CircXRN2 accelerates colorectal cancer progression through regulating miR-149-5p/MACC1 axis and EMT.

In China, there has been a persistent upward trend in the incidence and mortality rates of colorectal cancer (CRC), with CRC ranking second in incidence and fifth in mortality among all malignant tumors. Although circular RNAs (circRNAs) have been implicated in the progression of various cancers, their specific role in CRC progression remains largely unexplored. The objective of this study was to elucidate the role and underlying mechanisms of circXRN2 in CRC. Differential expression of circXRN2 was identified through whole transcriptome sequencing. The expression levels of circXRN2 and miR-149-5p were quantified in CRC tissues, corresponding adjacent normal tissues, and CRC cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The stability of circXRN2 was confirmed through RNase R and actinomycin D experiments. The binding interaction between circXRN2 and miR-149-5p was validated through RNA pull-down, RNA immunoprecipitation, and dual-luciferase assays. The biological functions of circXRN2 were assessed through a battery of in vitro experiments, including the CCK-8 assay, EdU assay, scratch assay, Transwell assay, and flow cytometry assay. Additionally, in vivo experiments involving a tumor transplantation model and a liver-lung metastasis model were conducted. The influence of circXRN2 on the expression of epithelial-mesenchymal transition (EMT)-related genes was determined via Western blotting analysis. In CRC tissues and cells, there was an upregulation in the expression levels of both circXRN2 and ENC1, while miR-149-5p exhibited a downregulation in its expression. The overexpression of circXRN2 was found to enhance tumor proliferation and metastasis, as evidenced by results from both in vitro and in vivo experiments. Functionally, circXRN2 exerted its antitumor effect by suppressing cell proliferation, migration, and invasion while also promoting apoptosis. Mechanistically, the dysregulated expression of circXRN2 had an impact on the expression of proteins within the EMT signaling pathway. Our results demonstrated that circXRN2 promoted the proliferation and metastasis of CRC cells through the miR-149-5p/ENC1/EMT axis, suggesting that circXRN2 might serve as a potential therapeutic target and novel biomarker in the progression of CRC.

Meta-analysis of the effectiveness and safety of Xingnaojing and naloxone in the treatment of carbon monoxide poisoning.

BACKGROUND: To evaluate the effectiveness and safety of Xingnaojing combined with naloxone in the treatment of carbon monoxide poisoning. METHODS: By retrieving the literatures published in the databases of PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, Weipu Database, and China National Knowledge Infrastructure from January 2010 to September 2021, the data of randomized controlled trials (RCTs) of Xingnaojing combined with naloxone in the treatment of carbon monoxide poisoning were extracted. The methodological quality of the included RCTs was evaluated by using the tools of bias risk evaluation of Cochrane Collaboration, and the data were statistically analyzed by using RevMan 5.3 software. RESULTS: A total of 20 literatures were included, involving in 771 cases treated by Xingnaojing combined with naloxone and 761 cases in the control group. The effective rate of the experimental group is higher than that of the control group [risk ratio (RR) = 1.20, 95% confidence interval (CI) (1.14, 1.26)]. The average awake time (STD mean difference = -2.08, 95% CI [-2.60, -1.56]), physical recovery time (STD mean difference = -2.94, 95% CI [-3.59, -2.28]), delayed encephalopathy (RR = 0.44, 95% CI [0.31, 0.62]), and adverse reactions (RR = 0.23, 95% CI [0.10, 0.54]) was lower than that of the control group. CONCLUSION: Xingnaojing combined with naloxone in the treatment of carbon monoxide poisoning is significantly superior to naloxone, but it still needs to be further verified by high-quality large samples of RCTs.

Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of chronic glomerulonephritis.

OBJECTIVE: To conduct a systematic review of the efficacy and safety of Shenyankangfu tablets in combination with losartan potassium in the treatment of chronic glomerulonephritis. METHOD: We searched PubMed, Embase, Cochrane Library, CNKI, WanFang Data, and WeiPu for comparative studies on Shenyankangfu tablets in combination with losartan potassium in the treatment of chronic glomerulonephritis. The search period runs from the establishment of the database until September 2021. Data extraction and quality evaluation were carried out on the documents that met the inclusion criteria, and a meta-analysis of the included literature was conducted using the RevMan5.3 software. RESULTS: A total of 17 randomized controlled trials that met the inclusion criteria were included, with a total sample size of 1680 patients (841 patients in the study group and 839 in the control group). The effective rate was significantly higher in the study group than in the control group [RR = 1.22, 95% CI (1.16, 1.27), P < 0.00001]. In addition, 24-hour urine protein levels [SMD = -1.11, 95% CI (-1.40, -0.83), P < 0.00001], urine NAG enzyme [SMD = -0.99, 95% CI (-1.27, -0.72), P < 0.00001], leukotactin-1 [SMD = -2.43, 95% CI (-3.50, -1.35), P < 0.00001], and the incidence of adverse reactions [RR = 0.43, 95% CI (0.28, 0.66), P < 0.00001] were lower in the study group when compared to the control group. CONCLUSION: It is safer to treat chronic glomerulonephritis with Shyenyankangfu tablets in combination with losartan potassium. At the same time, it alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions, making it more conducive to disease recovery. However, additional multi-center, randomized, control trials with large sample sizes must be conducted to confirm the findings.

