Frontiers in Pharmacology
·
2018
·
IF 3.831
Chen Donglai,Zhang Fuquan,Wang Jinhui,He Hua,Duan Shanzhou,Zhu Rongying,Chen Chang,Yin Lichen,Chen Yongbing
Background: Erlotinib (ELTN)-based targeted therapy as first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung cancers suffers from insufficient selectivity, side effects, and drug resistance, which poses critical challenges in the clinical setting. Acquired resistance of ELTN results in extremely poor prognoses of non-small cell lung cancer (NSCLC) patients, wherein activation of the JAK2/STAT3 signaling pathway has been proven to induce acquired ELTN resistance.Methods: In this study, we developed a nanoparticle (NP) delivery system based on Food and Drug Administration (FDA)-approved poly(ethylene glycol) (PEG)-poly(lactic acid) (PLA) for the co-delivery of ELTN and fedratinib (FDTN, a small-molecular, highly selective JAK2 inhibitor). Both ELTN and FDTN could be encapsulated into the PEG-PLA NPs via optimization of the encapsulation method. The effect of NPs on NSCLC cells was evaluated by MTT assay. Western blotting was performed to study the molecular mechanisms of NPs inhibiting the downstream pathways of EGFR in vitro. The histological analysis and protein expression in vivo were assessed by hematoxylin/eosin (H&E) staining and immunohistochemistry, respectively.Results: The drug cargoes exhibited great stability, and could be released more efficiently in the acidic tumorous condition. Mechanistic study showed that FDTN notably down-regulated the expression levels of proteins in the JAK2/STAT3 signaling pathway, including p-EGFR, p-JAK2, p-STAT3 and Survivin, therefore reversing the ELTN resistance. As a result, synergistic anti-cancer effect was achieved by PEG-PLA NPs encapsulating both ELTN and FDTN in ELTN-resistant NSCLC tumors both in vitro and in vivo, and lower systemic side effect was noted for the co-delivery NPs compared to free drugs.Conclusion: This study provides a promising approach to overcome the ELTN resistance in the treatment of NSCLC, and the use of FDA-approved materials with clinically applied/investigated chemical drugs may facilitate the translation of the current delivery system.
研究领域:
药学
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肿瘤学
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纳米技术
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
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IF 10.7
Xianglei Fu,Yanbin Shi,Zili Gu,Hengchang Zang,Lian Li,Qingjie Wang,Yongjun Wang,Xiaogang Zhao,Hang Wu,Shengnan Qiu,Yankun Zhang,Jiamin Zhou,Xiangqin Chen,Hua Shen,Guimei Lin
Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.
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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免疫疗法
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
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IF 4.8
Huanhuan Liu,Jiahui Li,Chunhong Yan,Jiaxiu Liu,Dongyun Zhao,Shugang Li,Xiaodong Xia
Inflammatory bowel disease is characterized by compromised epithelium barrier function and hyperactive intestinal inflammation. This study aims to investigate the effects of punicalagin, a bioactive ellagitannin in pomegranate, on dextran-sodium sulfate (DSS) - induced colitis in mice and to examine the underlying mechanisms involved. Oral administration of punicalagin (100 mg/kg/day) effectively mitigated the severity of experimental colitis in mice, evidenced by increased colon length, improved intestinal permeability, and decreased histological scores. Punicalagin up-regulated the mRNA expression level of Muc2 in and the protein expression of zonula occludens-1 (ZO-1) and Occludin in colitic mice. Moreover, punicalagin effectively decreased reactive oxygen species (ROS) levels in the colon, and in Caco-2 cells exposed to H 2 O 2 in vitro . Mechanistically, punicalagin attenuated inflammation by inhibiting the secretion of interleukin-6 (IL-6) and the phosphorylation of the NF-κB/STAT3 pathway. In addition, punicalagin increased adenosine monophosphate activated protein kinase (AMPK) phosphorylation in the colon of DSS-treated mice and lipopolysaccharide (LPS) -induced RAW 264.7 macrophages. Knocking down AMPKα by siRNA diminished punicalagin's anti-inflammatory function in RAW 264.7 macrophages exposed to LPS. Furthermore , molecular docking analysis, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) analysis supported the direct interaction between punicalagin and AMPK. In conclusion, punicalagin could mitigate DSS-induced colitis through enhancing intestinal epithelial barrier, alleviating oxidative stress, and attenuating inflammation partly through modulation of AMPK–NF–κB-STAT3 pathway.
