Design and synthesis of new alfa-naphthoflavanones as potent and selective CYP1B1 inhibitors.

Natural Flavanones are abundant in human diet and a few of them exhibited chemopreventive effects against xenobiotic procarcinogens through the inhibition of tumour specific CYP1B1 enzyme. Herein, a series of new alfa-naphthoflavanones were synthesised and evaluated for their enzymatic inhibitory potency and selectivity of CYP1B1 over its isoenzyme CYP1A1. The most active compound 8c displayed highest inhibitory potency against CYP1B1 with the IC50 value of 0.1 nM. The structure activity relationship studies implied that the methoxy groups on the core scaffold of naphthalene ring significantly influenced CYP1B1 inhibition efficacy, while B-ring substitutions played important roles in activity. Molecular docking studies were conducted to provide a better understanding on the key structural features involved in CYP1B1 inhibitory activity. The results of the study implied that these naphthoflavanones could be considered as new leads and further investigation be conducted to explore the flavanone scaffold as skeleton for inhibiting CYP1B1.

A cytotoxicity and mechanistic investigation of mono- and di-chloro naphthalenes.

Polychlorinated naphthalenes (PCNs) were characterized as persistent organic pollutants (POPs) that were widely distributed in the environment. Although the striking in vivo toxicity of these pollutants towards both animals and humans was well documented, their cytotoxicity and mechanism of action have not been extensively investigated. In this study, the in vitro antiproliferative activity of mono- and di-chloronaphthalenes as representative PCNs were evaluated and the results indicated strong growth inhibitory effects against mammalian cells, especially the human breast MCF-10A cell and human hepatic HL-7702 cells. 2-Chloronaphthalene with the most potent antiproliferative effects within the tested PCNs, which showed IC50 values ranging from 0.3 mM to 1.5 mM against selected human cell lines, was investigated for its working mechanisms. It promoted cellular apoptosis of MCF-10A cells upon the concentration of 200 µM. It also induced the autophagy of MCF-10A cells in a dose-dependent manner, resulting in cell death via the interaction of autophagy and apoptosis. Thus, these findings supported the theoretical foundation for interventional treatment of PCNs toxicity and also provided implications for the use of chemopreventive agents against the toxic chlorinated naphthalenes in the environments.

In vitro metabolism of triclosan and chemoprevention against its cytotoxicity.

Triclosan (TCS), a broad-spectrum antibacterial chemical, has been extensively used in personal daily care items, household commodities, and clinical medications; therefore, humans are at risk of being exposed to TCS in their daily lives. This chemical also accumulated in food chains, and potential risks were associated with its metabolism in vivo. The aim of this study was to investigate the difference in metabolic profile of TCS by hepatic P450 enzymes and extrahepatic P450s, and also identify chemical structures of its metabolites. The results showed that RLM mediated the hydroxylation and cleavage of the ether moiety of TCS, resulting in phenolic metabolites that are more polar than the parent compound, including 4-chlorocatechol, 2,4-dichlorophenol and monohydroxylated triclosan. The major metabolite of CYP1A1 and CYP1B1 mediated TCS metabolism is 4-chlorochol. We also performed molecular docking experiments to investigate possible binding modes of TCS in the active sites of human CYP1B1, CYP1A1, and CYP3A4. In addition to in vitro experiments, we further examined the cytotoxic effects of TCS on HepG2 cells expressing hepatic P450 and MCF-7/1B1 cells expressing CYP1B1. It exhibited significant cytotoxicity on HepG2, MCF-10A and MCF-7/1B1 cells, with IC50 values of 70 ± 10 µM, 20 ± 10 µM and 60 ± 20 µM, respectively. The co-incubation of TCS with glutathione (GSH) as a chemopreventive agent could reduce the cytotoxicity of TCS in vitro. The chemopreventive effects of GSH might be ascribed to the promotion of TCS efflux mediated by membrane transporter MRP1 and also its antioxidant property, which partially neutralized the oxidative stress of TCS on mammalian cells. This study contributed to our understanding of the relationship between the P450 metabolism and the toxicity of TCS. It also had implications for the use of specific chemopreventive agents against the toxicity of TCS.

