ACS Omega
·
2023
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IF 4.1
Ting Mao,Bao Chai,Yanpeng Xiong,Hongyan Wang,Lei Nie,Renhai Peng,Peiyu Li,Zhijian Yu,Fang Fang,Xianqiong Gong
Biofilm or persister cells formed by Staphylococcus aureus are closely related to pathogenicity. However, no antimicrobials exist to inhibit biofilm formation or persister cells induced by S. aureus in clinical practice. This study found that pinaverium bromide had antibacterial activity against S. aureus, with the MIC50/MIC90 at 12.5/25 μM, respectively. Pinaverium bromide (at 4 × MIC) showed a rapid bactericidal effect on S. aureus planktonic cells, and it was more effective (at least 1-log10 cfu/mL) than linezolid, vancomycin, and ampicillin at 4 h of the time-killing test. Pinaverium bromide (at 10 × MIC) significantly inhibited the formation of S. aureus persister cells (at least 3-log10 cfu/mL) than linezolid, vancomycin, and ampicillin at 24, 48, 72, 96, and 120 h of the time-killing test. Biofilm formation and adherent cells of S. aureus isolates were significantly inhibited by pinaverium bromide (at 1/2 or 1/4 × MICs). The fluorescence intensity of the membrane polarity of S. aureus increased with the treatment of pinaverium bromide (≥1 × MIC), and the MICs of pinaverium bromide increased by 4 times with the addition of cell membrane phospholipids, phosphatidyl glycerol and cardiolipin. The cell viabilities of human hepatocellular carcinoma cells HepG2 and Huh7, mouse monocyte-macrophage cells J774, and human hepatic stellate cells LX-2 were slightly inhibited by pinaverium bromide (<50 μM). There were 54 different abundance proteins detected in the pinaverium bromide-treated S. aureus isolate by proteomics analysis, of which 33 proteins increased, whereas 21 proteins decreased. The abundance of superoxide dismutase sodM and ica locus proteins icaA and icaB decreased. While the abundance of global transcriptional regulator spxA and Gamma-hemolysin component B increased. In conclusion, pinaverium bromide had an antibacterial effect on S. aureus and significantly inhibited the formation of biofilm and persister cells of S. aureus.
研究领域:
微生物学
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药理学
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感染病学
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DOI
PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Yiqun Xia,Jundixia Chen,Yun Yu,Fengjiao Wu,Xin Shen,Chenyu Qiu,Tingting Zhang,Lin Hong,Peisen Zheng,Rongrong Shao,Chenxin Xu,Fang Wu,Wei Chen,Congying Xie,Ri Cui,Peng Zou
Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
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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DOI
PubMed
高影响因子
FEBS Journal
·
2024
·
IF 5.5
Ling Wang,Shibo Sun,Haowen Liu,Qiuyu Zhang,Yao Meng,Fan Sun,Jianjun Zhang,Haiyan Liu,Weiping Xu,Zhiwei Ye,Jie Zhang,Bingbing Sun,Jianqiang Xu
Thioredoxin reductase 1 (TXNRD1) has been identified as one of the promising chemotherapeutic targets in cancer cells. Therefore, a novel TXNRD1 inhibitor could accelerate chemotherapy in clinical anticancer research. In this study, glaucocalyxin A (GlauA), a natural diterpene extracted from Rabdosia japonica var. glaucocalyx , was identified as a novel inhibitor of TXNRD1. We found that GlauA effectively inhibited recombinant TXNRD1 and reduced its activity in gastric cancer cells without affecting the enzyme's expression level. Mechanistically, the selenocysteine residue (U498) of TXNRD1 was irreversibly modified by GlauA through a Michael addition. Additionally, GlauA formed a covalent adduct with glutathione (GSH) and disrupted cellular redox balance by depleting cellular GSH. The inhibition of TXNRD1 and depletion of GSH by GlauA conferred its cytotoxic effects in spheroid culture and Transwell assays in AGS cells. The disulfide stress induced cytotoxicity of GlauA could be mitigated by adding reducing agents, such as DTT and β-ME. Furthermore, the FDA-approval drug auranofin, a TXNRD1 inhibitor, triggered oligomerization of the cytoskeletal protein Talin-1 in AGS cells, indicating that inhibiting TXNRD1 triggered disulfide stress. In conclusion, this study uncovered GlauA as an efficient inhibitor of TXNRD1 and demonstrated the potential of TXNRD1 inhibition as an effective anticancer strategy by disrupting redox homeostasis and inducing disulfide stress.
