EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Qi Wan,Hui Chen,Guirun Xiong,Rui Jiao,Yun Liu,Xiaolei Li,Yu Sun,Jingcheng Wang,Lianqi Yan
Intraarticular fibrosis following knee surgery is a troublesome complication and remains a challenging problem for clinicians. Artesunate (ART), a classical anti-malarial drug extracted from the Chinese medicinal herb Artemisia annua L, has been associated with some fibrosis-related diseases. However, its effect and underlying mechanism on knee arthrofibrosis are still obscure. In the present study, we found that ART induced cellular autophagy flux and inhibited cell proliferation in fibroblasts. Intriguingly, genetic depletion of Beclin-1 abolished ART-triggered cellular autophagy and further attenuated the inhibitory effect of ART on fibroblasts proliferation. Moreover, at molecular level, our results demonstrated that ART-induced autophagy activation was associated with the inhibition of mTOR signaling through PI3K/AKT/mTOR pathway and AMPK/mTOR pathway. In vivo, ART treatment triggered autophagy activation and alleviated the severity of surgery-induced knee arthrofibrosis. Taken together, we concluded that ART exhibited anti-proliferation efficacy in fibroblasts and alleviated the severity of knee arthrofibrosis in rabbits by inducing Beclin-1-mediated autophagy via inhibition of mTOR signaling. These findings indicated that ART might be a potential therapeutic agent for preventing the progression of surgery-induced intraarticular fibrosis of knee.
研究领域:
药理学
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骨科
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Jingyi Chen,Xuan Wang,Xuemei Yuan,Haiting Zou,Jiaye Li,Guopu Chen,Qian Tan
Fibroblast dysfunction is a key factor in the prolonged healing of diabetic wounds. Netrin-1 was found to be able to ameliorate high-glucose-induced fibroblast dysfunction. In this study, we developed a biomimetic dual-network hydrogel loaded with Netrin-1 to promote diabetic wound healing. The hydrogel was composed of natural ingredients, sodium alginate (SA) and glycyrrhizic acid (GA). In addition, with the octopus’s suction cup structure on the surface, this hydrogel exhibited strong adhesion properties and provided protective and sustained release of Netrin-1. The released could promote autophagy by activating the AMPK-mTOR pathway under sustained hyperglycemic conditions, thereby reversing fibroblast dysfunction and restoring cell migration and collagen synthesis. The resultant SA/GA@Netrin-1 hydrogel not only possessed potent antioxidant and antimicrobial effects but also enhanced collagen deposition in diabetic rat wounds, attenuated the inflammatory response, promoted autophagy, and significantly accelerated wound closure. These findings suggest that the SA/GA@Netrin-1 hydrogel provided an innovative solution for chronic diabetic wound management and has the potential to be applied to other refractory wound therapies.
研究领域:
生物材料学
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伤口修复与再生医学
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分子生物学
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糖尿病并发症
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药理学
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转化医学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Haili Xiao,Chao Wei,Huiying Liu,Zhiqiang Li,Cihua Zheng,Jun Luo
Lentinan, a natural drug with wide-ranging pharmacological activities, can regulate autophagy—the process through which Schwann cells (SCs) eliminate myelin fragments after peripheral nerve injury (PNI). However, the effect of lentinan after PNI and the role of accelerated myelin debris removal via autophagy in this process are unclear. This study examined the effect of lentinan on rat sciatic nerve repair following crush injury and the underlying mechanisms. After the successful establishment of the sciatic nerve compression injury model, group-specific treatments were performed. The treatment group received 20 mg/kg lentinan via intraperitoneal injection, while the model group was treated with normal saline. The recovery in each group was then evaluated. Further, a rat SC line (RSC96) was cultured in medium with/without lentinan after supplementation with homogenous myelin fractions to evaluate the removal of myelin particles. Our results showed that lentinan promotes autophagic flux in vivo via the AMPK/mTOR signaling pathway, accelerates the clearance of myelin debris by SCs, and inhibits neuronal apoptosis, thereby promoting neurological recovery. Similarly, in vitro experiments showed that lentinan promotes the phagocytosis of myelin debris by SCs. In conclusion, our results suggest that lentinan primarily promotes nerve regeneration by accelerating the autophagic clearance of myelin debris in SCs, and this process is likely regulated by the AMPK/mTOR signaling pathway. Therefore, this study provides compelling evidence that lentinan may be a cost-effective and natural treatment agent for PNI.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
