SCIENCE OF THE TOTAL ENVIRONMENT
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2025
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IF 8
Zhengfeng Guo,Tingting Zhang,Hao Yang,Xiaolin Zhu,Siyuan Lu,Anjie Chen,Mingyu Fan,Jiao Qu
In aquatic environments, antibiotics degrade into byproducts, potentially enhancing bacterial resistance. However, the specific mechanisms by which these byproducts induce bacterial resistance remain elusive. This study conducted experimental evolution experiments to explore how E. coli adapts to tetracycline (TC) and its primary degradation products—anhydrotetracycline (ATC), epitetracycline (ETC), and 4-epianhydrotetracycline (EATC)—through evolution experiments. Prolonged exposure to TC and its byproducts significantly increased frequency of resistant mutants in E. coli ATCC25922, with a maximum 10 6 -fold increase. Resistant mutants exhibited markedly elevated minimum inhibitory concentrations (MICs) for TC, ampicillin (AMP), and ciprofloxacin (CIP), indicating multidrug resistance. Transcriptomic analysis showed that the antibiotic resistance phenotype could be related to enhanced target protection, metabolic adaptations, and reduced membrane permeability. The induction pathways between TC and its byproducts were distinct. Specifically, TC 20d (where TC 20d represents the mutants collected after 20 days of continuous exposure to TC) was associated with more alterations in ribosome-associated genes, which was correlated with an enhanced defensive response as shown by the data. Moreover, variations in energy metabolism gene expression suggest a robust metabolic defense in ATC 20d and ETC 20d . When TC and its byproducts—ATC, ETC, and EATC—act together, they induce antibiotic resistant mutants at rates of 29.8 %, 18.9 %, 18.3 %, and 31.9 %, respectively. This study provides a descriptive overview of the possible adaptive mechanisms and pathways that may be involved in antibiotic resistance due to environmental exposure.
研究领域:
微生物学
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环境科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 11
·4073-4081
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IF 8.307
Liming Liu,Fanchu Zeng,Yujie Li,Wenjing Li,Hui Yu,Qingxing Zeng,Qun Chen,Huan Qin
Resistance to either radiation or chemotherapy remains a complex and stubborn obstacle in cancer therapy and is responsible for a significant portion of the treatment failure. While the underlying mechanisms of the resistance are often associated with multiple factors, direct destruction of mitochondria is likely to ensure the ultimate death of the cell. Herein, a strategy of precise mitochondrial destruction using a photoacoustic (PA) shockwave was proposed to overcome chemoresistance and radiation resistance in cancer therapy. A nanoparticle featuring mitochondria-targeting and high near-infrared absorbance is constructed. The nanoparticle was found to indiscriminately localize in the mitochondria of both parental and its corresponding resistant tumor cells due to the mitochondrial transmembrane potential. By absorbing a controllable amount of energy from a pulsed laser, the nanoparticle could generate a mechanical PA shockwave that physically damages the mitochondria leading to the opening of apoptotic pathways and thus yielding a precision antitumor effect. The cell-killing efficiency was validated in vitro and in vivo. The results demonstrate that a PA shockwave can result in undifferentiated killing of the resistant tumor cells via destruction of mitochondria. Given the critical importance of resistant tumor cells, although at its preliminary stage, the proposed modality may open a new window in cancer therapy.
研究领域:
肿瘤学
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生物医学工程
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2021
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IF 6.684
Wang Meng,Liu Haoyu,Zhang Xu,Zhao Wenbo,Lin Xiaoyan,Zhang Fei,Li Danyang,Xu Chengpeng,Xie Fei,Wu Zhen,Yang Qibing,Li Xiangzhi
Hypoxia-inducible factor-1α (HIF-1α) promotes oncogenesis in hepatocellular carcinoma and is functionally linked to cell proliferation, chemoresistance, metastasis and angiogenesis. It has been confirmed that the low expression level of Males absent on the first (MOF) in hepatocellular carcinoma leads to poor prognosis of patients. However, potential regulatory mechanisms of MOF in response to hypoxia remain elusive. Our results demonstrate that MOF expression is negatively associated with HIF-1α expression in hepatocellular carcinoma tissues and in response to chloride-mimicked hypoxia in hepatocellular carcinoma cell lines. MOF regulates HIF-1α mRNA expression and also directly binds to HIF-1α to mediate HIF-1α N-terminal lysine acetylation, ubiquitination and degradation, with downstream effects on MDR1 levels. Functional inactivation of MOF enhances HIF-1α stability and causes cell tolerance to hypoxia that is insensitive to histone deacetylase inhibitor treatment. Dysfunction of MOF in hepatocellular carcinoma cells also results in chemoresistance to trichostatin A, sorafenib and 5-fluorouracil via HIF-1α. Our results suggest that MOF regulates hypoxia tolerance and drug resistance in hepatocellular carcinoma cells by modulating both HIF-1α mRNA expression and N-terminal acetylation of HIF-1α, providing molecular insight into MOF-dependent oncogenic function of hepatocellular carcinoma cells.