Evaluation of 1,4-naphthoquinone derivatives as antibacterial agents: activity and mechanistic studies.

The diverse and large-scale application of disinfectants posed potential health risks and caused ecological damage during the 2019-nCoV pandemic, thereby increasing the demands for the development of disinfectants based on natural products, with low health risks and low aquatic toxicity. In the present study, a few natural naphthoquinones and their derivatives bearing the 1,4-naphthoquinone skeleton were synthesized, and their antibacterial activity against selected bacterial strains was evaluated. In vitro antibacterial activities of the compounds were investigated against Escherichia coli and Staphylococcus aureus. Under the minimum inhibitory concentration (MIC) of ⩽ 0.125 µmol/L for juglone (1a), 5,8-dimethoxy-1,4-naphthoquinone (1f), and 7-methyl-5-acetoxy-1,4-naphthoquinone (3c), a strong antibacterial activity against S. aureus was observed. All 1,4-naphthoquinone derivatives exhibited a strong antibacterial activity, with MIC values ranging between 15.625 and 500 µmol/L and EC50 values ranging between 10.56 and 248.42 µmol/L. Most of the synthesized compounds exhibited strong antibacterial activities against S. aureus. Among these compounds, juglone (1a) showed the strongest antibacterial activity. The results from mechanistic investigations indicated that juglone, a natural naphthoquinone, caused cell death by inducing reactive oxygen species production in bacterial cells, leading to DNA damage. In addition, juglone could reduce the self-repair ability of bacterial DNA by inhibiting RecA expression. In addition to having a potent antibacterial activity, juglone exhibited low cytotoxicity in cell-based investigations. In conclusion, juglone is a strong antibacterial agent with low toxicity, indicating that its application as a bactericidal agent may be associated with low health risks and aquatic toxicity. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s11783-023-1631-2 and is accessible for authorized users.

Anticancer activity of synthesized 5-benzyl juglone on selected human cancer cell lines.

BACKGROUND: Cancer is a malignant disease that causes millions of deaths each year worldwide. As one of the cancer therapeutic strategies, chemotherapy is a means to destroy rapidly dividing cells. The main problem with cancer chemotherapy is the lack of selectivity of conventional chemotherapeutic drugs, leading to toxicity towards normal cells. Therefore, the discovery of anticancer agents with selectivity for fast-growing cancer cells was desirable. OBJECTIVE: In this study, we report the synthesis and identification of the novel 5-benzyl juglone as a potential anticancer agent with selectivity toward certain cancer cell lines. METHODS: An efficient synthetic method for 5-benzyl juglone has been established. The proliferation of cancer cell lines and a normal cell line treated by the target compound were studied using an MTT assay. In addition, the cell cycle arrest and apoptosis were determined by flow cytometry. RESULTS: Based on the Diels-Alder (D-A) reaction between 3,6-dimethoxy benzyne intermediate with furan, further acid-catalyzed intramolecular rearrangement and CAN-mediated oxidation, a convenient synthesis of 5-benzyl juglone has been achieved with high overall yield. The results from in vitro biological evaluation indicated that the juglone derivative exhibited potent antiproliferative activity against HCT-15 human colorectal cancer cells with an IC50 value of 12.27 µM. It exerted high inhibitory activity toward MCF-7 human breast cancer cells and, to a much lesser extent, to corresponding MCF-10A human breast epithelial normal cells with the IC50 ratio (IC50 in MCF-7 divided by IC50 in MCF-10A) of 0.62. CONCLUSION: The mechanistic investigations indicated that 5-benzyl juglone could induce cell cycle arrest at the G0/G1 phase and promote apoptosis of HCT-15 cells. The apoptotic effects possibly also contributed to its higher selectivity toward cancer cells than normal cell lines.

