High antipersister activity of a promising new quinolone drug candidate in eradicating uropathogenic Escherichia coli persisters and persistent infection in mice.

AIMS: To develop more potent drugs that eradicate persister bacteria and cure persistent urinary tract infections (rUTIs). METHODS AND RESULTS: We synthesized eight novel clinifloxacin analogs and measured minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the time-kill curves in uropathogenic Escherichia coli (UPEC) UTI89, and applied the candidate drugs and combinations against biofilm bacteria in vitro and in mice. Transcriptomic analysis was performed for UPEC after candidate drug treatment to shed light on potential mechanism of action. We identified Compound 2, named Qingdafloxacin (QDF), which was more potent than clinafloxacin and clinically used levofloxacin and moxifloxacin, with an MIC of < 0.04 µg ml-1 and an MBC of 0.08∼0.16 µg ml-1. In drug combination studies, QDF + gentamicin + nitrofuran combination but not single drugs completely eradicated all stationary phase bacteria containing persisters and biofilm bacteria, and all bacteria in a persistent UTI mouse model. Transcriptome analysis revealed that the unique antipersister activity of QDF was associated with downregulation of genes involved in bacterial stress response, DNA repair, protein misfolding repair, pyrimidine metabolism, glutamate, and glutathione metabolism, and efflux. CONCLUSIONS: QDF has high antipersister activity and its drug combinations proved highly effective against biofilm bacteria in vitro and persistent UTIs in mice, which may have implications for treating rUTIs.

lncRNA ROR Promotes Gastric Cancer Drug Resistance.

OBJECTIVE: Gastric cancer is one of the most common malignant tumors worldwide, and for resectable tumors, the most effective treatment is surgery with chemotherapy in neoadjuvant or adjuvant setting. However, the majority of patients fail to achieve the ideal initial response and/or develop resistance to chemotherapy. It was reported that long noncoding RNA regulator of reprogramming (ROR) is highly associated with the progression of gastric cancer. However, the role ROR in multidrug resistance (MDR) remains unclear. METHODS: The messenger RNA levels of 63 specimens of patients with gastric cancer were determined by real-time polymerase chain reaction analysis and were correlated with drug resistance and survival of patients. To determine the cellular functions of ROR, we generated gastric cancer MDR cells. The effect of ROR depletion on multidrug resistance-associated protein 1 (MRP1) expression and cell apoptosis were examined by immunoblotting analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry. RESULTS: We found that ROR expression levels are positively associated with increased MDR and poor prognosis of patients with gastric cancer. Regulator of reprogramming expression is increased in gastric cancer cells resistant to adriamycin (ADR) and vincristine (VCR). Depletion of ROR reduced MRP1 expression and increased apoptosis of drug-resistant gastric cancer cells in response to ADR and VCR treatment. CONCLUSIONS: We demonstrated that ROR expression promotes MRP1 expression and MDR of gastric cancer cells and is correlated with increased MDR and poor prognosis of patients with gastric cancer. Our finding highlighted the potential of targeting ROR to improve the efficacy of chemotherapy.

[Retracted] Circular RNA, hsa_circRNA_102049, promotes colorectal cancer cell migration and invasion via binding and suppressing miRNA­455­3p.

[This retracts the article DOI: 10.3892/etm.2022.11169.].

Circular RNA, hsa_circRNA_102049, promotes colorectal cancer cell migration and invasion via binding and suppressing miRNA-455-3p.

