JOURNAL OF NATURAL PRODUCTS
·
2025
·
IF 3.6
Mi Zhou,Yanlan Yang,Shoulun He,Qiannan Xu,Chunchun Du,Wenjing Tian,Haifeng Chen
Phosphorylation of checkpoint kinase 1 at Ser-345 (p-CHK1(S345)) mediates the replication stress response in cancer cells, leading to chemotherapy resistance. Therefore, finding inhibitors of p-CHK1(S345) is currently a promising strategy to prevent acquired drug resistance. In this study, 14 ingenane diterpenoids (1–14), involving two undescribed compounds possessing an unprecedented exocyclic double bond Δ6(20), were identified from Euphorbia peplus. The inhibitory effects of the isolated compounds on p-CHK1(S345) and their structure–activity relationship (SAR) were investigated. Compounds 7 and 8 presented the strongest inhibitory effects, abrogated cell cycle arrest, and caused the accumulation of DNA damage, improving the sensitivity of cancer cells to chemotherapeutic drugs. An in vivo assay confirmed the enhancement of 8 on the anticancer effect of topotecan via blocking of p-CHK1(S345). Mechanistically, 8 increased CHK1 ubiquitination to inhibit p-CHK1(S345) via activation of protein kinase C (PKC). PKC activation was first found to enhance CHK1 ubiquitination to block p-CHK1(S345). Above all, this finding not only indicates that compound 8 could be developed as a novel CHK1 inhibitor but also reveals a previously unrecognized role of PKC in regulating cancer chemotherapy sensitivity.
研究领域:
肿瘤学
·
药理学
·
植物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Shang Wu,Jian Ji,Lina Sheng,Yongli Ye,Yinzhi Zhang,Xiulan Sun
Disinfectants are widely used in food production and environmental sanitation to prevent illness, but bacteria resistance to these disinfectants and co-resistance to antibiotics pose a threat to public health. This study investigated the impact of commonly used disinfectants on the resistance of Salmonella Typhimurium (ST) to disinfectants and antibiotics, and explored the metabolic mechanisms underlying the resistance changes. The results showed that subinhibitory concentrations of disinfectants had a minor impact on the resistance of ST to four disinfectants. However, chlorine-containing disinfectants stress enhanced bacteria resistance to ampicillin, while quaternary ammonium compounds stress increased resistance to tetracycline and gentamicin. Untargeted metabolomics analysis revealed significant changes in glutathione metabolism and lysine and valine degradation pathways after disinfectant exposure. Specifically, ST activated lysine decarboxylation, leading to a significant decrease in lysine levels after benzalkonium chloride exposure, while valine and leucine degradation pathways were activated by sodium hypochlorite stress. The addition of downregulated L-lysine and L-valine increased the sensitivity of ST to antibiotics, providing further evidence for the findings of metabolomics. This study provides guidance for the proper use of disinfectants in food processing and establishes a strategy based on metabolomics to control antibiotic-resistant bacteria.
研究领域:
微生物学
·
代谢组学
·
食品安全
·
公共卫生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2016
·Vol. 4
·期 36
·6043-6051
·
IF 4.872
Junling Wang,Ran Wang,Fangrong Zhang,Yajun Yin,Leixia Mei,Fengjuan Song,Mingtao Tao,Wanqing Yue,Wenying Zhong
Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy due to the overexpression of P-glycoprotein (P-gp). Herein, etoposide (ETO) was loaded onto oxidized carbon nanohorns (oxCNHs), which were modified by polyethylene glycol (PEG) and further functionalized with the targeting ligand P-gp monoclonal antibody (PA) in an attempt to overcome MDR. The obtained drug delivery system (ETO@oxCNHs/PEG-PA) showed high drug loading efficiency, enhanced drug release under laser irradiation, improved cellular uptake and increased therapeutic effect both in vitro and in vivo. In addition, NIR laser irradiation had a synergistic effect on overcoming MDR. The MDR-overcoming mechanism could be the efficient cellular uptake, enhanced drug release and reduced drug efflux by P-gp. These results demonstrated that ETO@oxCNHs/PEG-PA could be a promising drug delivery system for cancer MDR reversion.
