Cancer Immunology Research
·
2022
·Vol. 10
·期 4
·525-539
·
IF 12.02
Chen Yu,Cai Qiaomei,Pan Chaohu,Liu Wancheng,Li Lili,Liu Junxiao,Gao Meiling,Li Xiaorong,Wang Liguo,Rao Yu,Yang Heng,Cheng Genhong
Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8 + T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.
研究领域:
肿瘤学
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免疫学
·
分子生物学
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DOI
PubMed
高影响因子
Annals of Medicine and Surgery
·
2023
·Vol. 85
·期 11
·5469
·
IF 1.7
Ren Yuzhe,Li Xing,Zhang Yuanjie,Yan Zilong
Xiaoqinglong decoction (XQLD) is widely used clinically in the treatment of childhood cough variant asthma (CVA). However, its potential mechanism is still unknown. In the present study, the authors investigate the biological network and signalling pathway of XQLD in treatment of childhood CVA using network pharmacology-based analysis and experimental validation. By using the Bioinformatics Analysis Tool Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database, the authors confirmed the correlation between XQLD and asthma, and the authors screened 1338 potential target genes of Mahuang and Guizhi, the most active herbs in XQLD. By overlapping “Childhood asthma-related genes” of DisGeNET database, the authors identified 58 intersecting genes of Childhood asthma and 1338 target genes of Mahuang and Guizhi. The intersecting genes were used to construct the protein-to-protein interaction and performed Gene Ontology (GO) functional and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Gene Ontology enrichment analysis demonstrated 359 Biological Process terms, 16 Cellular Component terms, and 26 Molecular Function terms. Meantime, 75 terms of Kyoto Encyclopedia of Genes and Genomes signalling pathway were involved in enrichment analysis. These candidates showed a significant correlation with inflammatory response and positive regulation of tyrosine phosphorylation of STAT protein. In addition, XQLD treatment significantly upregulated serum interferon-γ expression, and downregulated serum interlukin-6 expression of CVA mice. XQLD treatment significantly inhibited phosphorylation of STAT3 in bronchial-lung tissues. Our data suggest that XQLD effectively alleviated bronchial-lung tissue damage in CVA mice and inhibited the body inflammatory response by regulating interlukin-6/STAT3 signalling pathway.
研究领域:
药理学
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免疫学
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分子生物学
·
中医
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DOI
PubMed
高影响因子
Small Methods
·
2020
·Vol. 4
·期 3
·1900799
·
IF 12.13
Yan Peng Jia,Kun Shi,Jin Feng Liao,Jin Rong Peng,Ying Hao,Ying Qu,Li Juan Chen,Li Liu,Xia Yuan,Zhi Yong Qian,Xia Wei Wei
The safety issues and immunological effects of nanosized materials have drawn considerable attention. Gold nanorods (Au NRs) have promising applications in biomedical diagnosis and therapy, but their biosafety and the mechanism underlying in vivo toxicity still remain to be explored. In this study, cetyltrimethylammonium bromide (CTAB) capped Au NRs and PEG modified Au NRs are both prepared, the cytotoxicity evaluation indicates that CTAB-Au NRs of different ratios all exhibit cytotoxicity while PEG-Au NRs show improved biocompatibility. Furthermore, it is investigated how the surface characteristics influence toxical effects of Au NRs both in vitro and in vivo. It is found that CTAB-Au NRs can induce acute cell necrosis, which results in the leakage of damage associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), subsequently triggering pulmonary inflammation. It is also revealed that the inflammation caused by CTAB-Au NRs is probably mediated by the stimulator of interferon genes (STINGs) signaling pathway. This study explores the cytotoxicity and inflammatory toxicity of CTAB-Au NRs, and how the surface modification affects the toxicity. The molecular pathways for the induction of pulmonary inflammation in vivo are further characterized. These findings might be of importance for designing safer and better gold-based nanomaterials in the future.