研究领域:
药理学
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免疫学
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胃肠病学
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DOI
高影响因子
Food & Function
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2023
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IF 6.1
Jiachen Zhuang,Qianqian Wang,Fei Shen,Jing Wang,Juan Du,Peng Yu,Fengqin Feng,Minjie Zhao
This study investigated the immunomodulatory effects of soft-shelled turtle (Pelodiscus sinensis) peptide (TP) and Chinese pond turtle (Chinemys reevesii) peptide (TMP) on the intestinal mucosal immune system (IMIS). The results demonstrated that TP and TMP improved holistic immunity by restoring the vital immune organ atrophy and proliferation capacity of spleen immune cells. Moreover, TP and TMP significantly increased the serum content of IgA and cytokines that are responsible for immune cell activation and antigen clearance. TP and TMP promoted intestinal B cell activation, class switching recombination, and antibody secreting processes in a T cell-independent manner to increase the SIgA content. Furthermore, TP and TMP enhanced the intestinal barrier by increasing the protein expression of tight junctions (TJs) and adhesion junctions (AJs) and ameliorating the intestinal morphology. Mechanistically, TP and TMP activated the AHR/IL-22/STAT3/IL-6 axis to enhance the IgA response and improve the intestinal barrier, indicating their potential in intestinal health modulation.
研究领域:
免疫学
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胃肠病学
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药理学
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产品关联
DOI
PubMed
高影响因子
Small
·
2023
·Vol. 19
·期 40
·2302834
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IF 13.3
Kaipei Luo,Lu Yang,Chunmei Yan,Yuxin Zhao,Qiuxia Li,Xing Liu,Long Xie,Qiang Sun,Xiaofang Li
Immunotherapy gains increasing focus in treating triple-negative breast cancer (TNBC), while its efficacy is greatly restricted owing to low tumor immunogenicity and immunosuppressive tumor microenvironment (ITM). Herein, a LyP-1 and chondroitin sulfate (CS) dual-modified liposome co-loaded with paclitaxel (PTX) and cryptotanshinone (CTS), namely CS/LyP-1-PC Lip, is engineered for TNBC chemoimmunotherapy via induction of immunogenic cell death (ICD) and inhibition of signal transducer and activator of transcript-3 (STAT3) activation. CS/LyP-1-PC Lip enhances cellular uptake through p32 and CD44 dual receptor-mediated endocytosis. Within the tumor, the CS layer is continuously detached by hyaluronidase to release drugs. Subsequently, CTS sensitizes the cytotoxicity of PTX to 4T1 tumor cells. PTX induces ICD of tumor cells and facilitates infiltration of cytotoxic T lymphocyte to provoke immune response. Meanwhile, the concomitant delivery of CTS inhibits STAT3 activation to decrease infiltration of regulatory T cell, M2-type tumor-associated macrophage, and myeloid-derived suppressor cell, thus reversing ITM. Markedly, the dual-targeting liposome shows superior anti-tumor efficacy in subcutaneous TNBC mice and significant lung metastasis suppression in tumor metastasis model. Overall, this work offers a feasible combination regimen and a promising nanoplatform for the development of TNBC chemoimmunotherapy.
