Journal of Pharmaceutical Analysis
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2025
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IF 8.9
Runan Zuo,Linran Fu,Wanjun Pang,Lingqing Kong,Liangyun Weng,Zeyuan Sun,Ruichao Li,Shaoqi Qu,Lin Li
Antimicrobial resistance (AMR) is a growing public health crisis that requires innovative solutions. Emerging multidrug resistant (MDR) Salmonella typhimurium has raised concern for its effect on pathogenic infection and mortality in humans caused by enteric diseases. To combat these MDR Salmonella typhimurium pathogens, highly effective and broad-spectrum antibiotics such as flufenicol (FFC) need to be evaluated for their potent antibacterial activity against Salmonella typhimurium . However, the low solubility and low oral bioavailability of flufenicol need to be addressed to better combat AMR. In this work, we develop a novel nano-formulation, flufenicol nano-micelles (FTPPM), which are based on D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)/poloxamer 188 (P188), for the targeted treatment of biofilms formed by drug-resistant Salmonella typhimurium in the intestine. Herein, FTPPM were prepared via a thin film hydration method. The preparation process for the mixed micelles is simple and convenient compared with other existing nanodrug delivery systems, which can further decrease production costs. The optimized FTPPM demonstrated outstanding stability and sustained release. An evaluation of the in vivo anti-drug-resistant Salmonella typhimurium efficacy demonstrated that FTPPM showed a stronger efficacy (68.17%) than did florfenicol-loaded TPGS polymer micelles (FTPM), flufenicol active pharmaceutical ingredients (FFC-API), and flufenicol commercially available medicine (FFC-CAM), and also exhibited outstanding biocompatibility. Notably, FTPPM also inhibited drug-resistant Salmonella typhimurium from forming biofilms. More importantly, FTPPM effectively restored intestinal flora disorders induced by drug-resistant Salmonella typhimurium in mice. In summary, FTPPM significantly improved the solubility and oral bioavailability of florfenicol, enhancing its efficacy against drug-resistant Salmonella typhimurium both in vitro and in vivo . FTPPM represent a promising drug-resistant Salmonella typhimurium treatment for curbing bacterial resistance via oral administration.
研究领域:
药学
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微生物学
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生物技术
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药物递送系统
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传染病学
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DOI
PubMed
高影响因子
BMC GENOMICS
·
2025
·Vol. 26
·期 1
·1-16
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IF 3.7
Liu Zhen,Ma Xiaoping,Zeng Xiangwen,Li Zhiguo,Liu Ruiguo,Luo Rongyan,Wang Weichen,Tahir Muhammad Salman,Wang Chengdong,Gu Yu
Alcohol dehydrogenase has been studied in regulation of fungal growth and development, stress response and pathogenesis, but its function in T. asahii remains unexplored. In this study, we analyzed the ADH gene family in T. asahii for the first time, identifying six ADH genes and containing conserved ADH_N and ADH_Zinc_N domains. We constructed an overexpression strain of the most significantly differentially expressed gene TaADH_like and compared its phenotypes with those of the wild-type strain, focusing on colony morphology, biofilm biomass, stress response, drug resistance, and pathogenicity. The results showed that TaADH_like overexpression reduced sensitivity to hypoxic conditions, altered the hyphae-to-yeast transition, and led to slower growth, decreased colonization ability, reduced tissue damage, and lower lethality. Increased osmotic stress sensitivity and the involvement of the HOG MAPK pathway in the hyphae-to-yeast conversion contributed to the reduced colonization capacity of T. asahii . Furthermore, the overexpression of TaADH_like promoted biofilm formation and led to a slight enhancement in fluconazole resistance in T. asahii . This study is the first to elucidate the function of the alcohol dehydrogenase gene in T. asahii , providing a foundation for future genetic research on this pathogen.
