Microorganisms
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2023
·Vol. 11
·期 7
·1823
·
IF 4.5
Li-Na Chai,Hua Wu,Xue-Jiao Wang,Li-Juan He,Chun-Feng Guo
The mechanism underlying antimicrobial activity of conjugated bile acids against strains of lactic acid bacilli is not well understood. The purpose of this study was to investigate two typical conjugated bile acids (glycochenodeoxycholic acid and taurochenodeoxycholic acid) for their mechanisms of antimicrobial activity against four strains of different species of lactic acid bacilli at the physiological pH of the small intestine of humans. The bacterial cell membrane integrity, transmembrane potential, and transmembrane pH gradient were examined using the fluorescence probes SYTO 9 plus propidium iodide, 3,3′-dipropylthiadicarbocyanine iodide, and 5(6)-carboxyfluorescein diacetate N-succinimidyl ester, respectively. The intracellular ATP levels were measured by the firefly luciferase-based bioluminescence method. It was found that the antimicrobial activity of conjugated bile acids against the strains of lactic acid bacilli is strain-specific, and glycochenodeoxycholic acid showed significantly greater antimicrobial activity than taurochenodeoxycholic acid against the strains of lactic acid bacilli. The conjugated bile acids inhibited the growth of strains of lactic acid bacilli by disrupting membrane integrity, dissipating transmembrane potential, reducing the transmembrane pH gradient, and depleting intracellular ATP. In conclusion, the antimicrobial activity of conjugated bile acids against lactic acid bacilli is a multifactorial phenomenon. This study will provide valuable information for developing strategies to improve the ability of lactic acid bacilli to tolerate bile in vivo.Keywords:conjugated bile acid;antimicrobial activity;membrane integrity;transmembrane potential;intracellular ATP
研究领域:
微生物学
·
分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
Scientific Reports
·
2017
·
IF 4.259
Xie Xiaoyun,Han Chaofei,Zeng Weiqi,Chen Chen,Lu Lixia,Liu Queping,Peng Cong,Zhao Shuang,Su Juan,Chen Xiang
The F1F0-ATP synthase, an enzyme complex, is mainly located on the mitochondrial inner membrane or sometimes cytomembrane to generate or hydrolyze ATP, play a role in cell proliferation. This study focused on the role of F1F0-ATP synthase in keratinocyte differentiation, and its relationship with intracellular and extracellular ATP (InATP and ExATP). The F1F0-ATP synthase β subunit (ATP5B) expression in various skin tissues and confluence-dependent HaCaT differentiation models was detected. ATP5B expression increased with keratinocyte and HaCaT cell differentiation in normal skin, some epidermis hyper-proliferative diseases, squamous cell carcinoma, and the HaCaT cell differentiation model. The impact of InATP and ExATP content on HaCaT differentiation was reflected by the expression of the differentiation marker involucrin. Inhibition of F1F0-ATP synthase blocked HaCaT cell differentiation, which was associated with a decrease of InATP content, but not with changes of ExATP. Our results revealed that F1F0-ATP synthase expression is associated with the process of keratinocyte differentiation which may possibly be related to InATP synthesis.
研究领域:
细胞生物学
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分子生物学
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皮肤病学
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2013
·
IF 4.57
Wenjing Li,Xinru Li,Yajie Gao,Yanxia Zhou,Shujin Ma,Yong Zhao,Jinwen Li,Yan Liu,Xinglin Wang,Dongdong Yin
The present study aimed to investigate the effect of monomethoxy poly(ethylene glycol)-block-poly(d,l-lactic acid) (mPEG-PLA) on the activity of P-glycoprotein (P-gp) in Caco-2 cells and further unravel the relationship between PLA chain length in mPEG-PLA and influence on P-gp efflux and the action mechanism. The transport results of rhodamine 123 (R123) across Caco-2 cell monolayers suggested that mPEG-PLA unimers were responsible for its P-gp inhibitory effect. Furthermore, transport studies of R123 revealed that the inhibitory potential of P-gp efflux by mPEG-PLA analogues was strongly correlated with their structural features and showed that the hydrophilic mPEG-PLA copolymers with an intermediate PLA chain length and 10.20 of hydrophilic–lipophilic balance were more effective at inhibiting P-gp efflux in Caco-2 cells. The fluorescence polarization measurement results ruled out the plasma membrane fluidization as a contributor for inhibition of P-gp by mPEG-PLA. Concurrently, mPEG-PLA inhibited neither basal P-gp ATPase (ATP is adenosine triphosphate) activity nor substrate stimulated P-gp ATPase activity, suggesting that mPEG-PLA seemed not to be a substrate of P-gp and a competitive inhibitor. No evident alteration in P-gp surface level was detected by flow cytometry upon exposure of the cells to mPEG-PLA. The depletion of intracellular ATP, which was likely to be a result of partial inhibition of cellular metabolism, was directly correlated with inhibitory potential for P-gp mediated efflux by mPEG-PLA analogues. Hence, intracellular ATP-depletion appeared to be possible explanation to the inhibition mechanism of P-gp by mPEG-PLA. Taken together, the establishment of a relationship between PLA chain length and impact on P-gp efflux activity and interpretation of action mechanism of mPEG-PLA on P-gp are of fundamental importance and will facilitate future development of mPEG-PLA in the drug delivery area.
