MOLECULAR CANCER RESEARCH
·
2026
·
IF 5.8
Han Tianci,Xie Junwei,Tong Wei,Zhang Liang
The poor prognosis of esophageal carcinoma (ESCA) highlights the need to identify novel targets for ESCA treatment. We found that inhibitor of differentiation 4 (ID4) was decreased in ESCA tumor tissues and its expression was associated with the survival of ESCA patients. However, the role of ID4 in ESCA remains unclear. Here, in this study, we found that overexpression of ID4 suppressed the cell proliferation of ESCA in vitro as well as tumor growth in vivo, whereas knockdown of ID4 presented the opposite trend. On the other hand, ESCA cells with overexpression of ID4 reduced macrophage migration and M2 polarization. However, significant increases in macrophage migration and M2 polarization were observed in cultures with ID4 silence. Interestingly, CCL2 was found to mediate the function of ID4 on macrophage polarization. Mechanistically, we identified for the first time that ID4 interacted physically with TCF4 to inactivate TCF4 transcriptional activity, which led to a decrease in CCL2 expression. Moreover, RNA binding protein cell cycle associated protein 1 (CAPRIN1) bound to ID4 mRNA and downregulated its stability, which may contribute to its low expression in ESCA. Taken together, these results support a novel hypothesis that ID4 downregulation may contribute to the development of ESCA by interacting with TCF4, resulting in abnormal proliferation of ESCA cells and tumor-associated macrophage infiltration. ID4 may contribute to the innovation of ESCA biotherapy.
Implications: ID4 inhibits ESCA through suppresses cancer cell proliferation and macrophage M2 polarization, and ID4 could be a potential prognostic marker for patients with ESCA.
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PubMed
高影响因子
MOLECULAR CANCER RESEARCH
·
2024
·
IF 4.1
Yao Huihui,Xu Jiancheng,Zhou Aina,Shen Danyang,Dong Qiuchen,Yang Xiaodong,Li Mengyu,Mi Xiuwei,Lu Yang,Zhong Runze,Shi Xinyu,Tai Qingliang,Chen Guoliang,Shi Bo,Sun Liang,Zhou Diyuan,Yao Yizhou,He Songbing
Recent evidence indicates that a high-fat diet (HFD) can promote tumor development, especially colorectal cancer (CRC), by influencing the microbiota. Regulatory circular RNAs (circRNAs) play an important role in modulating host–microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a HFD modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein referred to as circ_0126925) in CRC. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumours from limited branched-chain amino acids (BCAAs) interference by improving the metabolism of BCAAs in CRC. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of CRC by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host–microbe interactions in CRC.
Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome related pathology in humans.
研究领域:
肿瘤学
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微生物学
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分子生物学
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胃肠病学
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PubMed
高影响因子
MOLECULAR CANCER RESEARCH
·
2026
·
IF 5.8
Cao Feng,Cao Lei,Li Yu,Tian Guo,You Zhun,Liu Mei,Ding Yawen,Liu Lei,Liu Liang
Lung cancer is a highly malignant tumor and prone to recurrence and metastasis. Adenocarcinoma is the most common subtype. LIM zinc finger domain containing 2 (LIMS2) was reported to inhibit growth and metastasis of several tumors, while its role in lung adenocarcinoma remains unclear. This study aims to expound the function of LIMS2 in lung adenocarcinoma. The analysis from medical databanks showed that LIMS2 was lowly expressed in lung adenocarcinoma specimens, compared with the normal lung tissues, and our clinical data demonstrated that LIMS2 expression was associated with TNM stage of lung adenocarcinoma patients. Gain- and loss-of-function experiments revealed that LIMS2 suppressed proliferation, invasion, migration, epithelial-mesenchymal transition of lung adenocarcinoma cells, delayed xenograft and orthotopic growth, and blocked distant metastasis and lymph infiltration in nude mice. The medium supernatant from LIMS2-overexpressed lung adenocarcinoma cells intercepted the activation of fibroblasts from lung cancer. The co-IP results demonstrated that an E3 ubiquitin ligase ring finger and CHY zinc finger domain containing 1 (RCHY1) interacted with LIMS2, and mediated its K48 ubiquitination and degradation. LIMS2 overexpression reversed the promoting effects of RCHY1 on proliferation, migration and lung cancer-fibroblast activation of lung adenocarcinoma cells. In conclusion, decreased LIMS2 may mediate the tumor-promoting role of RCHY1 in lung adenocarcinoma cells.
Implications: These findings may provide novel diagnostic markers and therapeutic targets for lung adenocarcinoma in clinic.