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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细胞生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Wenyan She,Xuemin Shi,Tingting Liu,Yujiao Liu,Yi Liu
Targeting overexpressed thioredoxin reductase (TrxR) in cancer cells to induce oxidative stress has been proved to be an effective strategy for cancer therapy. However, the treatment was hindered by the low efficiency and frequent administration of TrxR inhibitors, and hence more potent TrxR inhibitors were urgently needed. Herein, we designed and synthesized a series of TrxR inhibitors based on arsenicals. Among these, compound 1d inhibited the proliferation of a variety of cancer cells at low micromolar concentrations and exhibited low toxicity to normal cells. Importantly, compound 1d induced the accumulation of reactive oxygen species (ROS) by inhibiting the TrxR activity, further causing the collapse of the redox system, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage, followed by oxidative stress-induced cell apoptosis. In vivo data showed that, compared with the clinical TrxR inhibitor auranofin (AUR), compound 1d could more effectively eliminate tumors by 90 % at a dose of 1.5 mg/kg without any obvious side effects. These results indicated that compound 1d was a potent TrxR inhibitor against cancer.
研究领域:
癌症研究
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药理学
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分子生物学
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化学生物学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
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IF 12.8
Jiajia Luo,Yaqi Shang,Ning Zhao,Xiaoying Lv,Zheng Wang,Xin Li,Xuan Meng,Yanjun Zhao
ABSTRACT Ferroptosis has been recognized as a promising therapeutic strategy for cancer due to its unique mechanism of action. However, the upregulation of stearoyl-CoA desaturase 1 (SCD1) in ovarian cancer leads to resistance to ferroptotic therapy. Zinc ion (Zn 2+ ) serves as the cofactor of SCD1. It was hypothesized that selective deprivation of Zn 2+ from SCD1 could sensitize ferroptotic ovarian cancer therapy. Here, we report a hypoxia-responsive polymer micelle for enhanced ferroptosis of ovarian cancer cells. An SCD1 inhibitor, PluriSIn 1 (Plu), and a ferroptosis inducer, Auranofin (Aur), were co-encapsulated in nitroimidazole-bearing micelles. Under the hypoxic tumor microenvironment, the conversion of nitroimidazole to aminoimidazole triggered the cargo release and induced the depletion of antioxidant molecules (e.g., glutathione, thioredoxin, and NADPH). Meanwhile, because of the strong coordination between aminoimidazole and Zn 2+ compared to that of histidine and Zn 2+ , such conversion can deprive the metal cofactor of SCD1, hence sensitizing the action of Plu and Aur. The proof-of-concept was demonstrated in cell and animal models with minimal systemic toxicity. The current work integrates ferroptosis induction with SCD1 inhibition in a hypoxia-responsive vehicle, offering a promising strategy for addressing the ferroptosis resistance and opening novel avenues for managing difficult-to-treat ovarian cancer.
研究领域:
癌症生物学
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药学
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材料科学
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治疗学
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DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Lanlan Fan,Panyu Du,Yaru Li,Xuefei Chen,Fang Liu,Yuning Liu,Alexey M. Petrov,Xin Li,Zheng Wang,Yanjun Zhao
Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
研究领域:
癌症治疗
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药学
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纳米技术
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肿瘤学
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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
Nature Communications
·
2024
·Vol. 15
·期 1
·1-24
·
IF 14.7
Ren Xijiao,Xue Rui,Luo Yan,Wang Shuang,Ge Xinyue,Yao Xuemei,Li Liqi,Min Junxia,Li Menghuan,Luo Zhong,Wang Fudi
Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors. Specifically, fusogenic liposomes are loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplifies IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as adenosine triphosphate (ATP) for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulates matrix metalloproteinase-2 (MMP-2) expression that combined with released ATP to activate ACP through an “and” logic operation-like process (AND-gate), thus triggering the in-situ release of engineered cytosine-phosphate-guanine aptamer-based immunoadjuvants (eCpG) for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibits tumor-intrinsic vascular endothelial growth factor signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Xinrong Zou,Xinyao Fan,Ping Xu,Xiufeng Yu,Chan Luo,Zhuxi Kang,Xin Shen,Jiaoni Zheng,Jisheng Wang,Baicheng He,Zeng Tu,Xiaoming Fu,Yongbo Peng
Diabetes mellitus (DM) aggravates periodontitis due to disordered glucose metabolism, leading to accelerated bone destruction and increasing dental plaque reproduction to induce local inflammation. The hyperglycemic state of DM leads to reactive oxygen species (ROS) overproduction that inhibits osteogenic differentiation in periodontal. These make a great challenge for the treatment of diabetic periodontitis. ROS-scavenging materials with additional anti-inflammation and anti-bacterial properties are highly sought after for the treatment of diabetic periodontitis. Herein, we have prepared the selenium-albumin corona rinse (H@Se NPs) through the albumin/nano-Se assembly strategy. H@Se NPs have better anti-inflammation via promoting the polarization of macrophages from the M1 to M2 phenotype and anti-bacterial effects than the commercially available selenium nanoparticles (Se NPs). Additionally, H@Se NPs can scavenge ROS to modulate the periodontal osteogenic microenvironment, a mechanism that involves regulating thioredoxin reductase 1 (TrxR1) synthesis and activating the TrxR1/ROS/β-catenin cascade. Furthermore, studies conducted in vivo have verified that H@Se NPs can suppress the formation of subgingival microbial colonies while enhancing osteogenic differentiation in diabetic pathological environments and improving periodontal bone regeneration via ROS scavenging. Collectively, these findings unveil new therapeutic paradigms for the clinical management of diabetic periodontitis.