研究领域:
微生物学
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遗传学
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医学
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DOI
PubMed
高影响因子
CURRENT MOLECULAR MEDICINE
·
2025
·Vol. 25
·期 3
·343-352
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IF 2.5
Weiqing Feng,Haixiong Zhang,Qing Yu,Hao Yin,Xiaowei Ou,Jie Yuan,Liang Peng
Background The emergence of treatment resistance has hindered the efficacy of targeted therapies used to treat patients with hepatocellular carcinoma (HCC). Objective This study aimed to explore the mechanism of organoids constructed from lenvatinib-resistant HCC cells. Methods Hep3B cell and human HCC organoids were cultured and identified using hematoxylin and eosin staining and Immunohistochemistry. Lenvatinib-sensitive/ resistant Hep3B cells were constructed using lenvatinib (0, 0.1, 1, and 10 μM) and lenvatinib (0, 1, 10, and 100 μM). qRT-PCR and flow cytometry were utilized to deter-mine HCC stem cell markers CD44, CD90, and CD133 expressions. Transcriptome sequencing was performed on organoids. Western blot evaluated Notch pathway-related proteins (NOTCH1 and Jagged) expressions. Furthermore, DAPT, an inhibitor of the Notch pathway, was used to investigate the effects of lenvatinib on resistance or stemness in organoids and human HCC tissues. Results The organoids were successfully cultivated. With the increase of lenvatinib concentration, sensitive cell organoids were markedly degraded and ATP activity was gradually decreased, while there was no significant change in ATP activity of resistant cell organoids. CD44 expressions were elevated after lenvatinib treatment compared with the control group. KEGG showed that lenvatinib treatment of organoids constructed from Hep3B cells mainly activated the Notch pathway. Compared with the control group, NOTCH1 and Jagged expressions elevated, and ATP activity decreased after lenvatinib treatment. However, ATP activity was notably decreased after DAPT treatment. Moreover, DAPT inhibited lenvatinib resistance and the increase in the expressions of CD44 caused by lenvatinib. Besides, 100 μM lenvatinib significantly inhibited the growth and ATP activity of human HCC organoids, and DAPT increased the inhibitory effect of lenvatinib. Conclusion Lenvatinib regulated resistance and stemness in organoids via the Notch pathway.
研究领域:
肿瘤学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
DRUG RESISTANCE UPDATES
·
2025
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IF 21.7
Muhammad Zubair Saleem,Ruyi Huang,Yingying Huang,Xin Guo,Yang Liu,Miao Gao,Yinjuan Fan,Zhe-Sheng Chen,Zun-Fu Ke,Shengnan Ye,Jianhua Xu
Aims TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1. Methods Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model. Results In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo anticancer efficacy which was particularly related to OXPHOS inhibition. Conclusions C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.
研究领域:
肿瘤学
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分子生物学
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药物研发
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL MEDICINE
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2025
·Vol. 222
·期 3
·e20241147
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IF 10.6
He Ying,Li Wei,Zhang Meiling,Wang Hui,Lin Peilu,Yu Ying,Huang Bin,Hao Meng,He Jianuo,Kong Weiyao,Luo Dan,Xu Tengteng,Wang Jiaqi,Huang Ying,Zhao Qinwen,Liu Ying,Zhang Jie,Nian Yong,Zhang Lei,Zhu Bo,Yin Chengqian
BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non–receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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细胞信号传导
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2019
·Vol. 7
·期 44
·6994-7005
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IF 5.047
Pengchong Wang,Yan Yan,Ying Sun,Rui Zhang,Chuanchuan Huo,Lu Li,Ke Wang,Yalin Dong,Jianfeng Xing
The transgelin-2 (TAGLN2) protein plays an important role in multidrug resistance in human breast cancer. siRNA mediated gene silencing of TAGLN2 is a promising strategy for paclitaxel resistance reversal in breast cancer. In this study, a series of bioreducible and acid-labile polydiethylenetriamines (PDs) with different proportions of cross-linkers were synthesized. TAGLN2 siRNA was condensed by PDs to form dual-responsive nanocomplexes, and these nanocomplexes were hypothesized to partially degrade in the acidic environment of endosomes, and then completely degrade in the reducing environment of the cytoplasm to release siRNA. It was found that PDs have good water solubility, acid–base buffering capacity, suitable degradability and high biocompatibility. Moreover, PDCKM can deliver TAGLN2 siRNA into MCF-7/PTX cells and inhibit the expression of TAGLN2 even better than PEI 25k. Besides, paclitaxel showed higher cytotoxicity in cells incubated with PDCKM/TAGLN2 siRNA nanocomplexes. These results suggested that PDs have great potential for safe and efficient siRNA delivery to reverse paclitaxel resistance in breast cancer.