研究领域:
肿瘤学
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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
ACS Applied Materials & Interfaces
·
2021
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IF 9.229
Furong Cheng,Qingqing Pan,Wenxia Gao,Yuji Pu,Kui Luo,Bin He
Mitochondrial drug delivery has attracted increasing attention in various mitochondrial dysfunction-associated disorders such as cancer owing to the important role of energy production. Herein, we report a lysosomal pH-activated mitochondrial-targeting polymer nanoparticle to overcome drug resistance by a synergy between mitochondrial delivery of doxorubicin (DOX, an anticancer drug) and erlotinib-mediated inhibition of drug efflux. The obtained nanoparticles, DE-NPs could maintain negative charge and have long blood circulation while undergoing charge reversal at lysosomal pH after internalization by cancer cells. Thereafter, the acidity-activated polycationic and hydrophobic polypeptide domains boost lysosomal escape and mitochondrial-targeting drug delivery, leading to mitochondrial dysfunction, ATP suppression, and cell apoptosis. Moreover, the suppressed ATP supply and erlotinib enabled dual inhibition of drug efflux by DOX-resistant MCF-7/ADR cells, leading to significantly augmented intracellular DOX accumulation and a synergistic anticancer effect with a 17-fold decrease of IC50 relative to DOX. In vivo antitumor study demonstrates that DE-NPs efficiently suppressed the tumor burden in MCF-7/ADR tumor-bearing mice and led to negligible toxicity. This work establishes that a combination of mitochondrial drug delivery and drug efflux inhibition could be a promising strategy for combating multidrug resistance.
研究领域:
肿瘤学
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药理学
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生物材料学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Xing Fa-liang,Li Bo-rui,Fang Ying-jin,Liang Chen,Liu Jiang,Wang Wei,Xu Jin,Yu Xian-jun,Qin Yi,Zhang Bo
Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC‐1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC‐1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC’s resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
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2024
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IF 4.1
Hongming Huang,Huang Yang,Shunhang Feng,Xiaoyan Zhang,Chu Chen,Hongyu Yan,Rui Li,Mengxin Liu,Juan Lin,Yancheng Wen,Feifei She
The burgeoning emergence of drug-resistant Helicobacter pylori strains poses a significant challenge to the clinical success of eradication therapies and is primarily attributed to mutations within drug-targeting genes that lead to antibiotic resistance. This study investigated the effect of high salt conditions on the occurrence of drug-resistance mutations in H. pylori. We found that high salt condition significantly amplifies the frequency of drug resistance mutations in H. pylori. This can be chiefly attributed to our discovery indicating that high salt concentration results in elevated reactive oxygen species (ROS) levels, initiating DNA damage within H. pylori. Mechanistically, high salt condition suppresses lipopolysaccharide (LPS) synthesis gene expression, inducing alterations in the LPS structure and escalating outer membrane permeability. This disruption of LPS synthesis attenuates the expression and activity of SodB, facilitates increased ROS levels, and consequently increases the drug resistance mutation frequency. Impairing LPS synthesis engenders a reduction in intracellular iron levels, leading to diminished holo-Fur activity and increased apo-Fur activity, which represses the expression of SodB directly. Our findings suggest a correlation between high salt intake and the emergence of drug resistance in the human pathogen H. pylori, implying that dietary choices affect the risk of emergence of antimicrobial resistance.
研究领域:
微生物学
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分子生物学
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传染病学
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药理学
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DOI
PubMed
高影响因子
Food & Function
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2022
·Vol. 13
·期 4
·2200-2215
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IF 6.317
Yi Wang,Jingwen Xu,Yihai Wang,Limin Xiang,Xiangjiu He
Multidrug resistance (MDR) is a major cause of chemotherapy failure. Adriamycin (ADR) has been widely used to treat cancer, however, as a substrate of the adenosine triphosphate binding cassette (ABC) transporter, it is easy to develop drug resistance during the treatment. Here, we demonstrated that steroidal saponin S-20 isolated from the berries of black nightshade has comparable cytotoxicity in ADR-sensitive and resistant K562 cell lines. Autophagy is generally considered to be a protective mechanism to mediate MDR during treatment. However, we found that S-20-induced cell death in K562/ADR is associated with autophagy. We further explored the underlying mechanisms and found that S-20 induces caspase-dependent apoptosis in ADR-sensitive and resistant K562 cell lines. Most importantly, S-20-induced autophagy activates the ERK pathway and then inhibits the expression of drug resistance protein, which is the main reason to overcome K562/ADR resistance, rather than apoptosis. Taken together, our findings emphasize that S-20 exerts anti-multidrug resistance activity in K562/ADR cells through autophagic cell death and ERK activation, which may be considered as an effective strategy.