研究领域:
牙科医学
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纳米医学
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糖尿病研究
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炎症生物学
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氧化应激与抗氧化剂
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骨组织再生
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产品关联
DOI
PubMed
高影响因子
Virulence
·
2025
·
IF 5.4
Jian-Guo Li,Wei-Cheng Zhong,Long-Gen Zhong,Chao-Yan Niu,Ting-Yin Lu,Chuan-Jian Zhang,Jian Sun,Xiao-Ping Liao,Yu-Feng Zhou
Methicillin-resistant Staphylococcus aureus (MRSA) remains a major therapeutic challenge and poses a significant global health threat. Developing adjuvants to enhance the efficacy of existing antibiotics represents a promising strategy to address this issue. In this study, we evaluated auranofin as an adjuvant to potentiate the activity of linezolid against MRSA. Auranofin significantly increased MRSA susceptibility to linezolid, promoted intracellular linezolid accumulation, and suppressed the emergence of MRSA resistance to linezolid. Mechanistically, auranofin inhibited the Trx/TrxR system, inducing redox imbalance and reactive oxygen species (ROS) accumulation, which triggers DNA damage and transcriptional dysregulation. Auranofin synergized with linezolid to achieve dual inhibition of MRSA protein synthesis. Furthermore, auranofin downregulated the global regulator sarA, impaired SarA DNA-binding activity, and enhanced SarA phosphorylation, thereby attenuating SarA-mediated virulence factors (eg, adhesins and toxins) and biofilm formation. Importantly, auranofin fully restored anti-MRSA activity of linezolid in both Galleria mellonella and murine bacteremia models. Collectively, these findings identify auranofin as a promising adjuvant to linezolid and highlight its potential to improve therapeutic outcomes against invasive MRSA infections.
研究领域:
微生物学
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传染病学
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抗生素耐药性
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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
JOURNAL OF APPLIED MICROBIOLOGY
·
2024
·Vol. 135
·期 12
·
IF 3.2
Li Jian-Guo,Zhang Chuan-Jian,Liang Liu-Yan,Lu Ting-Yin,Zhong Long-Gen,Zhong Wei-Cheng,Niu Chao-Yan,Sun Jian,Liao Xiao-Ping,Zhou Yu-Feng
AimsMethicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen with multidrug-resistant phenotypes increasingly prevalent in both human and veterinary clinics. This study evaluated the potential of auranofin (AF) as an antibiotic adjuvant to enhance the anti-MRSA activity of florfenicol (FFC) and established a pharmacokinetic/pharmacodynamic (PK/PD) model to compare the efficacy of FFC alone or in combination with AF against MRSA.Methods and resultsWe observed an increased susceptibility and significant synergistic effects of MRSA to FFC in the presence of AF. The combination treatment of FFC and AF significantly inhibited MRSA biofilm formation and decreased the metabolic activity of mature biofilms. Importantly, AF fully restored the efficacy of FFC in both Galleria mellonella larvae and murine models. PK/PD studies demonstrated that the AUC24h/MIC targets required to achieve the bacteriostatic and bactericidal effects were significantly lower with the combination therapy compared to florfenicol monotherapy.ConclusionsThese results reveal the potential of AF as a novel adjuvant to improve the efficacy of FFC in treating MRSA invasive infections and provide valuable PK/PD insights for designing effective combination therapies.
研究领域:
微生物学
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药理学
·
感染性疾病
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产品关联
DOI
PubMed
高影响因子
Research
·
2024
·
IF 8.5
Hao Liu,Ke Huang,Hao Zhang,Xiaohui Liu,Hui Jiang,Xuemei Wang
Achieving antitumor immunotherapy based on hybridization of multiple types of inactivated cells has attracted a lot of attention. However, the hybridized cells of disordered structure could result in the shedding of antigens and their transfer to immune cells, which suppresses tumor immunity through trogocytosis. Here, we report a strategy for in situ solidification of tumor whole cell by biomineralization for sustained stimulation of antitumor immunity. The near-infrared light was used to accelerate the breaking of Au=P bonds in auranofin, and the exposed Au atoms biomineralize at the secondary structure (β-corner) of the protein to form Au nanocrystals with in situ protein coronas in tumor cells. Au nanocrystals are anchored to the tumor cells through protein coronas, which fixes the morphology and antigens of whole tumor cells, rendering them physiologically inactive. Interestingly, this solidified tumor cell prevents immune cells from undergoing trogocytosis, which inhibits proximal and distal tumor growth. Thus, this study presents the strategy of solidified cells and its potential application in tumor immunotherapy.
研究领域:
肿瘤免疫学
·
生物医学工程
·
材料科学
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产品关联
DOI
PubMed
高影响因子
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