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PubMed
高影响因子
MOLECULAR CANCER RESEARCH
·
2026
·
IF 5.8
He Jiancheng,Huang Xinkun,Xing Danjie,Chen Shun,Chen Yu,Xue Wanjiang,Hu Yilin
Ubiquitin-conjugating enzymes (E2s) are essential mediators of ubiquitin-dependent signaling cascades, governing diverse cellular processes such as proteolysis and transcriptional regulation. Despite increasing evidence linking E2 enzymes to tumorigenesis, their precise roles in gastric cancer (GC) remain incompletely defined. Here, we identified UBE2B as a key oncogenic E2 enzyme significantly upregulated in GC tissues through integrative bioinformatics analysis and clinical validation. High UBE2B expression was associated with poor patient prognosis and aggressive clinicopathological features. Functional assays demonstrated that UBE2B promotes GC cell proliferation both in vitro and in vivo. Mechanistically, UBE2B interacts with the E3 ligase BIRC2 to catalyze K63-linked ubiquitination of TRAF1, thereby amplifying NF-κB signaling. Furthermore, chromatin immunoprecipitation and luciferase reporter assays revealed that NF-κB subunit P65 directly binds to the UBE2B promoter, enhancing its transcription and forming a feedforward regulatory loop. This UBE2B–BIRC2–TRAF1 axis, coupled with the UBE2B–TRAF1–P65 feedback circuitry, establishes a self-sustaining mechanism that drives NF-κB hyperactivation and tumor cell proliferation. Collectively, our findings highlight UBE2B as a critical modulator of GC progression and a potential target for therapeutic intervention.
Implications: This study characterizes the UBE2B–BIRC2–TRAF1 axis as a driver of NF-κB hyperactivation, identifying UBE2B as a prognostic biomarker and a potential therapeutic target for disrupting this oncogenic feedback loop in gastric cancer.
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PubMed
高影响因子
MOLECULAR CANCER RESEARCH
·
2022
·Vol. 20
·期 5
·810-822
·
IF 6.333
Ding Ming,Zhang Shuwei,Guo Yajuan,Yao Jingjing,Shen Qinghong,Huang Min,Chen Wenbo,Yu Shaofang,Zheng Yaqiu,Lin Yuefang,Yan Wenxin,Liu Zhongqiu,Su Tao,Lu Linlin
Acidification is recognized as the predominant characteristic of the tumor microenvironment (TME) and contributes to tumor progression. However, the mechanism of extracellular acidic TME directly influences intercellular pathologic responses remains unclear. Meanwhile, acidic TME is mainly ascribed to aberrant metabolism of lipids and glucose, but whether and how acidity affects metabolic reprogramming, especially for lipid metabolism, is still unknown. We found that lipid was significantly accumulated in liver cancer cells when exposed to acidic TME. Moreover, proteomic analysis showed that differentially expressed proteins were mainly clustered into fatty acid pathways. Subsequently, we found that acidification increased the expression of SCD1 by activating PI3K/AKT signaling pathway. Interestingly, we found that SCD1 directly bound to PPARα in the acidic TME, which vanished after 2-day reverse incubation in pH 7.4 medium, implying extracellular acidosis might influence intercellular function by mediating the binding affinity between SCD1 and PPARα under different pH gradients. In summary, our data revealed that acidosis could significantly trigger fatty acid synthesis to promote liver tumorigenesis by upregulating SCD1 in a PI3K/AKT activation dependent manner and simultaneously promote SCD1 binding to PPARα. Our study not only provides direct mechanistic evidence to support the vital role of acidosis in lipid metabolic reprogramming, but also provides novel insights for determining the binding affinity of functional proteins as a molecular mechanism to better understand the role of the acidic TME in tumor development. Implications: The acidic TME contributes to lipid accumulation in liver cancer by activating the PI3K/AKT signaling pathway and promoting SCD1–PPARα binding.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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PubMed
高影响因子
TALANTA
·
2023
·
IF 6.1
Anand Babu Perumal,Reshma B Nambiar,Xuelun Luo,Zhenzhu Su,Xiaoli Li,Yong He
Recently, essential oils (EO) have gained a lot of interest for use as antifungal agent in food and agricultural industry and extensive research is ongoing to understand their mode of action. However, the exact mechanism is not yet elucidated. Here, we integrated spectral unmixing and Raman microspectroscopy imaging to unveil the antifungal mechanism of green tea EO based nanoemulsion (NE) against Magnaporthe oryzae . The dramatic change in protein, lipid, adenine , and guanine bands indicate that NE has a significant impact on the protein, lipid and metabolic processes of purine . The results also demonstrated that the NE treatment caused damage to fungal hyphae by inducing a physical injury leading to cell wall damage and loss of integrity. Our study shows that MCR−ALS (Multivariate Curve Resolution-Alternating Least Squares) and N-FINDR (N-finder algorithm) Raman imaging could serve as a suitable complementary package to the traditional methods, for revealing the antifungal mechanism of action of EO/NE.