研究领域:
肿瘤学
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药学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Yan Chen,Ming Zhang,Zhifang Liu,Ning Zhang,Qingpeng Wang
Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-β1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3+ and CD8+ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Yinhuang Gao,Ke Ma,Zhibo Zhu,Yan Zhang,Qiong Zhou,Jing Wang,Xiaowen Guo,Liuting Luo,Haitao Wang,Kang Peng,Menghua Liu
Background Vascular dementia (VaD) is one of the most common clinical syndromes of progressive neurocognitive dysfunction with uncertain mechanisms. Modified Erchen decoction (MECD), developed from “Erchen decoction (ECD)” recorded in “Taiping Huimin Heji Jufang”, showed a good effect in the treatment of VaD. However, its therapeutic mechanism is still unclear. Purpose This study aimed to elucidate the multi-target mechanisms of MECD against VaD in vivo and in vitro . Methods VaD model was established by two-vessel obstruction (2-VO) in Sprague-Dawley rats. Six groups, including the control, 2-VO operation, MECD treatment (2.5, 5.0 and 10.0 g kg −1 d −1 ), donepezil hydrochloride (positive control, 0.45 g kg −1 d −1 ) were designed in the whole experiment. After oral administration for 4 weeks, the effects of MECD were verified by behavioral experiments, histological observation, and biochemical index analysis. The chemical profiling of MECD was performed by UHPLC-Orbitrap Fusion-HRMS, and a "compound-target-pathway" multivariate network was constructed to validate and elucidate its pharmacological mechanisms. Results Compared with 2-VO group, MECD treatment significantly alleviated anxiety and improved spatial memory in VaD rats according to the open field test (OFT) and Y-maze test. A significant increase in neuron number was observed from hematoxylin and eosin (H&E) stained images in cornu ammonis 1 (CA1) of the hippocampal region after MECD treatment. On the one hand, MECD reduced the plasma levels of triglyceride (TG), low-density lipoprotein (LDL), malondialdehyde (MDA), and amyloid-beta 42 (Aβ42), and inhibited mRNA expression of interleukin-1 beta ( Il-1β ) and Il-6 in the hippocampus. On the other hand, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly increased after treatment with MECD. Moreover, MECD reduced the mRNA expression and protein expression of janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and BCL2-associated X (BAX) in the brain of 2-VO rats. Furthermore, 71 compounds were identified from the extract of MECD. Among them, liquiritin and isochlorogenic acid C gave inhibiting effects on the mRNA expression of Jnk . In addition, liquiritin and hesperetin were conformed with the inhibition of Jak2 transcription level in vitro experiments. Conclusion MECD has demonstrated a significant amelioration effect on cognitive dysfunction in VaD rats via JAK2/STAT3 and JNK/BAX signaling pathways , which represents an innovative insight into the “activate blood and eliminate phlegm” theory.
研究领域:
药理学
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神经科学
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中医药
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INTERNATIONAL MEDICAL RESEARCH
·
2021
·
IF 1.671
Fangli He,Gang Wang,ZhengQing Xu,Zhihui Huang
ObjectiveTo investigate the anticancer effect of nelfinavir (NFV) on human A549 cells.MethodsThe inhibitory effects of NFV on the proliferation of human A549 cells were assessed using a MTT assay. Apoptotic cells were observed by fluorescence microscopy following Hoechst 33342 staining. Apoptosis of A549 cells was assessed using Annexin-V/propidium iodide staining and flow cytometry. Expression levels of signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured by western blotting. STAT3 RNA silencing was used to investigate the pro-apoptotic mechanism of NFV in A549 cells.ResultsNFV dose-dependently suppressed proliferation of human A549 cells and induced significant apoptosis. Western blotting showed that the antitumor function of NFV might be mediated by STAT3 inhibition. A549 cell apoptosis in response to 20 µM NFV was significantly increased following STAT3 silencing. NFV significantly impeded the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, by increased the expression of the pro-apoptotic protein Cle-PARP.ConclusionsOur findings highlight STAT3 as a promising therapeutic target. NFV is a novel anti-cancer drug for the treatment of non-small-cell lung cancer.
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
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xiaolei Ma,Rui Cong,Xin Cui,Yiwei Tang,Jie Ren,Jinfan Hou,Boyu Liu,Jiehui Zhao,Pengwei Li,Lei Li,Heyang Zhang,Jiasheng Tu,Lei Jiang
Psoriasis is a prevalent chronic inflammatory skin disease characterized by immune cell activation and aberrant keratinocyte proliferation. Signal transducer and activator of transcription 3 (STAT3) plays a key role in the pathology of psoriasis, positioning it as a promising target for therapeutic strategies. However, current STAT3 inhibitors often lack specificity, leading to adverse effects. Here, we present the development of dendritic lipopeptides (DLPs) designed to facilitate the transdermal delivery of small interfering RNA (siRNA) to specifically inhibit STAT3 expression in psoriatic lesions. The dendritic architecture and peptide composition of DLP are crucial for interaction with keratin of stratum corneum and gene transfection efficiency, while the lipid chain selection aims to increase lipophilicity and enhance interactions with cellular membranes. We conducted extensive in vitro and in vivo investigations to assess the therapeutic efficacy of these DLPs for siRNA delivery in psoriasis treatment. The results demonstrated that our DLPs effectively penetrated the skin barrier, delivered siRNA to target cells, and significantly reduced STAT3 expression, regulated immune cell imbalance, leading to a marked improvement in psoriasis symptoms. In conclusion, our study presents a promising non-invasive approach to psoriasis treatment by focusing on the targeted suppression of STAT3 expression. The dendritic lipopeptides offer a safe and effective platform of siRNA delivery, potentially revolutionizing the management of psoriasis and other chronic inflammatory dermatological conditions.