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IF 6.51
Hongyan Zhang,Jiandong Yu,Lisha Ma,Yue Zhao,Shujun Xu,Jingbin Shi,Ke Qian,Mancang Gu,Hongsheng Tan,Li Xu,Yun Liu,Chaofeng Mu,Yang Xiong
Multi-drug resistance (MDR) in breast cancer poses a great threat to chemotherapy. The expression and function of the ATP binding cassette (ABC) transporter are the major cause of MDR. Herein, a linear polyethylene glycol (PEI) conjugated with dicyandiamide, which called polymeric metformin (PolyMet), was successfully synthesized as a simple and biocompatible polymer of metformin. PolyMet showed the potential to reverse MDR by inhibiting the efflux of the substrate of ATP-binding cassette (ABC) transporter from DOX resistant MCF-7 cells (MCF-7/DOX). To test its MDR reversing effect, PolyMet was combined with DOX to treat mice carrying MCF-7/DOX xenografts. In order to decrease the toxicities of DOX and delivery PolyMet and DOX to tumor at the same time, PolyMet was complexed with poly-γ-glutamic acid-doxorubicin (PGA-DOX) electrostatically at the optimal ratio of 2:3, which were further coated with lipid membrane to form lipid/PolyMet-(PGA-DOX) nanoparticles (LPPD). The particle size of LPPD was 165.8 nm, and the zeta potential was +36.5 mV. LPPD exhibited favorable cytotoxicity and cellular uptake in MCF-7/DOX. Meanwhile, the bioluminescence imaging and immunohistochemical analysis indicated that LPPD effectively conquered DOX-associated MDR by blocking ABC transporters (ABCB1 and ABCC1) via PolyMet. Remarkably, LPPD significantly inhibited the tumor growth and lowered the systemic toxicity in a murine MCF-7/DOX tumor model. This is the first time to reveal that PolyMet can enhance the anti-tumor efficacy of DOX by dampening ABC transporters and activating the AMPK/mTOR pathway, which is a promising strategy for drug-resistant breast cancer therapy.
研究领域:
肿瘤学
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药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Shengnan Duan,Meiting Zhang,Hao Zeng,Jinyi Song,Min Zhang,Song Gao,Hua Yang,Ming Ding,Ping Li
Background Natural products are an important source for discovering novel drugs due to their various pharmacological activities. Salvia miltiorrhiza Burge (Danshen) has been shown to have promising therapeutic potential in the management of heart diseases, making it a candidate for cardiovascular drug discovery. Currently, there is limited quantitative analysis of the phosphorylation levels of Danshen-derived natural products on a proteome-wide, which may bias the study of their mechanisms of action. Purpose This study aimed to evaluate the global signaling perturbation induced by Danshen-derived bioactive compounds and their potential relationship with myocardial ischemia/reperfusion (IR) injury therapy. Study design We employed quantitative proteome and phosphoproteome analysis to identify dysregulated signaling in IR injury hearts from mice. We compared changes induced by Danshen-derived compounds based on IR-associated phospho-events, using an integrative approach that maps relative abundance of proteins and phosphorylation sites. Methods Isobaric chemical tandem mass tags (TMT) labeled multiplexing strategy was used to generate unbiased quantitative proteomics and phosphoproteomics data. Highly accurate and precise TMT quantitation was performed using the Orbitrap Fusion Tribrid Mass Spectrometer with synchronous precursor selection MS3 detection mode. Mass spectrometric raw files were analyzed with MaxQuant (2.0.1.0) and statistical and bioinformatics analysis was conducted with Perseus (1.6.15). Results We quantified 3661 proteins and over 11,000 phosphosites in impaired heart tissue of the IR mice model, expanding our knowledge of signaling pathways and other biological processes disrupted in IR injury. Next, 1548 and 5545 differently expressed proteins and phosphosites were identified by quantifying the proteome and phosphoproteome of H9c2 cells treated by five Danshen bioactive compounds respectively. Results revealed the vast differences in abilities of five Danshen-derived bioactive compounds to regulate phosphorylation modifications in cardiomyocytes, with dihydrotanshinone I (DHT) showing potential for protecting against IR injury by modulating the AMPK/mTOR signaling pathway. Conclusions This study provides a new strategy for analyzing drug/natural product-regulated phosphorylation modification levels on a proteome-wide scale, leading to a better understanding of cell signaling pathways and downstream phenotypic responses.