研究领域:
肿瘤学
·
纳米医学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2017
·
IF 6.402
Xiangyu Su,Chanchan Gao,Fangfang Shi,Xiaoyao Feng,Lin Liu,Ding Qu,Cailian Wang
Multidrug resistance (MDR) is the major underlying cause of the low 5-year survival rate of esophageal carcinoma. In this study, we developed a novel microemulsion system (SD-ME) co-loaded with docetaxel (DTX) and Schizandrin A, a potent chemotherapeutic agent and a potential drug resistance modulator, respectively. In the physicochemical characterization studies, SD-ME displayed a well-defined spherical shape and size (56.62 ± 4.16 nm), a narrow polydispersity index (PDI, 0.132 ± 0.002), and a negative surface charge (−19.81 ± 3.11 mv). In the cellular uptake studies, SD-ME with a DTX concentration of 30 μg/mL exhibited a 3.9-fold enhancement of DTX internalization in DTX-resistant EC109 (EC109/DDR) cells in comparison to that observed for EC109 cells, and the mechanisms were associated with reducing P-gp expression and inhibiting P-gp ATPease. The half-maximal inhibitory concentrations (IC50) of DTX and SD-ME against EC109/DDR cells were 40.57 ± 0.39 and 3.59 ± 0.06 μg/mL, respectively. Likewise, the apoptotic rate of EC109/DDR treated with SD-ME increased up to 20-fold compared to that observed with free DTX. In anticancer efficacy studies in vivo, SD-ME markedly retarded the tumor growth of nude mice bearing EC109/DDR tumor xenografts compared with D-ME and free DTX throughout the duration of study. Consequently, mice treated with SD-ME had the highest survival rate (37.5%) during the observation period (70 days). In addition, there were no apparent side effects after the administration of SD-ME. Overall, our study provides evidence for SD-ME as an effective drug delivery system for enhanced MDR tumor treatment.
研究领域:
肿瘤学
·
药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Applied Materials Today
·
2021
·
IF 10.041
Yu Chen,Yi Lu,Danrong Hu,Jinrong Peng,Yao Xiao,Ying Hao,Meng Pan,Liping Yuan,Zhiyong Qian
Colorectal cancer is the third most frequently diagnosed cancer in men and the second most frequent in women, with a mortality of approximately half the incidence. Currently, there is no specific consensus regarding standard treatments for colorectal cancer, and new and effective treatment regimens are yet to be developed. Cabazitaxel (CTX), a derivative of paclitaxel, has better anticancer activity than paclitaxel and docetaxel, and has low structural affinity with the MDR1 efflux pump, which offers the advantage of overcoming multidrug resistance. However, the adverse effects and poor stability impede its clinical applications; therefore, we synthesized a new block copolymer (MPEG 2k -PCL 10k ) to prepare CTX nanoparticle formulations to enhance its biocompatibility and bioavailability. Compared with the CTX preparation Jevtana®, the drug loading, stability and antitumor efficacy of the nanoparticles were significantly improved, while the cytoxicity was notably reduced. The results indicate that CTX-MPEG 2k -PCL 10k nanoparticle preparations have high security and excellent anti-tumor effects, and has great application potential in the colorectal cancer therapy.
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
MATERIALS & DESIGN
·
2021
·
IF 7.991
Youyou Huang,Jianan Zhang,Yue Zhang,Ling Shi,Xiru Qin,Bing Lu,Yue Ding,Yang Wang,Tingting Chen,Yong Yao
Multi-drug resistance (MDR) in tumor therapy often leads to relatively low efficiency of the current chemotherapeutics, attributing to the overexpression of P-glycoprotein (P-gp) increases the efflux of anticancer drugs out of the cells. To address this obstacle, herein, a photothermal-triggered nitric oxide (NO) gas releasing nanosystem was designed for reversing drug resistance in MDR cells based on mesoporous core–shell structured nanocomposites (MCSN) of Cu 2-x [email protected] 2 . The mesoporous shell provided the modification and encapsulation capacity for the NO donor— S -nitrosothiol (SNO) and doxorubicin (DOX) loading. Besides, the heat generated from the photothermal conversion of Cu 2-x Se could trigger NO gas generation and enhance DOX release in the acid microenvironment of cancer cells. The released NO gas in the cytoplasm could induce mitochondrial dysfunction to block adenosine triphosphate (ATP) synthesis and ATP-dependent drug efflux, thereby overcoming MDR. Therefore, this novel gas/chemo/photothermal triple-combination therapeutic nanoplatform is expected to be a potentially effective strategy against MDR and may reveal new insights for other NO gas-relevant medical applications.
研究领域:
肿瘤学
·
药理学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
ACS Omega
·
2023
·
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
·
药理学
·
感染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Qianwei Qu,Wenqiang Cui,Xingyu Huang,Zhenxin Zhu,Yue Dong,Zhongwei Yuan,Chunliu Dong,Yadan Zheng,Xueying Chen,Shuguang Yuan,Yanhua Li
Due to the large amount of antibiotics used for human therapy, agriculture, and even aquaculture, the emergence of multidrug-resistant Streptococcus suis (S. suis) led to serious public health threats. Antibiotic-assisted strategies have emerged as a promising approach to alleviate this crisis. Here, the polyphenolic compound gallic acid was found to enhance sulfonamides against multidrug-resistant S. suis. Mechanistic analysis revealed that gallic acid effectively disrupts the integrity and function of the cytoplasmic membrane by dissipating the proton motive force of bacteria. Moreover, we found that gallic acid regulates the expression of dihydrofolate reductase, which in turn inhibits tetrahydrofolate synthesis. As a result of polypharmacology, gallic acid can fully restore sulfadiazine sodium activity in the animal infection model without any drug resistances. Our findings provide an insightful view into the threats of antibiotic resistance. It could become a promising strategy to resolve this crisis.