研究领域:
食品科学
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农业科学
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微生物学
·
光谱学
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PubMed
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Gong Li,Lu Han,Li-Juan Xia,Ang Gao,Zhi-Peng Li,Shi-Ying Zhou,Lei Wan,Yao Deng,Tian-Hong Zhou,Xin-Yi Lu,Yang Luo,Dun-Sheng Liang,Gui-Ting Wu,Sheng-Qiu Tang,Xin-Lei Lian,Hao Ren,Xiao-Ping Liao,Liang Chen,Jian Sun
Plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) within the human and animal intestine represents a substantial global health concern. linoleic acid (LA) has shown promise in inhibiting conjugation in vitro , but its in vivo effectiveness in the mammalian intestinal tract is constrained by challenges in efficiently reaching the target site. Recent advancements have led to the development of waterborne polyurethane nanoparticles for improved drug delivery. In this study, we synthesized four waterborne polyurethane nanoparticles incorporating LA (WPU@LA) using primary raw materials, including N-methyldiethanolamine, 2,2'-(piperazine-1,4-diyl) diethanol, isophorone diisocyanate, castor oil, and acetic acid. These nanoparticles, identified as WPU 0.89 @LA, WPU 0.99 @LA, WPU 1.09 @LA, and WPU 1.19 @LA, underwent assessment for their pH-responsive release property and biocompatibility. Among these, WPU 0.99 @LA displayed superior pH-responsive release properties and biocompatibility towards Caco-2 and IPEC-J2 cells. In a mouse model, a dosage of 10 mg/kg/day WPU 0.99 @LA effectively reduced the conjugation of IncX4 plasmids carrying the mobile colistin resistance gene ( mcr-1 ) by more than 45.1-fold. In vivo toxicity assessment demonstrated that 10 mg/kg/day WPU 0.99 @LA maintains desirable biosafety and effectively preserves gut microbiota homeostasis. In conclusion, our study provides crucial proof-of-concept support, demonstrating that WPU 0.99 @LA holds significant potential in controlling the spread of antibiotic resistance within the mammalian intestine.
研究领域:
药理学
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纳米技术
·
微生物学
·
生物医学工程
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PubMed
高影响因子
mSphere
·
2024
·
IF 3.7
Xiao-die Cui,Xiao-kang Liu,Xiao-yuan Ma,Shuai-hua Li,Jun-kai Zhang,Rong-jia Han,Kai-fang Yi,Jian-hua Liu,Yu-shan Pan,Dan-dan He,Gong-zheng Hu,Ya-jun Zhai
The appearance and prevalence of multidrug-resistance (MDR) Gram-negative bacteria (GNB) have limited our antibiotic capacity to control bacterial infections. The clinical efficacy of colistin (COL), considered as the “last resort” for treating GNB infections, has been severely hindered by its increased use as well as the emergence and prevalence of mobile colistin resistance (MCR)-mediated acquired drug resistance. Identifying promising compounds to restore antibiotic activity is becoming an effective strategy to alleviate the crisis of increasing MDR. We first demonstrated that the combination of berberine (BBR) and EDTA substantially restored COL sensitivity against COL-resistant Salmonella and Escherichia coli. Molecular docking indicated that BBR can interact with MCR-1 and the efflux pump system AcrAB-TolC, and BBR combined with EDTA downregulated the expression level of mcr-1 and tolC. Mechanically, BBR combined with EDTA could increase bacterial membrane damage, inhibit the function of multidrug efflux pump, and promote oxidative damage, thereby boosting the action of COL. In addition, transcriptome analysis found that the combination of BBR and EDTA can accelerate the tricarboxylic acid cycle, inhibit cationic antimicrobial peptide (CAMP) resistance, and attenuate Salmonella virulence. Notably, the combination of BBR and EDTA with COL significantly reduced the bacterial load in the liver and spleen of a mice model infected with Salmonella. Our findings revealed that BBR and EDTA can be used as adjuvants collectively with COL to synergistically reverse the COL resistance of bacteria.
研究领域:
微生物学
·
药理学
·
传染病学
·
分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Li Jie,Xiong Wenguang,Zeng Zhenling
The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Methods: Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models. Results: In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive andnegative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species (ROS), causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models. Conclusion: These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.