研究领域:
药理学
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心血管研究
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蛋白质组学
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系统生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
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IF 8.2
Zhiruo Fang,Yu Yao,Liping Cao,Jiancao Gao,Quanjie Li,Zhijuan Nie,Yi Sun,Gangchun Xu,Jinliang Du
This study investigated the toxicological mechanism of deltamethrin on Chinese mitten crab Eriocheir sinensis juveniles in fresh water. We first conducted an acute toxicity test, followed by laboratory methods to detect changes in immune-related indices in terms of antioxidant enzyme markers, lipid metabolism-related genes, and autophagy-related and apoptosis genes. The acute toxicity (96-h LC50) of deltamethrin to E. sinensis was 7.195 μg/L. After 48 h of exposure, serum showed elevated immune-related indices ( P < 0.05) for alkaline phosphatase (AKP), acid phosphatase (ACP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement components C3 and C4, and the key pro-inflammatory cytokines interleukin-6, interleukin-1β, and tumor necrosis factor alpha (TNF-α). In hepatopancreas at 48 h, indicators related to the antioxidant system, namely superoxide dismutase (SOD) and glutathione (GSH), were significantly elevated, whereas nitric oxide and total antioxidant capacity (T-AOC) were decreased ( P < 0.05). In contrast, lipid metabolism indices for triglyceride (TG), total cholesterol (TC), and malondialdehyde (MDA) were increased ( P < 0.05). Transcriptomics and metabolomics revealed that exposure to deltamethrin disrupted the lipid metabolic process in the hepatopancreas mainly by altering fatty acid synthesis, amino acid metabolism, immune signaling, and autophagy activation, while the exposure increased the content of phospholipids and cholesterol but decreased the levels of amino acids and palmitoleic acid. Quantitative genetics revealed significantly aberrantly expressed ( P < 0.05) lipid metabolism-related genes, including acc1 , fasn , scd1 , and pnpla2 , all key genes involved in lipid accumulation. Deltamethrin exposure also significantly altered ( P < 0.05) gene expression levels for Toll-like receptor ( tlr ), myeloid differentiation factor 88 ( myd88 ), crustin1 , anti-lipopolysaccharide factor isoform 3 ( alf3 ), tumor necrosis factor alpha ( tnf-α ), and NF-κB transcription factor relish . Furthermore, deltamethrin activated the toll-like receptor/major myeloid differentiation response gene 88/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR/MyD88/NF-kB) signaling pathway, which activates a nonspecific immune response in E. sinensis . Additionally, carnitine palmitoyltransferase 1 A ( cpt1a ), cytochrome c ( cyt-c ), adenosine 5′-monophosphate (amp)-activated protein kinase ( ampk ), the autophagosomal protein microtubule-associated protein 1 light chain 3c ( lc3c ), and the autophagy-related proteins beclin1 , atg5 , atg12 were significantly induced ( P < 0.05) in the adenosine monophosphate-activated protein kinase/rapamycin (AMPK/mTOR) signaling pathway. These changes resulted in excess free radicals, causing oxidative stress in the mitochondrial membrane, promoting mitochondrial autophagy. The results confirm that deltamethrin exposure can induce hepatopancreatic injury by promoting mitochondrial autophagy, activating an immune response, and inhibiting lipid metabolism. Overall, this study provides multi-level information to reveal the toxic effects of deltamethrin on E. sinensis .
研究领域:
毒理学
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分子生物学
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环境科学
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水生生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-13
·
IF 4.259
Hu Dongfang,Cao Shengliang,Zhang Guihua,Xiao Yihong,Liu Sidang,Shang Yingli
Florfenicol (FLO) is one of the most popular antibiotics used in veterinary clinic and aquaculture. FLO can inhibit both bacterial and mitochondrial protein synthesis. However, the effects of FLO on mitochondrial function and cellular homeostasis remain unclear. Here we show that FLO inhibits expression of mitochondrial DNA-encoded proteins, decreases mitochondrial membrane potential, and promotes generation of reactive oxygen species (ROS) in vitro . As a result, activities of mitochondrial respiratory chain complex I and IV and the cellular ATP level are decreased and mitochondrial morphology is damaged. FLO represses cell growth and proliferation by suppression of phosphorylation of p70S6K through AMPK/mTOR/p70S6K pathway. Furthermore, FLO also induces G0/G1 cell cycle arrest via increase of p21 levels through activating ROS/p53/p21 pathway. Moreover, the clearance of damaged mitochondria by autophagy is impaired, leading to cell proliferation inhibition and promotes cell senescence. In addition, FLO-induced upregulation of cytosolic p53 may contribute to mitophagy deficiency via regulation of Parkin recruitment. In summary, our data suggest that florfenicol is an inhibitor of mitochondrial protein synthesis that can induce noticeable cytotoxicity. Thus, these findings can be useful for guiding the proper use of FLO and the development of safe drugs.
