Decoding selectivity: computational insights into AKR1B1 and AKR1B10 inhibition.

Understanding selectivity mechanisms of inhibitors towards highly homologous proteins is of paramount importance in the design of selective candidates. Human aldo-keto reductases (AKRs) pertain to a superfamily of monomeric oxidoreductases, which serve as NADPH-dependent cytosolic enzymes to catalyze the reduction of carbonyl groups to primary and secondary alcohols using electrons from NADPH. Among AKRs, AKR1B1 is emerging as a promising target for cancer treatment and diabetes, despite its high structural similarity with AKR1B10, which leads to severe adverse events. Therefore, it is crucial to understand the selectivity mechanisms of AKR1B1 and AKR1B10 to discover safe anticancer candidates with optimal therapeutic efficacy. In this study, multiple computational strategies, including sequence alignment, structural comparison, Protein Contacts Atlas analysis, molecular docking, molecular dynamics simulation, MM-GBSA calculation, alanine scanning mutagenesis and pharmacophore modeling analysis were employed to comprehensively understand the selectivity mechanisms of AKR1B1/10 inhibition based on selective inhibitor lidorestat and HAHE. This study would provide substantial evidence in the design of potent and highly selective AKR1B1/10 inhibitors in future.

Correction to "Metabolomics of Artichoke Bud Extract in Spontaneously Hypertensive Rats".

[This corrects the article DOI: 10.1021/acsomega.1c01135.].

Metabolomics of Artichoke Bud Extract in Spontaneously Hypertensive Rats.

Hypertension adversely affects the quality of life in humans across modern society. Studies have attributed increased reactive oxygen species production to the pathophysiology of hypertension. So far, a specific drug to control the disease perfectly has not been developed. However, artichoke, an edible vegetable, plays an essential role in treating many diseases due to its potent antioxidant activities. The objective of this study is to evaluate the effect of artichoke bud extract (ABE) on heart tissue metabolomics of hypertensive rats. Spontaneously hypertensive rats and Wistar-Kyoto (WKY) rats were divided into six groups, then exposed to different doses comprising ABE, Enalapril Maleate, or 1% carboxylmethyl cellulose for 4 weeks. Their blood pressures were recorded at 0, 2, 3, and 4 weeks after the start of the test period. Thereafter, all rats were anesthetized, and blood was collected from their cardiac apexes. Then, we measured the levels for 15 kinds of serum biochemical parameters. An established orthogonal partial least square-discriminant analysis model completed the metabolomic analysis. Hypertensive rats in the ABE group exhibited well-controlled blood pressure, relative to those in the model group. Specifically, artichoke significantly lowered serum levels for total protein (TP), albumin (ALB), and uric acid (UA) in the hypertensive rats. This effect involved the action of eight metabolites, including guanine, 1-methylnicotinamide, p-aminobenzoic acid, NAD, NADH, uridine 5'-monophosphate, adenosine monophosphate, and methylmalonic acid. Collectively, these findings suggest that ABE may play a role in affecting oxidative stress and purine, nicotinate, and nicotinamide metabolism.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Obstructing Colorectal Cancer Treated by Endoscopic Stenting as a Bridge to Surgery.

PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) has been reported to predict adverse survival outcomes among patients with colorectal cancer (CRC). This study evaluates the prognostic value of NLR among patients with obstructing CRC who successfully underwent stenting before curative surgery. METHODS: We retrospectively reviewed patients who underwent stenting before surgery. Patient demographics, tumor characteristics, perioperative outcomes, recurrence-free survival (RFS), and overall survival (OS) were analyzed. NLR was calculated from the differential white blood cell counts at least 4 days after successful stenting, before elective surgery. Optimal cutoff to dichotomize NLR was obtained by maximizing log-rank test statistic with recursive partitioning of KaplanMeier RFS and OS curves. The optimal cutoff for high NLR was ≥ 5 at presentation before stenting, and ≥ 4 after stenting. RESULTS: Fifty-seven patients with localized obstructing CRC underwent successful endoscopic stenting before curative surgery. High NLR was associated with lymphovascular invasion (P = 0.006) and apical lymph node involvement (P = 0.034). Major perioperative complication(s) (hazard ratio [HR], 11.34; 95% confidence interval [CI], 2.49 to 51.56; P < 0.01) and high NLR (HR, 3.69; 95% CI, 1.46 to 9.35; P < 0.01) negatively impacted OS on univariate and multivariate analyses. High NLR negatively impacted RFS on univariate analysis (HR, 2.91; 95% CI, 1.29 to 6.60; P = 0.01). CONCLUSION: NLR of ≥ 4 after stenting is an independent prognostic factor among patients with obstructing localized CRC who are successfully decompressed by endoscopic stenting before curative surgery.