研究领域:
生物化学
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肿瘤学
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药物递送系统
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2022
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IF 5.999
Jiayin Lin,Gang Li,Ke Jiang,Tao Xu,Chang Liu,Lipin Wang,Xu Zhang,Defu Cai,Chao Wu,Xianshi Meng,Wenquan Zhu
Recently, the therapeutic effect of chemotherapy has been obviously impaired due to premature drug release, low tumor penetration, and multidrug resistance of nanoplatforms. In this paper, a novel multiple-sensitive drug delivery system (MC-ss-CDs) was developed by gating long-wavelength emitting carbon dots (CDs) on the openings of mesoporous carbon nanoparticles (MC) through disulfide bonds. The MC with excellent photothermal transition efficiency and high drug storage capacity for doxorubicin (DOX) was used as the delivery carrier. The CDs had multiple functions, including intelligent switching to hinder unwanted release, photothermal therapy (PTT) agents to improve the heat generation effect of MCs and bioimaging trackers to monitor drug delivery. The disulfide bonds, as the linkers between MC carriers and CDs, are stable under normal physical conditions and relatively labile under high GSH concentrations in the cytoplasm of tumor cells. After arriving at the tumor microenvironment, DOX/MC-ss-CDs can rapidly break into DOX/MC and CDs under high GSH concentrations. DOX/MC could realize efficient integration of PTT and chemotherapy on the surface of the tumor by stimuli-responsive DOX release and synergetic heating of MC and CDs. The small-sized CDs with excellent penetrating ability could effectively enter the deep tumor and realize NIR-triggered photothermal ablation. The DOX/MC-ss-CDs showed a chemophotothermal effect with a combination index of 0.38 in vitro and in vivo . Therefore, the DOX/MC-ss-CDs could be employed as a trackable nanovehicle for synergistic chemotherapy and PTT at different depths.
研究领域:
纳米医学
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生物材料
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Infection and Drug Resistance
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2022
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IF 4.177
Yingying Du,Shikui Mu,Yan Liu,Yinghua Yuan,Yunlou Zhu,Lijie Ma,Qixing Wang,Zhengfang Zhu,Yuhao Liu,Sheng Wang
Purpose This study retrospectively analyzed the genome characteristics of blaKPC-2 in multidrug-resistant Klebsiella pneumoniae collected from the ICU of a teaching hospital in Shanghai, China.Methods From February 2018 to December 2019, 36 strains of multidrug-resistant Klebsiella pneumoniae were collected from the bronchoalveolar lavage fluid of critically ill patients. The genome of all isolates was obtained through the Illumina sequence, and single nucleotide polymorphisms of the blaKPC-2 gene were analyzed to explore blaKPC-2’s evolutionary characteristics. Different strains’ genetic relationships and homology were studied by constructing an evolutionary tree on a single copy orthologue. Pacbio combined Illumina sequence was conducted to evaluate the structure and potential mobility of drug-resistant plasmids of the strain KP-s26.Results The distribution of resistance and virulence genes had little difference, but most strains had significant differences in the plasmid-encoded region. Most strains (31/36) carried the carbapenemase gene blaKPC-2, with no single nucleotide polymorphism in different strains. Extended-spectrum β-lactamase resistance genes, such as blaCTX-M and blaSHV, were found in the isolates, but no metallo-β-lactamases were detected. All strains with blaKPC-2 coexisted with chromosomal-associated fosfomycin resistance genes fosA6, and the coexistence of blaKPC-2 and blaCTX variants (blaCTX-M-15, blaCTX-M-65, and blaCTX-M-27) was also detected in 29/31 strains. The isolate KP-s26 carried five circular plasmids. pA and pB were conjugate plasmids, as they carried drug resistance genes and contained a complete IV secretion system.Conclusion The blaKPC-2 carbapenemase gene is relatively conservative in the process of evolution; drug-resistant plasmids containing conjugated transfer elements contribute to the spreading of drug resistance. The coexistence of blaKPC-2 with fosA6 or blaCTX-M variants was associated with increased fosfomycin resistance and broad-spectrum β-lactam resistance, respectively.Clinical Trials Registration Clinical Trials.gov Identifier: NCT03950544
