿瘤学
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药理学
·
纳米技术
·
代谢调控
·
光疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
·
2023
·
IF 4.4
Mengmeng Zheng,Yanmei Zhang,Yao Xu,Ying Han,Yingli Wu,Jingwu Kang
Salvianolic acid A (SAA), a major active ingredient of Salvia miltiorrhiza Bunge (Danshen), displays strong antiproliferative activity against cancer cells. However, their protein targets remain unknown. Here, we deconvoluted the protein targets of SAA using chemoproteomics and phosphoproteomics. By using alkynylated SAA as a probe, we discovered that SAA is a covalent ligand that can modify cellular proteins via its electrophilic α,β-unsaturated ester moiety. The subsequent chemoproteomics profiling revealed that 46 proteins were covalently modified by SAA, including Raptor, a subunit of mTORC1 for recruiting substrates for mTORC1. Although gene ontology enrichment analysis of these proteins suggested that SAA displays a promiscuous protein interaction, phosphoproteomics profiling revealed that the SAA modulated phosphoproteins were mainly enriched in the signaling pathways of PI3K-Akt-mTOR, which is closely related to cell growth and proliferation. This was confirmed by the biochemical assay with purified mTORC1, a Western blot assay with phospho-specific antibodies, and a cellular thermal shift assay. Our work discovered that SAA is a covalent ligand for protein modification and mTORC1 is one of its targets. Moreover, our work demonstrated that the integrative profiling of chemoproteomics and phosphoproteomics can be a powerful tool for target deconvolution for bioactive natural products.
研究领域:
药理学
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蛋白质组学
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癌症研究
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分子生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Jie Xiong,Jia-Juan Wu,Dong-mei Liu,Muhammad Yousaf,Liu-Jun Liu,Suping Zeng,Qinqin Li,Jun Tang,Yaping Wu
Hyperuricemia (HUA) is a chronic disorder resulting from purine metabolic dysregulation. This research explored the alleviating effects and potential mechanisms of Lactiplantibacillus plantarum MC14 on HUA in a mouse model. Further, it investigated the impact of MC14 intervention on the intestinal flora and metabolites of HUA model mice. Results indicated that the activity of MC14 in alleviating HUA may be linked to its abilities to lower serum levels of uric acid, creatinine, and blood urea nitrogen, reduce inflammation, alleviate renal tissue damage, enhance uric acid excretion, inhibit the overactivation of the PI3K/AKT/mTOR signaling pathway, suppress hepatic adenosine deaminase and xanthine oxidase activities, competitively absorb nucleosides and nucleobases, and regulate the intestinal flora. Our research demonstrates that MC14 is a potential candidate for developing novel therapeutics for hyperuricemia.
研究领域:
微生物学
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药理学
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分子生物学
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营养学
✓ 已验证
产品关联
DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2021
·
IF 3.575
Dandan Zheng,Jinglong Wang,Genju Li,Lulu An,Ying Qu,Qinxiu Zhang,Wenhui Ye,Xin Zhao,Zhongxi Zhao
Autophagy-impairment is involved in the pathological process of chronic obstructive pulmonary disease (COPD), and relates to inflammation and emphysema in lung injury. This study aimed to elucidate the protective effect of S -Allylmercapto- N -acetylcysteine (ASSNAC) against COPD via regulating the autophagy. Firstly, porcine pancreatic elastase (PPE)-induced COPD model in A549 cells was established, and ASSNAC was verified to alleviate the autophagy-impairment from the results of western blotting analysis of LC3BⅡ/Ⅰ and monodansylcadaverine (MDC) staining of autophagosome . Secondly, Balb/c mice were stimulated by PPE to induce the COPD model in vivo . The histological analysis of lung tissues presented that ASSNAC could alleviate the lung injury induced by PPE. Thirdly, the secretions of NO , TNF- α and IL-1 β in serum and BALF were reduced by ASSNAC compared with the PPE group. Finally, the mechanism of therapeutic effects of ASSNAC against COPD through regulating the autophagy-impairment was clarified. That is, ASSNAC inhibits the phosphorylation of PI3K/Akt/mTOR signaling pathways. In a word, this research provides a reference for ASSNAC to be an effective drug for pulmonary diseases.