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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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xuan Jiang,Manli Wang,Guoliang Cui,Yuanyuan Wu,Zhonghong Wei,Suyun Yu,Aiyun Wang,Wei Zou,Yanhong Pan,Xiaoman Li,Yin Lu
Background Tetramethylpyrazine (TMP), a key bioactive constituent derived from Ligusticum wallichii Franchat , has demonstrated efficacy in mitigating multidrug resistance (MDR) in human breast cancer (BC) cells. However, the precise mechanisms underlying its action remain poorly understood. Purpose Cancer stem cells (CSCs) are widely recognized as the primary contributors to MDR. This investigation seeks to elucidate the role and mechanisms through which TMP counteracts MDR by attenuating CSC-like characteristics. Methods Various assays, including flow cytometry, sphere formation, and Western blotting, were employed to evaluate TMP's effects on breast cancer stem cell (BCSC)-like phenotypes in vitro. In vivo , extreme limiting dilution assays and immunohistochemistry (IHC) were executed to assess the impacts of TMP on BCSC frequency and the levels of stemness markers. Mechanistically, RNA sequencing was performed to uncover the key biological processes involved in TMP's effects on BCSCs. Further experiments, encompassing micro scale thermophoresis (MST), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and amino acid mutation analyses, were utilized to identify the essential targets and corresponding binding sites of TMP. Finally, the effects of TMP on BCSC-like phenotypes were confirmed using cells with mutated amino acid residues, which allowed us to investigate the specificity of TMP's binding sites. To further evaluate the impact of TMP on drug resistance, doxorubicin-resistant MCF7 (MCF-7 ADR ) cells, along with corresponding cell lines harboring mutated amino acid residues, were employed. Results TMP was found to inhibit BCSC-like properties both in vitro and in vivo , evidenced by a reduction in the CD44 + /CD24 - population, sphere formation capability, and expression of stemness markers. Mechanistic studies revealed that TMP targets 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. TMP binds to Asp-767 of HMGCR, thereby inhibiting its activity and reducing cholesterol synthesis. The influence of TMP on BCSC-like phenotypes was nullified by overexpression of wild-type HMGCR, while mutations in the binding site of HMGCR had no effect on TMP's inhibition of BCSC-like properties. Additionally, TMP mitigated MDR by targeting HMGCR. Conclusion These findings suggest that TMP alleviates MDR by reducing BCSC-like traits through targeting HMGCR and disruption of cholesterol biosynthesis in BC. This provides new insights into the mechanisms through which TMP alleviates MDR and offers new lead compound for exploring HMCGR antagonists.
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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产品关联
DOI
PubMed
高影响因子
Journal of Global Antimicrobial Resistance
·
2022
·
IF 4.349
Wenting Zhang,Tengfei Zhang,Chen Wang,Guixing Liang,Qin Lu,Guoyuan Wen,Yunqing Guo,Yiluo Cheng,Zui Wang,Huabin Shao,Qingping Luo
ABSTRACT Objectives This study investigated the prevalence and characteristics of mcr-1- harbouring Escherichia coli isolated from chickens in central China from 2014 to 2019. Methods A total of 1132 E. coli isolated from 1647 chicken swabs were analysed for colistin susceptibility by broth microdilution method and prevalence of mcr-1 gene by PCR. The colistin-resistant E. coli isolates were typed by multi-locus sequence typing (MLST) and tested with 12 antimicrobial agents. The transconjugation assay was conducted for the mcr-1 -positive isolates using the transconjugant E. coli C600. Results Of the 1132 E. coli isolated from chickens, 131 isolates (11.6%) exhibited colistin resistance, and 51 isolates (4.5%) were mcr-1 positive. The mcr-1 -positive rate was quite low in 2014 (2.3%) and 2015 (1.7%), increased to peak in 2016 (12.6%) and 2017 (11.4%), and then decreased significantly in 2018 (1.7%) and 2019 (0.9%). The 131 colistin resistant isolates were assigned to 66 unique sequence types (STs), 27 of which contained mcr-1 -positive isolates. Compared with mcr-1 -negative E. coli, mcr-1 -positive E. coli showed higher resistance rates to nalidixic acid, ciprofloxacin, ceftriaxone, cefotaxime, and tetracycline. Furthermore, 30 of the 51 mcr-1 positive isolates transduced their mcr-1 gene into E. coli C600, and 13 of the 30 transconjugants carried more than one replicon types. Conclusion The mcr-1 positive rate varied enormously during 2014–2019 in central China. The ban on colistin likely decreased the dissemination of mcr-1 in E. coli isolates from chickens. Multidrug-resistant trait is observed in mcr-1 positive E. coli isolates and can be transferred into other transconjugants.