研究领域:
微生物学
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基因组学
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传染病学
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DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2024
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IF 6.1
Qi Shang,Ziyan Chen,Jing Li,Mingmei Guo,Jiapei Yang,Zhu Jin,Yuanyuan Shen,Shengrong Guo,Feihu Wang
Chemotherapy treatment outcomes are severely restricted by multidrug resistance (MDR), in which tumors develop a multiple cross-resistance toward drug involving the pump and nonpump resistance mechanisms, resulting in drug efflux and defending against drug toxicity. Herein, we constructed a pH and near infrared (NIR) light responsive nanomedicine DOX@FG based on gold nanorods (GNRs) that demonstrated the potential to improve chemotherapy outcomes by overcoming MDR. DOX@FG was constructed by conjugating folic acid (FA) and doxorubicin (DOX) derivatives onto GNRs, where the DOX derivatives possessed an acid-labile hydrazone bond. Stimulated by the acidic media in endocytic organelles, DOX@FG exhibited a responsive dissociation for the controlled release of chemotherapeutic DOX. Surprisingly, we found the mild photothermal effect elicited by GNRs under NIR irradiation simultaneously inhibited the pump and nonpump resistance mechanisms, enhancing the intracellular DOX accumulation and sensitizing the cancer cells to DOX, collectively amplify the chemotherapy efficacy and delay the MCF-7/ADR breast tumor growth. This intelligent DOX@FG nanomedicine with the potential for two-pronged reversal of MDR may provide a prospective way to encourage chemotherapy efficacy.
研究领域:
纳米医学
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癌症治疗
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光热疗法
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Zhihao Wu,Tao Shi,Qi Shao,Dongmei Chen,Peisheng Gao,Jie Wang,Ting Xu,Qingqing Meng,Shaoshun Li
Early detection and precise treatment for breast cancer are crucial, given its high global incidence rate. Hence, the development of novel imaging targets is essential for diagnosing and monitoring resistance to chemotherapy, which is pivotal for achieving precise and personalized treatment for breast cancer patients. In our previous work, we successfully developed a near-infrared (NIR) probe 1 for CYP1B1-targeted imaging. In this study, we aimed to investigate the utility of the probe as a NIR fluorescence and photoacoustic dual-mode imaging probe for the detection and surveillance of breast cancer. Western blotting of cancer cell lines has confirmed that CYP1B1 is widely expressed in breast cancer and gynecological cancer. In vitro NIR fluorescence imaging capability of the probe for tracking CYP1B1-positive tumor cells was validated by using confocal microscopy. Further studies, including in vivo fluorescence and photoacoustic dual-model imaging and ex vivo biological distribution analysis on a triple-negative breast cancer xenograft mouse model, demonstrated that the probe selectively accumulated in tumor tissue within as early as 0.5 h postinjection. The results of the surgical resection experiment revealed that the tumor could be entirely removed under the guidance of NIR imaging, thereby indicating the probe’s efficacy in surgical navigation. CYP1B1 expression was found to be upregulated in adriamycin (ADR)-resistant breast cancer cells, MCF-7/ADR. Consequently, the sensitivity of CYP1B1 overexpressed cells, MCF-7/1B1, to ADR was significantly reduced, with an IC50 value of 0.586 ± 0.0934 μM, compared to the parental MCF-7 cells with an IC50 value of 0.183 ± 0.0444 μM. In vivo and ex vivo imaging assays conducted on MCF-7/ADR tumor-bearing mice demonstrated that the probe was specifically enriched in tumor sites, suggesting its potential for monitoring chemotherapy resistance in breast cancer. This study expands the scope of application for NIR probe 1, establishing its utility in breast cancer diagnosis through fluorescence-photoacoustic dual-model imaging, monitoring of chemotherapy resistance, and guidance for surgical resection. This strategy paves the way for novel approaches to precise and personalized treatment for breast cancer patients.