研究领域:
兽医学
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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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产品关联
DOI
PubMed
高影响因子
Aging and Disease
·
2024
·Vol. 16
·期 3
·1652
·
IF 7
Cheng Zhuang,Ruiqi Sun,Yuchen Zhang,Qing Zou,Jianxin Zhou,Naijun Dong,Xuyu Zhao,Wenjun Fu,Xiaoke Geng,Jiao Wang,Qian Li,Robert Chunhua Zhao
Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.
研究领域:
纳米医学
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免疫学
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药理学
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细胞生物学
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生物医学工程
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风湿病学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Yang Bing,Yang Nan,Chen Yaping,Zhu Maomao,Lian Yuanpei,Xiong Zhiwei,Wang Bei,Feng Liang,Jia Xiaobin
Lung cancer is one of the most devastating diseases worldwide, with high incidence and mortality worldwide, and the anticancer potential of traditional Chinese medicine (TCM) has been gradually recognized by the scientific community. Astragali Radix (AR) is commonly used in traditional Chinese medicine in the treatment of lung cancer and has a certain clinical effect, but effective components and targets are still unclear. In the study, we established an integrated strategy for effective-component discovery of AR in the treatment of lung cancer based on a variety of techniques. First, the effective components and potential targets of AR were deciphered by the “component-target-disease” network using network pharmacology, and potential signal pathways on lung cancer were predicted by Gene Ontology (GO) biological function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Then, the therapeutic effects of AR in the treatment of lung cancer were evaluated in vivo using A/J mice, and the potential targets related to autophagy and potential signal pathway were verified by Western blot analysis, immunofluorescence staining, and real-time PCR technology at protein and gene expression level. Finally, metabolism in vitro by rat intestinal flora and cell membrane immobilized chromatography technology were used to screen the effective components of AR in the treatment of lung cancer, and remaining components from the cell immobilized chromatography were collected and analyzed by ultra-performance liquid chromatography–electrospray quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The screening results of the integrated strategy showed that calycosin-7-O-β-D-glucoside, ononin, calycosin, astragaloside IV, astragaloside II, cycloastragenol, and formononetin may be effective components of AR in the treatment of lung cancer, and they may play a role in the treatment of lung cancer through autophagy and p53/AMPK/mTOR signaling pathway. The integrated strategy for effective-component discovery provided a valuable reference mode for finding the pharmacodynamic material basis of complex TCM systems. In addition, the prediction for targets and signal pathways laid a foundation for further study on the mechanism of AR in the treatment of lung cancer.
研究领域:
药理学
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肿瘤学
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中医药
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2023
·Vol. 13
·期 1
·1-13
·
IF 4.6
Liang Chenchen,Gao Siyuan,Gao Jianpeng,Xu Yanwen,Li Qilong
To investigate the effects and potential mechanisms of human umbilical cord mesenchymal stem cells, exosomes, and their conditioned media on lipid storage in oleic acid (OA) and palmitic acid (PA) treated hepatocytes and high-fat methionine- choline deficient diet (HFMRCD) induced non-alcoholic steatohepatitis (NASH) mice. AML12 cells were stimulated with OA and PA to establish the lipid storage cell model. HucMSCs, exosomes, and culture medium were then co-cultured. At the same time, C57BL/6 mice were fed an HFMRCD for 6 or 8 weeks to establish a NASH mouse model. The effect of HucMSCs, exosomes, and culture medium on lipid droplet repair of hepatocytes or NASH mice was then assessed. The weight of hepatocytes or liver tissue, Oil Red O, hematoxylin–eosin staining, Masson staining, Western blot, and qPCR were used to detect the related IL-6, TNF-α, TGF-β1 andEI24/AMPK/mTOR pathway expression in hepatocytes and liver tissue. Compared with the model group, the effect of HucMSCs-Ex on inhibiting the accumulation of lipid droplets was more obvious at the cell level. In vivo study showed that HucMSCs-Ex reduces activity scores in NASH mice and improves liver tissue morphology by reducing vacuolar degeneration, fat deposition, and collagen deposition of liver tissue. Western blot and qPCR results showed that inflammatory factors and AMPK/mTOR or EI24-related autophagy pathways were altered before and after treatment. HucMSCs, HucMSC-Ex, and CM can promote autophagy in hepatocytes or NASH mice through the AMPK/mTOR or EI24-related autophagy pathway and alleviate injury associated with lipid deposition, collagen deposition or inflammation, reversing the progression of NASH.