研究领域:
微生物学
·
药理学
·
传染病
·
抗菌素耐药性
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 6
·e70470
·
IF 4.2
Chuchu Xu,Renjun Zhu,Qingfeng Dai,Yaoqing Li,Gengyuan Hu,Kelong Tao,Yuhong Xu,Guangen Xu,Guolin Zhang
The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC 50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK–STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.
研究领域:
肿瘤学
·
分子生物学
·
药物研发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Microbiology Spectrum
·
2022
·Vol. 10
·期 6
·
IF 9.043
Shuyi Wang,Qi Ding,Yawei Zhang,Anru Zhang,Qi Wang,Ruobing Wang,Xiaojuan Wang,Longyang Jin,Shuai Ma,Hui Wang
Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is recognized as a threat worldwide, but the mechanisms underlying its emergence remain unclear. As most CR-hvKP isolates are not hypermucoviscous, we speculated that the evolution of the capsule might result in the convergence of carbapenem resistance and hypervirulence. Here, 2,096 K. pneumoniae isolates were retrospectively collected to screen the ST23-K1 clone, and hypervirulence was roughly defined as being highly resistant to serum killing. The effect of wcaJ on the capsule, virulence, fitness, and resistance acquisition was further analyzed. The capsule gene wcaJ, inserted by ISKpn26/ISKpn74, was identified via whole-genome sequencing in four hvKP, but not hypermucoviscous, isolates. Uronic acid quantitation results revealed that these isolates produced significantly less capsular polysaccharides than NTUH-K2044. A significant increase in capsular production was observed in wcaJ-complemented isolates and confirmed by transmission electron microscopy. Further, all wcaJ-complemented isolates acquired greater resistance to macrophage phagocytosis, and one representative isolate resulted in a significantly higher mortality rate than the parental isolate in mice, indicating that wcaJ inactivation might compromise virulence. However, isolates with wcaJ interruption demonstrated a lower fitness cost and a high conjugation frequency of the blaKPC-2 plasmid, raising concerns about the emergence of carbapenem resistance in hvKP.IMPORTANCE Klebsiella pneumoniae is one of the most common nosocomial pathogens worldwide, and we speculated that the evolution of the capsule might result in the convergence of carbapenem resistance and hypervirulence of K. pneumoniae. The wcaJ gene was first reported to be interrupted by insertion sequence elements in ST23-K1 hypervirulent Klebsiella pneumoniae, resulting in little capsule synthesis, which plays an important role in virulence. We examined the effect of wcaJ on the capsule, virulence, and fitness. Isolates with wcaJ interruption might compromise virulence and demonstrated a lower fitness cost and a high conjugation frequency of the blaKPC-2 plasmid, highlighting its role as a potential factor facilitating hypervirulence and carbapenem resistance.
研究领域:
微生物学
·
感染病学
·
基因组学
✓ 已验证
DOI
高影响因子
APPLIED CATALYSIS B-ENVIRONMENTAL
·
2021
·
IF 19.503
Daiyong Chao,Qing Dong,Jinxing Chen,Zhixuan Yu,Weiwei Wu,Youxing Fang,Ling Liu,Shaojun Dong
Cu 3 P nanoparticles (NPs) were proposed as an efficient antibacterial agent for impeding bacterial resistance. Both sensitive and resistant strains of E. coli and S. aureus (3 × 10 6 CFU mL −1 ), and the microbial populations from a fishery water were completely inactivated by Cu 3 P NPs (≤ 1.5 µg mL −1 ) within 30 min with no regrowth. The antibacterial mechanism of Cu 3 P NPs relied on their own multiple enzyme-like activities, to elucidate, the action of ROS produced by their oxidase- and peroxidase- like activities was facilitated by their inherent activities for glutathione depletion and the lipid peroxidation. Comparing with that traditional antibiotics induced bacterial resistance (6 out of 7) within 3 passages, Cu 3 P NPs kept their initially inactivated efficiency, demonstrating that they can delay the onset of bacterial resistance. Furthermore, the Cu 3 P NPs shown no obviously toxic effect on aquatic organisms and a negligible side-effect toward mammalian tissues. This strategy is insightful for struggle with resistant bacteria.
研究领域:
微生物学
·
生物化学
·
环境科学
✓ 已验证
DOI
高影响因子
Heliyon
·
2024
·
IF 3.4
Feifei Sun,Yao Xiao,Lili Kong,Haibo Mu,Xing Wang,Jinyou Duan
The consequences caused by bacterial resistance are becoming more and more serious. The rate of antibiotic development is far behind the rate of bacterial resistance, so it is urgent to develop a new drug system. In this study, photoresponsive nanogels based on hyaluronic acid were prepared and loaded with ciprofloxacin as a model molecule. The results showed that the nanogels had the advantages of high stability and good cytocompatibility. The inhibition effect of drug-loaded nanogels after light irradiation on the growth of Staphylococcus aureus and Salmonella typhimurium was significantly better than that before light irradiation, and ciprofloxacin could be released on demand and in control. This strategy is of great significance to reduce the unnecessary use of antibiotics and weaken bacterial resistance.
研究领域:
生物医学工程
·
微生物学
·
药剂学
✓ 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）