Circular RNAs' cap-independent translation protein and its roles in carcinomas.

Circular RNAs a kind of covalently closed RNA and widely expressed in eukaryotes. CircRNAs are involved in a variety of physiological and pathological processes, but their regulatory mechanisms are not fully understood. Given the development of the RNA deep-sequencing technology and the improvement of algorithms, some CircRNAs are discovered to encode proteins through the cap-independent mechanism and participate in the important process of tumorigenesis and development. Based on an overview of CircRNAs, this paper summarizes its translation mechanism and research methods, and reviews the research progress of CircRNAs translation in the field of oncology in recent years. Moreover, this paper aims to provide new ideas for tumor diagnosis and treatment through CircRNAs translation.

Asymmetric dimethylarginine level as biomarkers of cardiovascular or all-cause mortality in patients with chronic kidney disease: a meta-analysis.

BACKGROUND: Studies have yielded conflicting findings on the association of asymmetric dimethylarginine (ADMA) level with cardiovascular or all-cause mortality in patients with chronic kidney disease (CKD). This meta-analysis sought to evaluate the association of blood ADMA level with cardiovascular or all-cause mortality in CKD patients. MATERIALS AND METHODS: PubMed and Embase databases were comprehensively searched until September 9, 2020 for studies investigating the association of ADMA level with cardiovascular or all-cause mortality in CKD patients. RESULTS: Data were collected from nine prospective studies involving 6553 patients. The pooled adjusted risk ratio (RR) of all-cause mortality was 2.06 (95% confidence interval [CI] 1.43-2.96) for the highest versus the lowest ADMA level. Each 0.20 µmol/L ADMA increase was associated with 21% (95% CI 1.09-1.35) higher risk of all-cause mortality but not cardiovascular mortality (RR 1.07; 95% CI 0. 99-1.16). Subgroup analysis showed that each 0.20 µmol/L ADMA increase was significantly associated with all-cause mortality in end-stage renal disease (ESRD) patients (RR 1.22; 95% CI 1.05-1.41) but not in patients with stage 3 to 4 CKD (RR 1.16; 95% CI 0.86-1.56). CONCLUSIONS: Elevated ADMA level is independently associated with higher risk of all-cause mortality in ESRD patients.

The Interaction Between N6-Methyladenosine Modification and Non-Coding RNAs in Gastrointestinal Tract Cancers.

N6-methyladenosine (m6A) is the most common epigenetic modification of eukaryotic RNA, which can participate in the growth and development of the body and a variety of physiological and disease processes by affecting the splicing, processing, localization, transport, translation, and degradation of RNA. Increasing evidence shows that non-coding RNAs, particularly microRNA, long non-coding RNA, and circular RNA, can also regulate the RNA m6A modification process by affecting the expression of m6A-related enzymes. The interaction between m6A modification and non-coding RNAs provides a new perspective for the exploration of the potential mechanism of tumor genesis and development. In this review, we summarize the potential mechanisms and effects of m6A and non-coding RNAs in gastrointestinal tract cancers.

Research and application of single-cell sequencing in tumor heterogeneity and drug resistance of circulating tumor cells.

Malignant tumor is a largely harmful disease worldwide. The cure rate of malignant tumors increases with the continuous discovery of anti-tumor drugs and the optimisation of chemotherapy options. However, drug resistance of tumor cells remains a massive obstacle in the treatment of anti-tumor drugs. The heterogeneity of malignant tumors makes studying it further difficult for us. In recent years, using single-cell sequencing technology to study and analyse circulating tumor cells can avoid the interference of tumor heterogeneity and provide a new perspective for us to understand tumor drug resistance.

Circulating Selenium and Cardiovascular or All-Cause Mortality in the General Population: a Meta-Analysis.