研究领域:
纳米技术
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毒理学
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免疫学
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生物医学工程
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DOI
高影响因子
ANALYTICA CHIMICA ACTA
·
2020
·
IF 5.977
Jianli Zuo,Yonghua Yuan,Min Zhao,Jie Wang,Yuhan Chen,Qiqi Zhu,Lijuan Bai
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with unclear pathogenesis, for which diagnosis has been a great challenge. Recent researches have revealed that miR-3675-3p is a promising biomarker for IPF diagnosis. Herein, the present work describes a novel electrochemical microRNA biosensor for rapid and sensitive detection of miR-3675-3p based on multiple signal amplification strategies. First of all, fullerene (C 60 ) is doped with poly(amidoamine) (PAMAM)-functionalized metal-organic framework (MOF) to form a new nanohybrid of C 60 @PAMAM-MOF, which exhibits more remarkable redox activity compared with the other two synthesized C 60 -based nanohybrids when triggered by tetraoctylammonium bromide (TOAB). C 60 @PAMAM-MOF also possesses a large specific surface area and abundant amino groups to anchor Au nanoparticles (AuNPs) for the immobilization of signal probe (SP) to form tracer label and enhance the electrochemical response signal. In addition, [email protected] Au–Pt nanoparticles ( [email protected] ) are absorbed on chitosan-acetylene black (CS-AB) to act as sensing platform, which can promote electron transfer and increase the loading of capture probe (CP). Under optimum conditions, the proposed biosensor displays a wide linear range for miR-3675-3p from 10 fM to 10 nM, with a limit of detection (LOD) as low as 2.99 fM. More significantly, this biosensor shows a lower LOD and wider linear range than that of qRT-PCR, and its trial application in human serum shows favorable results, which exhibits a promising prospect for IPF diagnosis.
研究领域:
生物化学
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纳米技术
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电化学
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医学诊断
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2024
·Vol. 52
·期 11
·1332-1344
·
IF 4.4
Yuqing Wang,Jun Luo,Mengru Bai,Zhiyuan Ma,Ying Xu,Dan Liu,Huidi Jiang,Shenglin Ma,Shirong Zhang
Antifolates are important for chemotherapy in non–small cell lung cancer (NSCLC). They mainly rely on reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) to enter cells. PCFT is supposed to be the dominant transporter of the two in tumors, as it operates optimally at acidic pH and has limited transport activity at physiological pH, whereas RFC operates optimally at neutral pH. In this study, we found RFC showed a slightly pH-dependent uptake of antifolates, with similar affinity values at pH 7.4 and 6.5. PCFT showed a highly pH-dependent uptake of antifolates, with an optimum pH of 6.0 for pemetrexed and 5.5 for methotrexate. The Michaelis-Menten constant (Km) value of PCFT for pemetrexed at pH 7.4 was more than 10 times higher than that at pH 6.5. Interestingly, we found that antifolate accumulations mediated by PCFT at acidic pH were significantly affected by the efflux transporter, breast cancer resistance protein (BCRP). The highest pemetrexed concentration was observed at pH 7.0–7.4 after a 60-minute accumulation in PCFT-expressing cells, which was further evidenced by the cytotoxicity of pemetrexed, with the IC50 value of pemetrexed at pH 7.4 being one-third of that at pH 6.5. In addition, the in vivo study indicated that increasing PCFT and RFC expression significantly enhanced the antitumor efficacy of pemetrexed despite the high expression of BCRP. These results suggest that both RFC and PCFT are important for antifolates accumulation in NSCLC, although there is an acidic microenvironment and high BCRP expression in tumors.
研究领域:
肿瘤学
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药理学
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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
Advanced Healthcare Materials
·
2024
·
IF 10
Hairui Zhang,Xiaoling Xu,Xin Shou,Wucan Liao,Chengkang Jin,Changjiang Chen,Chen Zhang,Wenhua Gao,Junfeng Zhang,Weihong Ge,Liyun Shi
Cellular senescence is a significant risk factor for aging and age-related diseases (ARD). The canonical senolytics Dasatinib and Quercetin (DQ) have shown promise in clearing senescent cells (SnCs); however, the lack of selectivity poses a challenge in achieving optimal outcomes. Despite the recent occurrence of the nanomaterial-based approaches targeting SnCs, limited therapeutic effects and potential toxicity still remain a major concern. Herein, we developed a “double locks-like” nanoplatform that integrated Galactan coating and mesoporous polydopamine to encase the senolytic drug DQ. By this way, DQ was only released in SnCs that were featured with higher levels of β-galactosidase (β-gal) and low PH. Additionally, the nanoparticles were equipped with 2,2,6,6-Tetramethylpiperidine-1-oxyl (Tempo) to gain enhanced photothermal converting potential. Consequently, the synthesized nanosenolytics demonstrated remarkable specificity and efficacy in eradicating SnCs, and accordingly reversed pulmonary fibrosis in mice without affecting normal tissues. Upon exposure of near-infrared (NIR) light, the nanoparticles demonstrated to efficiently remove senescent tumor cells inducted by chemotherapy, thereby hindering the outgrowth and metastasis or breast cancer. Collectively, the present study develops an “On/Off” switchable nanoplatform in response to SnCs, and produces a more safe, efficient and feasible way to delay aging or alleviate age-associated diseases. This article is protected by copyright. All rights reserved