研究领域:
皮肤病学
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分子生物学
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药物递送
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Feng Zhou,Fanyun Zhu,Tianru Zhu,Zhucheng Zhao,Luyao Li,Shichong Lin,Haiyang Zhao,Lehe Yang,Chengguang Zhao,Liangxing Wang,Jifa Li,Xiaoying Huang
Lung cancer is a part of the commonest malignancies with the highest mortality rate in cancer-related deaths worldwide. Signal transducer and activator of transcription 3 (STAT3) and cyclin-dependent kinases (CDKs) are promising prognostic marker and therapeutic target in cancers. Our previous study has demonstrated the closely relationship between CDK9 and STAT3 in lung cancer. The inhibition of cell viability and migration in vitro by AT7519 were evaluated using methyl thiazolyl tetrazolium (MTT) assay, clonogenic assay and scratch wound model. The cell cycle analysis was evaluated using flow cytometry analysis and western blotting analysis. The apoptotic-induced efficiency was assessed by flow cytometry analysis, hoechst 33342 staining, caspase-3 activity analysis and western blotting analysis. The roles of STAT3 in AT7519 treatment for lung cancer were assessed by docking model and western blotting analysis. The patient-derived xenograft (PDX) models were used to investigate the effect of AT7519 in vivo. In this study, we found that AT7519, a CDK inhibitor, reduced the viability of lung cancer cells in vitro and strongly suppressed tumor growth in PDX model. AT7519 blocked cell cycle progression and induced apoptosis by inhibiting IL-6/STAT3 pathway. Taken together, AT519 exhibits great anti-tumor effects in lung cancer, and the mechanism was related closely to IL-6/STAT3 signaling pathway , which suggests the important roles of STAT3 in CDKs inhibitors. AT7519 might be a novel potential therapeutic agent based on this rationale.
研究领域:
肿瘤学
·
分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Endocrine Metabolic & Immune Disorders-Drug Targets
·
2026
·Vol. 26
·期 1
·E18715303420913
·
IF 2
Jiawei Cao,Yuewen Tang,Feng Wan,Tingjiao Xu,Ruchun Yang
Introduction In this study, we aim to investigate the mechanism by which extracellular phosphate (Pi) regulates the transcription of fibroblast growth factor 23 (FGF23) in osteoblasts and the effects of celastrol on FGF23 expression in UMR-106 cells and in chronic kidney disease (CKD) rat models. Methods We used Pi to induce FGF23 expression in a rat osteoblastic cell line as a model and then treated the cells with celastrol. The cytotoxicity of Pi and celastrol was assessed using the CCK-8 assay. FGF23 expression was measured using real-time quantitative PCR (RT-qPCR), and its promoter activity was evaluated using luciferase reporter assays. To detect active signal transducer and activator of transcription 3 (STAT3), immunofluorescence and Western blotting were performed. The 5/6 nephrectomized rat model was established to investigate the effects of celastrol on FGF23 expression in vivo. An enzyme-linked immunosorbent assay was carried out to examine serum FGF23 levels in rats. RT-qPCR detected the mRNA levels of FGF23 and STAT3 in the femurs of CKD rats. Results We found that high Pi activated STAT3 and promoted its nuclear translocation, leading to elevated FGF23 expression, which was suppressed by celastrol. Additionally, in rats subjected to 5/6 nephrectomy with high serum Pi levels, serum FGF23 levels and skeletal STAT3 expression were significantly decreased after celastrol treatment. Discussion Therefore, celastrol could have therapeutic effects on CKD by decreasing serum FGF23. Conclusion High Pi activates STAT3 and induces FGF23 expression. Furthermore, celastrol can attenuate increased FGF23 expression induced by high Pi, potentially via inhibition of STAT3 activation.
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DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
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IF 5.3
Chenyu Cao,Yifei Li,Fangzhou Shi,Shanshan Jiang,Yutong Li,Leilei Yang,Xinyi Zhou,Yuqiong Gao,Feiyan Tang,Huan Li,Shulan Han,Zhuo Yu,Yifang Zou,Jianfeng Guo
Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.
研究领域:
肿瘤学
·
药理学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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