Lipidomics and transcriptomics analyses of altered lipid species and pathways in oxaliplatin-treated colorectal cancer cells.

Drug resistance and adverse reactions to oxaliplatin remain a considerable issue in clinical practice. Emerging evidence has suggested that alterations in the lipid metabolism during drug therapy affect cancer cells. To gain insight into the important process of lipid metabolism, we investigated the lipid and gene expression profile changes in HT29 cells treated with oxaliplatin. A total of 1403 lipid species from 16 lipid classes were identified by UHPLC-MS. Interestingly, phospholipids, including phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylcholine (PC), and most of phosphatidylethanolamine (PE) with polyunsaturated fatty acid (PUFA) chains, were significantly higher due to oxaliplatin treatment, while triacylglycerols (TAGs) with a saturated fatty acid chain or monounsaturated fatty acid were significantly downregulated. Gene Set Enrichment Analysis (GSEA) based on RNA sequencing data suggested that neutral lipid metabolism was enriched in the control group, whereas the phospholipid metabolic process was enriched in the oxaliplatin-treated group. We observed that altered lipid metabolism enzyme genes were involved in the synthesis and lipolysis of TAGs and the Lands cycle pathway based on the network between the core lipid-related gene and lipid species, which was further verified by qRT-PCR. In summary, our findings revealed that oxaliplatin impressed a specific lipid profile signature and lipid transcriptional reprogramming in HT29 cells, which provides new insights into biomarker discovery and pathways for overcoming drug resistance and adverse reactions.

In vitro and in vivo analysis of metabolites involved in the TCA cycle and glutamine metabolism associated with cisplatin resistance in human lung cancer.

Elucidating the dysregulated metabolic pathways in cancer cells and their relevance to cisplatin resistance could yield new insights into cancer therapy. We previously reported that eight metabolites involved in the tricarboxylic acid (TCA) cycle and glutamine metabolism were associated with platinum-based chemotherapy efficacy in human lung cancer. Here, we investigated the metabolic differences upon cisplatin treatment in lung cancer in vitro and in vivo. A simple and partially validated standard addition method was applied for the quantification of five metabolites involved in the TCA cycle and glutamine metabolism using amide hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). The present study investigated the levels of these biomarkers in A549 cells and the cisplatin-resistant A549-DDP cells, as well as in the plasma before and after cisplatin treatment in A549 xenograft mice. Levels of five metabolites, including 2-hydroxyglutaric acid (2-HG), α-ketoglutarate (α-KG), succinate, glutamine, and glutamate, showed a decreasing trend in A549-DDP cells. In addition, 2-HG and glutamine were the most significantly altered metabolites in cisplatin-treated A549 xenograft mice. These data indicate that the TCA cycle and glutamine metabolism play important roles in cisplatin-based chemotherapy resistance in lung cancer. Our results provide a new angle for exploring the molecular mechanisms underlying cisplatin resistance.

[Retracted] Norcantharidin reverses cisplatin resistance and inhibits the epithelial mesenchymal transition of human non­small lung cancer cells by regulating the YAP pathway.