研究领域:
微生物学
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药理学
·
传染病学
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PubMed
高影响因子
Engineering
·
2023
·
IF 12.8
Huangwei Song,Xueyang Wang,Muchen Zhang,Zhiyu Zou,Siyuan Yang,Tian Yi,Jianfeng Wang,Dejun Liu,Yingbo Shen,Chongshan Dai,Zhihai Liu,Timothy R. Walsh,Jianzhong Shen,Congming Wu,Yang Wang
The emergence and spread of the mobile colistin-resistance gene, mcr-1 , and its variants pose a challenge to the use of colistin, a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant (XDR) Gram-negative pathogens. Antibiotic adjuvants are a promising strategy to enhance the efficacy of colistin against colistin-resistant pathogens; however, few studies have considered the effects of adjuvants on limiting resistance-gene transmission. We found that chelerythrine (4 mg∙L −1 ) derived from Macleaya cordata extract, which is used as an animal feed additive, reduced the minimal inhibitory concentration (MIC) of colistin against an mcr-1 positive E. coli strain by 16-fold (from 2 to 0.125 mg∙L −1 ), eliminated approximately 10 4 colony-forming units (CFUs) of an mcr-1 -carrying strain in a murine intestinal infection model, and inhibited the conjugation of an mcr-1 -bearing plasmid in vitro (by >100-fold) and in a mouse model (by up to 5-fold). A detailed analysis revealed that chelerythrine binds to phospholipids on bacterial membranes and increases cytoplasmic membrane fluidity, thereby impairing respiration, disrupting proton motive force (PMF), generating reactive oxygen species (ROS), and decreasing intracellular adenosine triphosphate (ATP) levels, which subsequently downregulates mcr-1 and conjugation-associated genes. These dual effects of chelerythrine can expand the use of antibiotic adjuvants and may provide a new strategy for circumventing mobile colistin resistance.
研究领域:
微生物学
·
药理学
·
抗菌素耐药性
·
传染病学
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高影响因子
ACS Nano
·
2023
·
IF 17.1
Huimin Zhao,Lan-lan Zhong,Chuan Yang,Ning Tang,Yanwei He,Wan He,Zihan Zhao,Changbu Wu,Peiyan Yuan,Yi Yan Yang,Guo-bao Tian,Xin Ding
Colistin is the last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections that are untreatable by other clinically available antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance (mcr) leads to modification of the colistin target (i.e., bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated mcr-positive colistin-resistant bacteria including MDR E. coli and K. pneumoniae, while monotreatment of polymer or antibiotic at equivalent doses exhibits no antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both in vitro and in vivo. Taken together, the self-assembled antibiotic–polymer nanocomplex with two complementary antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR bacterial infections.
研究领域:
药学
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纳米技术
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微生物学
·
传染病学
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
Infection and Drug Resistance
·
2022
·
IF 4.177
Xiucai Zhang,Chao Fang,Junfeng Zhang,Wang Hua,Rong He,Mingming Zhou
Background The emergence of carbapenem and colistin co-resistant Escherichia coli poses a huge challenge to infection control. The purpose of this study was to clarify the mechanism of the carbapenems and colistin co-resistance in E. coli strains.Methods Antimicrobial susceptibility test was carried out by agar dilution methods and colistin resistance was confirmed by broth microdilution methods. Whole genome sequencing was carried out, and resistance genes, sequence types and virulence genes of carbapenems and colistin co-resistance E. coli isolates were analyzed.Results The results showed that among the 176 carbapenem-resistant Enterobacteriaceae strains, 5 multidrug resistant E. coli strains exhibiting coresistance to carbapenem and colistin. The main mechanism of 5 E. coli strains in this study was generating carbapenem. Four E. coli strains were mcr-positive, while one mcr-negative strain had a new MgrB mutation. The blaNDM-5, blaCTX-M-65, blaOXA-10, blaTEM-1 and mcr-1.1 genes were simultaneously detected in E. coli 20IR1127 strain belonging to ST156 lineage. Other antimicrobial resistance genes encoding aminoglycosides-, sulfonamide-, chloramphenicol-, tetracyclines- and macrolides resistance were also detected.Conclusion The main mechanisms of carbapenem and colistin resistance were encoded by blaNDM and mcr1.1, meanwhile mgrB mutations also contribute to colistin resistance. To our knowledge, this study is the first to report of E. coli ST156 strain in which the blaNDM-5, blaCTX-M-65, blaOXA-10, blaTEM-1 and mcr1.1 genes coexist. In addition, there is also an E. coli ST457 strain, which carries blaTEM-1, blaNDM-9, blaCTX-M-199 and is positive for mcr1.1 gene.
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高影响因子
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