The association of circulating selenium level with mortality remains controversial. This meta-analysis investigated the association between elevated circulating selenium level and cardiovascular or all-cause mortality in the general population. PubMed and Embase databases (up to January 20, 2019) were searched for observational studies or post hoc analyses of randomized controlled trials that evaluated the association between elevated circulating selenium level and cardiovascular or all-cause mortality in the general population. Twelve observational studies (ten cohort and two case-control studies) with a total of 25,667 individuals were included. Comparison with the lowest and the highest circulating selenium level showed that the pooled risk ratio (RR) values of all-cause mortality and cardiovascular mortality were 1.36 (95% confidence intervals [CI] 1.18-1.58) and 1.35 (95% CI 1.13-1.62), respectively. When analyzed selenium level as a continuous variable, each standard deviation selenium increase significantly reduced 20% all-cause mortality risk. However, the lowest circulating selenium level was not associated with a high risk of coronary mortality (RR 1.43; 95% CI 0.93-2.19). This meta-analysis indicated that low circulating selenium level was associated with higher risk of cardiovascular or all-cause mortality in the general population. Low circulating selenium level did not confer significant effect on coronary death.

Frailty for predicting all-cause mortality in elderly acute coronary syndrome patients: A meta-analysis.

BACKGROUND: Frailty has been identified as a risk factor for mortality in patients with acute coronary syndrome (ACS). This meta-analysis aimed to evaluate the association between frailty and all-cause mortality outcome in patients with ACS. METHODS: Pubmed and Embase databases were searched up to September 26, 2018 for the observational studies evaluating the association between frailty and all-cause mortality in elderly ACS patients. Outcome measures were in-hospital death, short-term all-cause mortality (≤6 months),and long-term all-cause mortality (≥12 months).The impact of frailty on all-cause mortality was summarized as hazard ratios (HR) with 95% confidence intervals (CI) for the frail versus nonfrail patients. RESULTS: A total of 9 cohort studies involving 2475 elderly ACS patients were included. Meta-analysis showed that ACS patients with frailty had an increased risk of in-hospital death (HR 5.49; 95% CI 2.19-13.77), short-term all-cause mortality (HR 3.56; 95% CI 1.96-6.48), and long-term all-cause mortality (HR 2.44; 95% CI 1.92-3.12) after adjustment for confounding factors. In addition, prefrailty was also associated with an increased all-cause mortality (HR 1.65; 95% CI 1.01-2.69). CONCLUSIONS: This meta-analysis demonstrates that frailty independently predicts all-cause mortality in elderly ACS patients. Elderly ACS patients should be assessed the frailty status for improving risk stratification.

Prognostic significance of C-reactive protein to albumin ratio in colorectal cancer patients: a meta-analysis.

PURPOSE: Inconsistent results on the prognostic significance of C-reactive protein to albumin ratio (CAR) in colorectal cancer patients have been reported. This meta-analysis sought to assess the prognostic value of pretreatment CAR for survival outcomes in colorectal cancer patients. METHODS: We conducted a systematic literature search of PubMed and Embase databases until February 16, 2019. Observational studies investigating the prognostic role of pretreatment CAR for survival outcome in patients with colorectal cancer were included. Outcome measures included overall survival (OS), disease-free survival (DFS), or progression-free survival (PFS). Pooled hazard ratio (HR) with 95% confidence interval (CI) was utilized to summarize the prognostic significance of CAR for patient survival. RESULTS: Nine retrospective studies involving 2492 colorectal cancer patients were identified. A fixed-effect model meta-analysis showed that high pretreatment CAR was an independent predictor of poor OS (HR 2.25; 95% CI 1.84-2.76) and DFS (HR 2.49; 95% CI 1.43-4.33). On the other hand, no significant association was observed between high CAR and PFS (HR 1.71; 95% CI 0.44-6.60). The predictive values of OS with high pretreatment CAR caused no significant changes in different sample sizes, countries, cut-off values of CAR, treatment methods, and study quality of subgroups. CONCLUSION: This meta-analysis suggests that CAR may be a powerful prognostic indicator for colorectal cancer prognosis. High pretreatment CAR is associated with poor OS and DFS in patients with colorectal cancer.