研究领域:
微生物学
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兽医学
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公共卫生
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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 Global Antimicrobial Resistance
·
2024
·
IF 3.7
Xiaoqian Long,Feng Lin,Biao Tang,Fengcheng Miao,Zhiyu Li,Yao Shen,Hua Yang,Jiangang Ma
Objectives Acinetobacter indicus is an important pathogen of nosocomial infection. The purpose of this study was to analyze the resistance and transmission of A. indicus strain AIBD14 isolated from slaughterhouse environment. Methods A total of 96 environmental samples were collected from slaughterhouse. The antimicrobial susceptibility test was carried out by microbroth dilution method and E -test. Whole genome sequencing and bioinformatics analysis of the AIBD14 were performed, then S1-PFGE and southern blot verified the location of bla NDM-1 and tet (X6). Results The AIBD14 is resistant to meropenem but susceptibility to tigecycline, and coharboring bla NDM-1 and tet (X6). The bla NDM-1 is located on the pAIBD14-NDM-1 that cannot be transferred by conjugation. Specifically, bla NDM-1 is located on the transposon Tn 125 , and bla NDM-1 can be transferred to other species with the help of transposon. The genetic background of bla NDM-1 is "IS Aba125 - bla NDM-1 - ble MEL - dsbD - cutA - groES - groEL -insE-IS Aba125 ". pAIBD14-NDM-1 is classified into the GR31 plasmid based on the homology of the repB . Meanwhile, there are two XerC/D-like binding sites on the plasmid, which can mediate the transfer of resistance genes. The tet (X6) gene is located on the chromosome of AIBD14, its downstream is accompanied by the neglected macrolide resistance gene estT , and there is a single copy of the insertion element IS CR2 around tet (X6) as the genetic background "IS Aba4 -IS 3 -hp-hp- tet (X6)- estT - guaA -IS CR2 ". Conclusions This is the first report of the coexistence of tet (X6) and bla NDM-1 in the A. indicus , and it has the risk of horizontal transfer across multiple species. So strict monitoring the multiple-resistant bacteria in the industrial chain is necessary based on the "One Heath".
研究领域:
微生物学
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传染病学
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基因组学
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DOI
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 70
·40873-40882
·
IF 3.049
Lu Diao,Ao Shen,Yunxu Yang,Jin Tao,Ying Hu
Chemotherapeutic drug resistance poses a great challenge in cancer therapy. Drug efflux and anti-apoptotic processes are the two most common mechanisms leading to chemotherapy resistance. In this study, we focused on the applicability of curcumin (CUR) as a sensitizer for chemotherapeutics (doxorubicin [DOX] as the model drug) modified with hyaluronic acid (HA) as an effective therapeutic strategy against multidrug resistance (MDR) in cancer cells. We constructed an HA–CUR/DOX delivery system measuring approximately 180 nm with superior encapsulation efficacy and serum stabilities. In vitro, we found that HA modification could facilitate the efficient delivery of chemotherapeutics through CD44 receptor-mediated targeted delivery. MTT assay results confirmed that the combination of CUR and DOX/paclitaxel (PTX) had a significant synergistic effect and significantly reversed MDR. Further experiments including real-time polymerase chain reaction and western blotting proved that the main mechanisms by which CUR reversed MDR in tumor cells were inhibiting the expression and activity of P-glycoprotein (P-gp) and inducing apoptosis through mitochondrial pathway. Taken together, our new engineered tumor-targeting nanoparticle delivery system may have the potential for overcoming MDR in cancer.
研究领域:
肿瘤学
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药学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Yuting Sun,Hui Yang,Jiaqi Yuan,Limin Wang,Shanshan Song,Rongrong Chen,Xubin Bao,Li Jia,Tiantian Yang,Xiaofei Zhang,Qian He,Yong Gan,Zehong Miao,Jinxue He,Chunhao Yang
Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure–activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.
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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药物化学
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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）