Colorectal cancer (CRC) is the second most prevalent malignant gastrointestinal tumor type worldwide, displaying poor prognosis. Accumulating studies have reported the significance of circular RNAs (circRNAs) and microRNAs (miRNAs) in CRC carcinogenesis and development. At present, the functions and mechanisms of action underlying the circular RNA, hsa_circRNA_102049, in CRC are not completely understood. The present study aimed to establish the involvement of hsa_circRNA_102049 in CRC, as well as the associated mechanisms. The expression levels of hsa_circRNA_102049 and miRNA-455-3p were measured in CRC cell lines and tissues via reverse transcription-quantitative PCR. CRC progression was evaluated by performing Cell Counting Kit-8, flow cytometry, wound healing and Transwell invasion assays. The results demonstrated that hsa_circRNA_102049 was highly expressed in both CRC tissues and cell lines, which was associated with enhanced CRC cell proliferation, migration and invasion. Furthermore, miR-455-3p expression was downregulated in CRC cells and served as a target of has_circRNA_102049, which was validated by performing the dual luciferase reporter assay. hsa_circRNA_102049 knockdown significantly increased miR-455-3p expression, which was significantly reversed by co-transfection with the miR-455-3p inhibitor. Notably, miRNA-455-3p overexpression alleviated hsa_circRNA_102049-mediated induction of CRC cell proliferation, migration and invasion. The present study clearly demonstrated that miRNA-455-3p was a target of hsa_circRNA_102049. Moreover, the results indicated that the circular RNA, hsa_circRNA_102049, may function as a tumor promoter in CRC via directly sponging miRNA-455-3p.

One-step modification to identify dual-inhibitors targeting both pancreatic triglyceride lipase and Niemann-Pick C1-like 1.

Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as attractive therapeutic targets for obesity and hypercholesteremia, respectively. Obesity and hypercholesteremia usually co-exist, however no dual-inhibitors against PTL and NPC1L1 were reported for the treatment of obesity patients with hypercholesteremia so far. In this work, molecular hybridization-based one-step modification screening identified a potent dual-inhibitor against PTL and NPC1L1. Compound P1-11 has IC50 values of 2.1 µM against PTL through covalent binding, as well as significantly reduces cholesterol absorption in a non-competitive inhibitory manner. Molecule docking and molecular dynamics studies revealed the reason of its activity to both PTL and NPC1L1. Moreover, the gene and protein expression levels of PTL and NPC1L1 were also determined respectively after the treatment of P1-11. Development of dual-inhibitors against PTL and NPC1L1 could provide novel treatment options for obesity patients with hypercholesteremia. The results of current research would great support the development of dual-inhibitors against PTL and NPC1L1.

Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer.

Colorectal cancer (CRC) has become one of the major factors of tumor-related morbidity and mortality in the world because of its poor prognosis and consequences of metastatic spread. Currently, chemoprevention has been considered as a way of preventing cancer who takes advantage of plant phytochemicals and synthetic compounds. Phytochemical compounds are receiving much considerable attention for their ability in chemoprevention due to low toxicity and cost. For strategies of chemoprevention, keeping the balance of internal and external environment in cells or tissues is important. Hence, it is particularly important to eliminate overmuch carcinogens and carcinogenic metabolites by phase 2 detoxifying enzymes and antioxidant enzymes such as glutathione S-transferase (GST), heme oxygenase-1(HO-1) and so on. Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a key role in regulating these enzymes via mediating antioxidant response elements (ARE). In this review, we collected recent studies of phytochemical compounds targeting on Nrf2 in CRC treatment. We summarized the mechanisms of these compounds in activating Nrf2, and their effects on chemotherapeutic agents.

Recent advances in duplex-specific nuclease-based signal amplification strategies for microRNA detection.

In recent years, miRNAs had emerged as promising biomarkers for diagnosis and prognosis of the health-threatening diseases (e.g., cancers), which associated with a broad range of pathological and biological processes, including drug resistance, apoptosis, metastasis, and proliferation. Therefore, accurate detection of the levels of miRNA shown excellent prospects for early diagnosis of the health-threatening diseases. Considering that only trace miRNA existed in biological fluids, many newly developed biosensors for miRNA detection mainly focused on introducing various of signal amplification strategies for improving the detection sensitivity. Duplex-specific nuclease (DSN), a nuclease purified from hepatopancreas of Kamchatka crab, was capable of specifically cleaving double-stranded DNA or DNA in DNA-RNA heteroduplexes and was inactive toward single-stranded oligonucleotides or double-stranded RNA, endowing a possibility for construction of newly miRNA biosensors. Recently, many newly developed DSN-based biosensors architectures for miRNA analysis were reported. In this review, we explained the great potential of miRNAs as promising biomarkers by overviewing DSN-based signal amplification strategies for miRNA detection in the last decades.