研究领域:
衰老
·
纳米技术
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药理学
·
癌症研究
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 20
·2100985
·
IF 9.933
Yuanyuan Jia,Peiliang Shen,Tao Yan,Weijia Zhou,Jia Sun,Xin Han
Robust isolation of cancer stem cells (CSCs) in a high-throughput, label-free manner is critical for understanding tumor heterogeneity and developing therapeutic strategies targeting CSCs. Cell-mechanics-based microfluidic sorting systems provide efficient and specific platforms for investigation of stem cell-like characteristics on the basis of cell deformability and cell-substrate adhesion properties. In the present study, a microfluidic tandem mechanical sorting system is developed to enrich CSCs with high flexibility and low adhesive capacity. In the integrated microfluidic system, cancer cells are driven by hydrodynamic forces to flow continuously through two featured devices, which are functionalized with sequentially variable microbarriers and surface-coated fluid mixing microchannels, respectively. Collected deformable and low-adhesive cancer cells exhibit enhanced stem cell-like properties with higher stemness and metastasis capacity both in vitro and in vivo, compared with each single device separation. Using these devices, bioactive natural compound screening targeting CSCs is performed and a potent therapeutic compound isoliquiritigenin from licorice is identified to inhibit the lung cancer stem cell phenotype. Taken together, this microfluidic tandem mechanical sorting system can facilitate drug screening targeting CSCs and the analysis of signals regulating CSC function in drug resistance.
研究领域:
生物医学工程
·
癌症生物学
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药理学
·
细胞生物学
·
药物发现
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Jin Wang,Ye Qian,Xuemin Gao,Na Mao,Yucong Geng,Gaojie Lin,Guibin Zhang,Han Li,Fang Yang,Hong Xu
Background N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a short peptide with an anti-silicosis effect. However, the short biological half-life and low plasma concentration of Ac-SDKP hamper discovery of specific targets in organisms and reduce the anti-silicosis effect. A novel peptide, Ac-SDK (biotin) proline, termed “Ac-B”, with anti-fibrotic properties was synthesized.Methods Ac-B was detected quantitatively by high-performance liquid chromatography. Phagocytosis of Ac-B by the alveolar epithelial cell line A549 was investigated by confocal laser scanning microscopy and flow cytometry. To further elucidate the cellular-uptake mechanism of Ac-B, chemical inhibitors of specific uptake pathways were used. After stimulation with transforming growth factor-β1, the effects of Ac-B on expression of the myofibroblast marker vimentin and accumulation of collagen type I in A549 cells were analyzed by Western blotting. Sirius Red staining and immunohistochemical analyses of the effect of Ac-B on expression of α-smooth muscle actin (SMA) in a rat model of silicosis were undertaken.Results Ac-B had good traceability during the uptake, entry, and distribution in cells. Ac-B treatment prevented an increase in α-SMA expression in vivo and in vitro and was superior to that of Ac-SDKP. Caveolae-mediated uptake of Ac-B by A549 cells led to achieving anti-epithelial–mesenchymal transformation (EMT) effects.Conclusion Ac-B had an anti-fibrotic effect and could be a promising agent for the fibrosis observed in silicosis in the future.
研究领域:
药理学
·
肺科学
·
细胞生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2021
·
IF 5.858
Shisong Jing,Li Wang,Tiedong Wang,Lianghai Fan,Lin Chen,Hua Xiang,Yan Shi,Dacheng Wang
Methicillin-resistant Staphylococcus aureus is one of the leading causes of community and nosocomial infections, which has created the urgent need for innovative anti-infective agents to control MRSA-associated infections. A conserved serine protease , caseinolytic peptidase P (ClpP) in Staphylococcus aureus is highly associated with pathogenicity and has been claimed to be a novel antimicrobial target. We aim to search suitable inhibitors of ClpP to attenuate the virulence of MRSA and combat their infections in vivo . Over 500 natural compounds were pre-screened via fluorescence resonance energy transfer using the Suc-LY-AMC substrate. The binding of myricetin to ClpP was determined and the mechanism of action was elucidated by thermal shift assay, surface plasmon resonance , and molecular dynamics simulations. The therapeutic effects of myricetin on S. aureus infection were further investigated using a S. aureus -induced pneumonia model. We revealed that myricetin could effectively block the activity of ClpP without disturbing the growth of the bacteria and the Gln-47 and Met-31 residues were necessary for myricetin binding to ClpP. Importantly, myricetin attenuated the pathogenicity of S. aureus in vivo , while improving the efficacy of the traditional antibiotic oxacillin against MRSA infection and protecting mice from fatal lung infections caused by MRSA. These findings indicate that myricetin has the potential to be applied in the pharmaceutical industry as a promising therapeutic agent.