研究领域:
肿瘤学
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医学影像学
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药物动力学
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DOI
PubMed
高影响因子
Pharmaceutics
·
2021
·Vol. 13
·期 4
·438
·
IF 6.321
Jingru Shi,Chen Chen,Dejuan Wang,Ziwen Tong,Zhiqiang Wang,Yuan Liu
The emergence and prevalence of multidrug-resistant (MDR) bacteria have posed a serious threat to public health. Of particular concern are methicillin-resistantStaphylococcus aureus(MRSA) andblaNDM,mcr-1andtet(X)-positive Gram-negative pathogens. The fact that few new antibiotics have been approved in recent years exacerbates this global crisis, thus, new alternatives are urgently needed. Antimicrobial peptides (AMPs) originated from host defense peptides with a wide range of sources and multiple functions, are less prone to achieve resistance. All these characteristics laid the foundation for AMPs to become potential antibiotic candidates. In this study, we revealed that peptide WW307 displayed potent antibacterial and bactericidal activity against MDR bacteria, including MRSA and Gram-negative bacteria carryingblaNDM-5,mcr-1ortet(X4). In addition, WW307 exhibited great biofilm inhibition and eradication activity. Safety and stability experiments showed that WW307 had a strong resistance against various physiological conditions and displayed relatively low toxicity. Mechanistic experiments showed that WW307 resulted in membrane damage by selectively targeting bacterial membrane-specific components, including lipopolysaccharide (LPS), phosphatidylglycerol (PG), and cardiolipin (CL). Moreover, WW307 dissipated membrane potential and triggered the production of reactive oxygen species (ROS). Collectively, these results demonstrated that WW307 represents a promising candidate for combating MDR pathogens.Keywords:antimicrobial peptide;antibiotic resistance;multidrug-resistant bacteria;membrane damage
研究领域:
微生物学
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药理学
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DOI
PubMed
高影响因子
TALANTA
·
2019
·
IF 4.916
Ning Xu,Mingxing Piao,Kamile Arkin,Lina Ren,Jinyu Zhang,Jiawei Hao,Yuxin Zheng,Qingkun Shang
Two different colors of water-soluble core-shell quantum dots CdTe/CdS (green and orange red) have been synthesized and characterized in this paper. The formation of core-shell quantum dots not only improves the fluorescence quantum yield , but also reduces the biological toxicity of quantum dots, and improves the fluorescence lifetime . Two novel fluorescent bioprobes, CdTe/CdS (λ em = 545 nm)-5-Fu and Bio-CdTe/CdS (λ em = 600 nm)-TAM, have been synthesized via the interaction of these two core-shell quantum dots with anticancer drugs (5-Fu) and P-gp inhibitors (TAM), respectively. These two fluorescent probes have been simultaneously used in fluorescence imaging of human breast cancer cells MDA-MB-231/MDR. It can be observed that under the action of P-gp inhibitors distributed on the cell membrane, anticancer drugs can be retained in cancer cells. According to the color of quantum dots on the probe, the visualization results of the action of anticancer drugs and P-gp inhibitors can be obtained. This study shows that to prepare functional bioprobes using core-shell quantum dots CdTe/CdS has great potential in the field of biomedical research such as anticancer drugs.
研究领域:
生物医学
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纳米技术
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肿瘤学
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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）