研究领域:
药学
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药理学
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药物递送系统
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DOI
PubMed
高影响因子
ZOOLOGICAL RESEARCH
·
2023
·
IF 4.9
Xue-Yang Wang,Huang-Wei Song,Tian Yi,Ying-Bo Shen,Chong-Shan Dai,Cheng-Tao Sun,De-Jun Liu,Jian-Zhong Shen,Cong-Ming Wu,Yang Wang
Conjugative transfer of antibiotic resistance genes (ARGs) by plasmids is an important route for ARG dissemination. An increasing number of antibiotic and nonantibiotic compounds have been reported to aid the spread of ARGs, highlighting potential challenges for controlling this type of horizontal transfer. Development of conjugation inhibitors that block or delay the transfer of ARG-bearing plasmids is a promising strategy to control the propagation of antibiotic resistance. Although such inhibitors are rare, they typically exhibit relatively high toxicity and low efficacy in vivo and their mechanisms of action are inadequately understood. Here, we studied the effects of dihydroartemisinin (DHA), an artemisinin derivative used to treat malaria, on conjugation. DHA inhibited the conjugation of the IncI2 and IncX4 plasmids carrying the mobile colistin resistance gene ( mcr-1 ) by more than 160-fold in vitro in Escherichia coli , and more than two-fold (IncI2 plasmid) in vivo in a mouse model. It also suppressed the transfer of the IncX3 plasmid carrying the carbapenem resistance gene bla NDM-5 by more than two-fold in vitro . Detection of intracellular adenosine triphosphate (ATP) and proton motive force (PMF), in combination with transcriptomic and metabolomic analyses, revealed that DHA impaired the function of the electron transport chain (ETC) by inhibiting the tricarboxylic acid (TCA) cycle pathway, thereby disrupting PMF and limiting the availability of intracellular ATP for plasmid conjugative transfer. Furthermore, expression levels of genes related to conjugation and pilus generation were significantly down-regulated during DHA exposure, indicating that the transfer apparatus for conjugation may be inhibited. Our findings provide new insights into the control of antibiotic resistance and the potential use of DHA.
研究领域:
微生物学
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分子生物学
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药理学
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传染病学
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DOI
PubMed
高影响因子
MICROBIOLOGICAL RESEARCH
·
2023
·
IF 6.7
Yanan Li,Weikang Liang,Chenghua Li
Vibrio splendidus is an opportunistic pathogen, its pathogenicity continues to be a major aquaculture disease infection problem in many parts of the world. Bacteria can form dormant and persister cells, which may be responsible for the difficulty in treating latent infections. Bacterial persister cells are a small subpopulation with high phenotypic heterogeneity that have the ability to persist in response to high concentrations of antibiotics. In our previous work, we have confirmed tetracycline could induce V. splendidus AJ01 persister cells formation. Here, we show that exogenous adenosine and/or guanosine supply restores susceptibility of AJ01 persister cells to tetracycline, leading to effective killing of this persist subpopulation upon wake-up. Mechanistically, exogenous adenosine and/or guanosine promotes the intracellular ATP level, reduces percentage of cells with protein aggresomes , and destroys membrane stability. In addition, when cells were exposed to tetracycline, we found that cells with small nucleocytoplasmic ratio is easy to survive. Overall, our results support that exogenous adenosine or guanosine could be an effective strategy for treating infections with antibiotic-persist bacteria via regulating persisters cells formation.