Photoclick Reaction Constructs Glutathione-Responsive Theranostic System for Anti-Tuberculosis.

Tuberculosis (TB) is a virulent form of an infectious disease that causes a global burden due to its high infectivity and fatality rate, especially the irrepressible threats of latent infection. Constructing an efficient strategy for the prevention and control of TB is of great significance. Fortunately, we found that granulomas are endowed with higher reducibility levels possibly caused by internal inflammation and a relatively enclosed microenvironment. Therefore, we developed the first targeted glutathione- (GSH-) responsive theranostic system (RIF@Cy5.5-HA-NG) for tuberculosis with a rifampicin- (RIF-) loaded near-infrared emission carrier, which was constructed by photoclick reaction-actuated hydrophobic-hydrophobic interaction, enabling the early diagnosis of tuberculosis through granulomas-tracking. Furthermore, the loaded rifampicin was released through the dissociation of disulfide bond by the localized GSH in granulomas, realizing the targeted tuberculosis therapy and providing an especially accurate treatment mapping for tuberculosis. Thus, this targeted theranostic strategy for tuberculosis exhibits the potential to realize both granulomas-tracking and anti-infection of tuberculosis.

The Intracellular Mechanism of Berberine-Induced Inhibition of CYP3A4 Activity.

BACKGROUND: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. METHODS: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. RESULTS: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. CONCLUSION: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR.

Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway.

Context: Shikonins, a series of natural occurring naphthoquinones extracted from Arnebia euchroma (Royle) Jonst. (Boraginaceae), have antitumor activities and low toxicity. Objective: To illuminate potential activity and mechanism of shikonins against colorectal cancer (CRC). Materials and methods: Five shikonins were isolated from A. euchroma, and elucidated by extensive spectroscopic analysis. Anti-proliferative activities of shikonins (0-100 µg/mL) on human colorectal cells were evaluated by MTT and CCK-8 for 24 or 48 h. Cell apoptosis and cycle distribution were examined by FCM analysis. The expression of PI3K/Akt/mTOR pathway mRNAs and proteins was analysed by RT-PCR and Western blot, respectively. Cell viability, cell apoptosis, cell cycle and protein expression were measured, when co-treated with PI3K/Akt/mTOR pathway inhibitors. The in vivo activity of deoxyshikonin was evaluated using xenograft tumour model. Results: Deoxyshikonin and another four shikonins were isolated and identified. Deoxyshikonin exhibited anti-proliferative activity with IC50 of 10.97 µM against HT29 cells. Moreover, the percentage of early apoptotic cells and G0/G1 cells increased from 1 to 29% and 44 to 67% with 0-50 µg/mL deoxyshikonin, respectively. Deoxyshikonin also down-regulated the expression of PI3K, p-PI3K, Akt, p-Akt308 and mTOR proteins in HT29 and DLD-1 cells. Moreover, LY294002, NVP-BEZ235 and MK-2206 can make deoxyshikonin more cell proliferation inhibited, cell cycle arrested at G0/G1 and apoptosis promoted. In vivo study, the weight of tumour tissues at deoxyshikonin groups was significantly reduced compared with the control group, and PI3K, p-PI3K, Akt, p-Akt308 and mTOR expression was decreased. Discussion and conclusions: We can conclude that deoxyshikonin isolated from Arnebia euchroma inhibited CRC through the PI3K/Akt/mTOR pathway.

Comparative studies on DNA-binding and in vitro antitumor activity of enantiomeric ruthenium(II) complexes.

A pair of ruthenium(II) complex enantiomers, Δ- and Λ-[Ru(bpy)2PBIP]2+ {bpy=2,2'-bipyridine, PBIP=2-(4-bromophenyl)imidazo[4,5-f]1,10-phenanthroline} have been synthesized and characterized. The systematic comparative studies between two enantiomers on their DNA binding-behaviors with calf thymus DNA (CT DNA) were carried out by viscosity measurements, spectrophotometric methods and molecular simulation technology. Additional assays were performed to explore the cytotoxicity of the ruthenium(II) enantiomers against tumor cell lines. DNA-binding studies show that both the enantiomers can bind to CT DNA via intercalative mode, and the Δ form binds to CT DNA more strongly than the Λ form does. Molecular simulation further shows that both the two enantiomers intercalate between base pairs of DNA in minor groove, and that the Δ form intercalates into DNA more deeply than the Λ form does. In addition, the cell proliferation assays show that the Δ form induces a greater cytotoxicity than the Λ form on human cervical cancer HeLa cells, which is positive correlated with the results in DNA binding studies and molecular docking, and implies that the DNA binding affinities of ruthenium(II) polypyridyl complexes might be constitute to the part of their anticancer mechanisms.