An interested reader drew to our attention that the western blots featured in Figs. 1B and 6C contained strikingly similar protein bands, and repeating patterns of bands, comparing across the lanes of the gels. Furthermore, an image representing the Myc­YAP colony­formation assay experiment in Fig. 2C was strikingly similar to the data shown for the Control colony­formation assay experiment in Fig. 5B. The Editorial office subsequently investigated this matter further, and noted that the western blots shown in Fig. 6A and B likewise contained strikingly similar bands that were purportedly showing the results from different experiments. After having considered the various issues that have been brought to light with this paper, together with an appeal from the authors that a Corrigendum be published, the Editor of Oncology Reports has ruled that the article should be retracted from the publication on account of a lack of overall confidence in the presented data. Note that the authors were not in agreement that the errors reported and identified were sufficient to merit the retraction of the article. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 40: 609-620, 2018; DOI: 10.3892/or.2018.6486].

[Retracted] Suppression of YAP by DDP disrupts colon tumor progression.

Following the publication of this paper, it was drawn to the authors' attention by an interested reader that Fig. 6D contained images featuring overlapping data, which reportedly had been derived under different experimental conditions. Subsequently, further issues of data duplication were brought to light by another interested reader concerning the above article; first, certain of the images showing colony­forming assays in Fig. 4D were strikingly similar to images that had appeared in a previous publication by the same research group, and secondly, a couple of instances of data duplication were identified among the histopathological images presented within Fig. 7D. After having considered the various issues that have been brought to light with this paper, together with an appeal from the authors that a Corrigendum be published, the Editor of Oncology Reports has ruled that the article should be retracted from the publication on account of a lack of overall confidence in the presented data. Note that the authors were not in agreement that the number of errors reported and identified were sufficient to merit the retraction of the article. Additionally, the authors carefully checked the raw data and drew a conclusion that the final scientific conclusions were not affected. The Editor and the authors apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 39: 2114­2126, 2018; DOI: 10.3892/or.2018.6297].

Corrigendum to "UBE2C Induces Cisplatin Resistance via ZEB1/2-Dependent Upregulation of ABCG2 and ERCC1 in NSCLC Cells".

[This corrects the article DOI: 10.1155/2019/8607859.].

Aaptamine attenuates the proliferation and progression of non-small cell lung carcinoma.

CONTEXT: Aaptamine is a potent ocean-derived non-traditional drug candidate against human cancers. However, the underlying molecular mechanisms governing aaptamine-mediated repression of lung cancer cells remain largely undefined. OBJECTIVE: To examine the inhibitory effect of aaptamine on proliferation and progression of non-small cell lung carcinoma (NSCLC) and dissect the potential mechanisms involved in its anticancer functions. MATERIALS AND METHODS: In vitro assays of cell proliferation, cell cycle analysis, clonal formation, apoptosis and migration were performed to examine the inhibitory effects of aaptamine (8, 16 and 32 µg/mL) on NSCLC cells. The expression levels of proteins were analysed using western blotting analysis when cells were treated with a single drug or a combination treatment for 48 h. RESULTS: Aaptamine significantly inhibited A549 and H1299 cells proliferation with IC50 values of 13.91 and 10.47 µg/mL. At the concentrations of 16 and 32 µg/mL, aaptamine significantly reduced capacities in clonogenicity, enhanced cellular apoptosis and decreased the motile and invasive cellular phenotype. In addition, aaptamine arrested cell cycle at G1 phase via selectively abating cell cycle regulation drivers (CDK2/4 and Cyclin D1/E). Western blotting results showed that aaptamine attenuated the protein expression of MMP-7, MMP-9 and upregulated the expression of cleaved-PARP and cleaved-caspase 3. Moreover, aaptamine inhibited PI3K/AKT/GSK3ß signalling cascades through specifically degrading the phosphorylated AKT and GSK3ß. DISCUSSION AND CONCLUSIONS: Aaptamine retarded the proliferation and invasion of NSCLC cells by selectively targeting the pathway PI3K/AKT/GSK3ß suggesting it as a potential chemotherapeutic agent for repressing tumorigenesis and progression of NSCLC in humans.

Author Correction: Disruption of SHH signaling cascade by SBE attenuates lung cancer progression and sensitizes DDP treatment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Retraction of "UBE2C, Directly Targeted by miR-548e-5p, Increases the Cellular Growth and Invasive Abilities of Cancer Cells Interacting with the EMT Marker Protein Zinc Finger E-box Binding Homeobox 1/2 in NSCLC".

[This retracts the article DOI: 10.7150/thno.32738.].