研究领域:
微生物学
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水产养殖
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药理学
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细菌学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2024
·
IF 4
Sun Feifei,Zhang Lin,Ma Xuan,Ali Tariq,Wu Yongning,Li Lin
The emergence and widespread of tigecycline resistance undoubtedly poses a serious threat to public health globally. The exploration of combination therapies has become preferred antibacterial strategies to alleviate this global burden. In this study, tigecycline-resistant tet(X4)-positive Escherichia coli were selected for adjuvant screening. Interestingly, 9-aminominocycline (9-AMC), one of the tigecycline metabolites, exhibits synergistic antibacterial activity with tigecycline using checkerboard assay. The efficacy in vitro and in vivo was evaluated, and the synergistic mechanism was further explored. The results suggested that 9-AMC combined with tigecycline could inhibit the growth of antibiotic resistant bacteria, efficiently retard the evolution of tet(X4) gene and narrow the drug mutant selection window. In addition, the combination of tigecycline and 9-AMC could destroy the normal membrane structure of bacteria, inhibit the formation of biofilm, remarkably reduce the level of intracellular ATP level, and accelerate the oxidative damage of bacteria. Furthermore, 9-AMC is more stable in the bind of Tet(X4) inactivating enzyme. The transcriptomics analysis revealed that the genes related to the 9-AMC and tigecycline were mainly enriched in ABC transporters. Collectively, the results reveal the potentiation effects on tigecycline and the probability of 9-AMC as a novel tigecycline adjuvant against tet(X4)-positive Escherichia coli, which provides new insights for adjuvant screening.
研究领域:
微生物学
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药理学
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传染病学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2020
·Vol. 10
·期 29
·17050-17057
·
IF 3.119
Menghuan Tang,Peng Zhang,Jiahui Liu,Yijuan Long,Yuan Cheng,Huzhi Zheng
Mitochondria play an important role in supplying cellular energy, cell signaling and governing cell death. In addition, mitochondria have also been proved to be essential for tumor generation and development. Thus, mitochondrion-targeting therapeutics and treatments have emerged as promising strategies against cancer. However, the lack of mitochondrion-targeting agents has limited their application. To this end, we report cetyltrimethylammonium chloride-loaded mesoporous silica nanoparticles conjugated with human serum albumin (CTAC@MSNs-HSA) as a mitochondrion-targeting agent for anticancer treatment. As the structure-directing agent in the synthesis of MSNs, CTAC is stored within MSNs. Due to their desirable size and HSA receptor-mediated transcytosis, CTAC@MSNs-HSA show great cellular uptake and enhanced accumulation in the cytoplasm. Positively charged CTAC could actively target mitochondria by interacting with the negatively charged mitochondria membrane, and then lead to the dysfunction of mitochondria by decreasing mitochondrial potential and intracellular ATP levels, resulting in the necrosis and apoptosis of MCF-7 cells. Therefore, significant antitumor activity is observed by in vitro studies. Moreover, in vivo studies confirm that the CTAC@MSNs-HSA are able to induce cancer cell death and efficiently inhibit tumor growth. These results demonstrate the potential of CTAC@MSNs-HSA in cancer therapeutics as well as providing insights into mitochondrion-targeting treatment.
研究领域:
纳米技术
·
药学
·
肿瘤学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 31
·16451-16461
·
IF 6.895
Yuqian Jiang,Zheng Wang,Wei Duan,Lingyan Liu,Mahan Si,Xiaoyuan Chen,Chen-Jie Fang
Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.
研究领域:
癌症研究
·
药学
·
纳米技术
·
细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Jinmei Lai,Qunying Shi,Yongqi Xie,Yinyin Zhu,Shiyu Liang,Yi Chen,Jiali Yuan,Lihan Liu
Tumoral thermal defense mechanisms considerably attenuate the therapeutic outcomes of mild-temperature photothermal therapy (PTT). Thus, developing a simple, efficient, and universal therapeutic strategy to sensitize mild-temperature PTT is desirable. Herein, we report self-delivery nanomedicines ACy NPs comprising a near-infrared (NIR) photothermal agent (Cypate), mitochondrial oxidative phosphorylation inhibitor (ATO), and distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE–PEG2000), which have a high drug-loading efficiency that can reverse tumoral thermal resistance, thereby increasing mild-temperature PTT efficacy. ACy NPs achieved targeted tumor accumulation and performed NIR fluorescence imaging capability in vivo to guide tumor PTT for optimized therapeutic outcomes. The released ATO reduced intracellular ATP levels to downregulate multiple heat shock proteins (including HSP70 and HSP90) before PTT, which reversed the thermal resistance of tumor cells, contributing to the excellent results of mild-temperature PTT in vitro and in vivo. Therefore, this study provides a simple, biosafe, advanced, and universal heat shock protein-blocking strategy for tumor PTT.
研究领域:
纳米技术
·
肿瘤学
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治疗诊断学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
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