研究领域:
细胞生物学
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分子生物学
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肝病学
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干细胞研究
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Xiaoyang Wu,Shiji Lu,Yusheng Zhang,Kai Wu,Junzhong Jiang,Xiaoyin Liu,Dan Wei,Chengheng Wu,Jie Ding,Liangxue Zhou,Jing Sun,Hongsong Fan
Ischemic stroke induces catastrophic neurovascular damage through hypoxia- driven neuronal death and metabolic collapse, characterized by Adenosine Triphosphate (ATP) depletion and mitochondrial dysfunction. In this work, an injectable granular hydrogel platform GUD-HB@PDA is developed, composed of ureidopyrimidinone/dopamine (UPy/DA)-functionalized gelatin (GUD) microspheres and polydopamine-coated hemoglobin (HB@PDA). Attributing to UPy-based quadruple hydrogen bonding and catechol-mediated crosslinking, the hydrogel platform achieves brain-mimetic dynamic viscoelasticity and sustained oxygenation delivery. The import role of viscoelasticity and oxygen supplementation in energy metabolism regulation is confirmed. Notably, it is found that the oxygen supplementation contributes 36–39% ATP increase through alleviates hypoxia, while viscoelastic mechanics contributes 61–64% of ATP increase, dominating the energy regulation through TRPV4-mediated mechanotransduction. This study proves this mechanical bioenergetic regulation synergizing with oxygen-dependent pathways promotes neuronal differentiation and angiogenesis in ischemic-hypoxic environment, through concurrent activation of AMPK-mTOR metabolic pathways and neurogenic differentiation programs. In a photothrombotic stroke model, superior therapeutic efficacy with 5.4-fold neuronal maturation, 1.6-fold vascular infiltration, and 2.8-fold axonal regeneration versus present reports are demonstrated. In summary, focusing on mechanical mismatch and bioenergetic deficits, a unique strategy of viscoelasticity-oxygenation synergy through mechanical cues as fundamental metabolic regulators is established, providing a robust solution for energy-intensive neurovascular regeneration following ischemic stroke.
研究领域:
生物材料
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神经工程
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组织工程
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卒中治疗
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机械生物学
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生物能量学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2020
·
IF 3.69
Yunfeng Zhou,Mingzhu Yan,Ruile Pan,Zhi Wang,Xue Tao,Chenchen Li,Tianji Xia,Xinmin Liu,Qi Chang
Ethnopharmacological relevance Radix Polygalae (RP) has been traditionally used for the treatment of various psychiatric disorders in East Asia. Aim of the study Depression is a severe mental disease with high prevalence in people, and neurobiology changes of depression are not fully clarified yet. The present study aimed to investigate the antidepressant effect and underlying mechanism of RP in behavioral despair mice and chronic restraint stress (CRS)-induced rats. Materials and methods ICR mice were treated with various doses of RP (0.13–1.0 g/kg) for 14 days and then subjected to forced swimming test (FST). Wistar rats were exposed to 6-hour restraint stress daily for 28 days, and RP (0.5 and 1 g/kg) was administered by gavage 1 h prior to CRS procedure. Subsequently, behavioral tests were performed and brains were collected for biochemical analysis. Results RP reduced immobility time of mice in FST and reversed abnormal behaviors of rats induced by CRS in sucrose preference test, novelty-suppressed feeding test, open field test and FST. Moreover, RP could enhance the expression of LC3-II and beclin1 and decrease the level of p62 both in cortex of mice and prefrontal cortex (PFC) of rats, and regulate the dysfunction of AMPK-mTOR pathway in PFC of CRS rats. Activated microglia, impaired astrocyte, elevated protein expression of NLRP3, ASC and caspase-1, and increased mRNA levels of proinflammatory cytokines were observed in PFC of CRS rats, all of which were corrected by RP treatment. Conclusion RP exerted remarkable antidepressant activity in behavioral despair mice and CRS-induced rats, probably by promoting autophagy and inhibiting neuroinflammation .
研究领域:
药理学
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神经科学
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民族药理学
✓ 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）