研究领域:
药理学
·
肺病学
·
分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2016
·
IF 7.145
Jiao Wang,Yue Wang,Qiang Liu,Linnan Yang,Rongrong Zhu,Chengzhong Yu,Shilong Wang
Breast cancer is the primary reason for cancer-related death in women worldwide and the development of new formulations to treat breast cancer patients is crucial. Curcumin (Cur), a natural product, exerts promising anticancer activities against various cancer types. However, its therapeutic efficacy is hindered as a result of poor water solubility, instability, and low bioavailability. The aim of this work is to assess the curative effect of a novel nanoformulation, i.e., Cur-loaded and calcium-doped dendritic mesoporous silica nanoparticles modified with folic acid (Cur-Ca@DMSNs-FA) for breast cancer therapy. The results manifested that Cur-Ca@DMSNs-FA dispersed very well in aqueous solution, released Cur with a pH-responsible profile, and targeted efficiently to human breast cancer MCF-7 cells. Further investigations indicated that Cur-Ca@DMSNs-FA effectively inhibited cell proliferation, increased intracellular ROS generation, decreased mitochondrial membrane potential, and enhanced cell cycle retardation at G2/M phase, leading to a higher apoptosis rate in MCF-7 compared to free Cur. Moreover, the Western blotting analysis demonstrated that Cur-Ca@DMSNs-FA were more active than free Cur through suppression of PI3K/AKT/mTOR and Wnt/β-catenin signaling, and activation of the mitochondria-mediated apoptosis pathway. In addition, hemolysis assay showed that the Ca@DMSNs-FA exhibited good biocompatibility. Last, in vivo studies indicated that when Cur was encapsulated in Ca@DMSNs-FA, the Cur concentration in blood serum and tumor tissues was increased after 1 h intraperitoneal injection. In conclusion, Cur-Ca@DMSNs-FA might act as a potential anticancer drug formulation for breast cancer therapy.
研究领域:
药学
·
纳米技术
·
肿瘤学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Baixi Shan,Haoyan Zhou,Congying Guo,Xiaolu Liu,Mingyu Wu,Rao Zhai,Jun Chen
Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U- 13 C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of TGF-β1- dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro . We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan ⅡA in treating PF using 13 C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.
研究领域:
药理学
·
代谢组学
·
肺医学
·
细胞生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ARCHIV DER PHARMAZIE
·
2024
·
IF 4.3
Jiahong Su,Xingyue Wang,Sha Li,Xu Wu,Mingxing Li,Fukuan Du,Shuai Deng,Jing Shen,Yueshui Zhao,Zhangang Xiao,Yu Chen
Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.
研究领域:
药理学
·
肿瘤学
·
药物化学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2016
·
IF 2.326
Wenjuan Yao,Lei Huang,Qinju Sun,Lifeng Yang,Lian Tang,Guoliang Meng,Xiaole Xu,Wei Zhang
Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis . 2,3,5,4′-Tetrahydroxystilbene-2- O -β- d -glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively.
研究领域:
心血管疾病
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2019
·Vol. 10
·期 10
·6915-6926
·
IF 3.241
Sen Guo,Li Liu,Shanshan Zhang,Chuang Yang,Wenping Yue,Haoan Zhao,Chi-Tang Ho,Junfeng Du,Hai Zhang,Naisheng Bai
Morus species, commonly known as mulberry, is widely distributed in China. The mulberry tree is a high-value plant in agriculture. Morus australis is one of the major Morus species growing in Northern China. However, the biological properties of the main constituents of M. australis roots were not well studied. In the present study, through extensive chromatographic and spectral analysis, 12 phenolic compounds were isolated and identified from the M. australis roots. Compounds 1, 2, 8, 9 and 12 were isolated from M. australis roots for the first time. Antitumor activities of these polyphenols were studied on the A549 cell line. Compounds 1, 5 and 6 exhibited cytotoxicity on A549 cells and induced apoptosis in A549 cells via the intrinsic mitochondrial pathway. They also mediated inhibition of autophagic flux contributed cell death via the PI3k/Akt/mTOR pathway. In order to explore more potential bioactivities of these isolates, α-glucosidase, acetylcholinesterase and tyrosinase inhibitory activities were studied, and the results demonstrated that the inhibitory activity of these polyphenols on enzymes was not defined by their basic structural skeletons, but by the substituted position.
研究领域:
药理学
·
生物化学
·
植物科学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Peng Wu,Xiyalatu Sai,Zhetao Li,Xing Ye,Li Jin,Guihuan Liu,Ge Li,Pingzhen Yang,Mingyi Zhao,Shuoji Zhu,Nanbo Liu,Ping Zhu
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have an irreplaceable role in the treatment of myocardial infarction (MI), which can be injected into the transplanted area with new cardiomyocytes (Cardiomyocytes, CMs), and improve myocardial function. However, the immaturity of the structure and function of iPSC-CMs is the main bottleneck at present. Since collagen participates in the formation of extracellular matrix (ECM), we synthesized nano colloidal gelatin (Gel) with collagen as the main component, and confirmed that the biomaterial has good biocompatibility and is suitable for cellular in vitro growth. Subsequently, we combined the PI3K/AKT/mTOR pathway inhibitor BEZ-235 with Gel and found that the two combined increased the sarcomere length and action potential amplitude (APA) of iPSC-CMs, and improved the Ca 2+ processing ability, the maturation of mitochondrial morphological structure and metabolic function. Not only that, Gel can also prolong the retention rate of iPSC-CMs in the myocardium and increase the expression of Cx43 and angiogenesis in the transplanted area of mature iPSC-CMs, which also provides a reliable basis for the subsequent treatment of mature iPSC-CMs.
研究领域:
干细胞生物学
·
心脏病学
·
再生医学
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生物材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）