研究领域:
微生物学
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药理学
·
传染病学
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DOI
PubMed
高影响因子
Scientific Reports
·
2015
·Vol. 5
·期 1
·1-17
·
IF 5.578
Cao Wei,Liu Ying,Zhang Ran,Zhang Bo,Wang Teng,Zhu Xianbing,Mei Lin,Chen Hongbo,Zhang Hongling,Ming Pinghong,Huang Laiqiang
Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia , on Gefitinib-resistant NSCLC cell lines in vitro and in viv o. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFβ signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo . Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Biochemistry and Cell Biology
·
2022
·Vol. 101
·期 1
·
IF 3.73
Guihua Song,Suping Yu,Yan Zhang,Mengmeng Sun,Bingxue Zhang,Minghao Peng
Asthma is characterized by airway inflammation and remodeling. 2-Undecanone (methyl nonyl ketone), a volatile organic compound originating from Houttuynia cordata, has the potential to ameliorate inflammatory diseases. This study aimed to explore potential benefits of 2-undecanone in asthma. 2-Undecanone (100, 200, or 400 mg/kg) was administered intragastrically to ovalbumin (OVA)-challenged BALB/c mice. Lung tissues were collected to observe histopathological changes, and bronchoalveolar lavage fluid (BALF) was collected for the detection of inflammatory cells and cytokine production. The results showed that 2-undecanone ameliorated OVA-induced pathologic changes of lungs, including reducing inflammatory cell infiltration, goblet cell hyperplasia, and airway smooth muscle thickness. The number of inflammatory cells and the levels of IL-4, IL-5, IL-13, and IgE in BALF were decreased by 2-undecanone in asthmatic mice. Furthermore, abnormal activation of NF-κB pathway in lung tissues of asthmatic mice was impeded by 2-undecanone. In vitro, 2-undecanone (12.5, 25, or 50 µM) suppressed platelet-derived growth factor-BB-induced proliferation and migration of primary airway smooth muscle cells (ASMCs), and inhibited the switching of ASMCs from contractile phenotype to synthetic phenotype. Consistently, 2-undecanone blocked NF-κB activation in ASMCs. Collectively, 2-undecanone relieves asthma through alleviating airway inflammation and remodeling, and this beneficial effect is achieved by inhibiting NF-κB pathway.
研究领域:
免疫学
·
药理学
·
呼吸医学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Xiuju Liu,Yuhui Sun,Xue Lv,Mengmeng Song,Jian Sun,Yulan Sun
Lung carcinoma is a frequently encountered cancerous growth that affects the respiratory tract and has a high occurrence rate globally. In light of the ongoing worldwide health emergency, the significance of efficient therapeutic agents and strategies is of utmost importance. A meticulous control of the cell cycle is crucial for comprehending the pathophysiology and molecular causes of lung cancer, as well as for the formulation of efficacious therapeutic medicines. The mechanism by which cells synchronize cell cycle with cell survival and death is still not fully understood. In this study, we demonstrate that the halting of the cell cycle has a strong inhibitory impact on ferroptosis, a specific type of controlled cell death triggered by excessive lipid peroxidation at the membranes of cells. Ferroptosis is halted through the mechanism of cell cycle arrest, which involves the deposition of intracellular lipids mediated by diacylglycerol acyltransferase (DGAT). Excessive amounts of polyunsaturated fatty acids (PUFAs) are stored as triacylglycerols (TAGs) within inactive cells. As a result, inhibiting DGAT causes a rearrangement of PUFAs from TAGs to phospholipids and makes arrested cells more susceptible to ferroptosis. We demonstrate that certain lung cancer cells that are resistant to antimitotic drugs and have a slow-cycling behavior exhibit an increase in lipid droplets. Furthermore, we find that the growth of tumors resistant to 5-fluorouracil, lorlatinib, and docetaxel can be effectively suppressed by a combination treatment involving the use of ferroptosis inducers and DGAT inhibitors, which induces ferroptosis. Collectively, these findings demonstrate the involvement of cell cycle arrest in conferring resistance to ferroptosis and propose a potential therapeutic approach for addressing the challenge of slow-cycling malignancies that exhibit resistance to ferroptosis.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
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