Evaluation of the liver targeting and anti­liver cancer activity of artesunate­loaded and glycyrrhetinic acid­coated nanoparticles.

Globally, liver cancer ranks among the most lethal cancers, with chemotherapy being one of its primary treatments. However, poor selectivity, systemic toxicity, a narrow treatment window, low response rate and multidrug resistance limit its clinical application. Liver-targeted nanoparticles (NPs) exhibit excellent targeted delivery ability and promising effectivity in treating liver cancer. The present study aimed to investigate the liver-targeting and anti-liver cancer effect of artesunate (ART)-loaded and glycyrrhetinic acid (GA)-decorated polyethylene glycol (PEG)-poly (lactic-co-glycolic acid) (PLGA) (ART/GA-PEG-PLGA) NPs. GA-coated NPs significantly increased hepatoma-targeted cellular uptake, with micropinocytosis and caveolae-mediated endocytosis as its chief internalization pathways. Moreover, ART/GA-PEG-PLGA NPs exhibited pro-apoptotic effects on HepG2 cells, mainly via the induction of a high level of reactive oxygen species, decline in mitochondrial membrane potential and induction of cell cycle arrest. Additionally, ART/GA-PEG-PLGA NPs induced internal apoptosis pathways by upregulating the activity of cleaved caspase-3/7 and expression of cleaved poly (ADP-Ribose)-polymerase and Phos-p38 mitogen-activated protein kinase in HepG2 cells. Furthermore, ART/GA-PEG-PLGA NPs exhibited higher liver accumulation and longer mean retention time, resulting in increased bioavailability. Finally, ART/GA-PEG-PLGA NPs promoted the liver-targeting distribution of ART, increased the retention time and promoted its antitumour effects in vivo. Therefore, ART/GA-PEG-PLGA NPs afforded excellent hepatoma-targeted delivery and anti-liver cancer efficacy, and thus, they may be a promising strategy for treating liver cancer.

Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents.

Objective: Silibinin, a natural product extracted from the seeds of the Silybum marianum, is versatile with various pharmacological effects. However, its clinical application was strongly hampered by its low bioavailability and poor water solubility. Herein, a series of glycosylated silibinin derivatives were identified as novel anti-tumor agents. Materials and Methods: The cell viability was evaluated by CCK8 assay. Furthermore, cell apoptosis and cell cycle progression were tested by flow cytometry. In addition, the pharmacokinetic assessment of compound 15 and silibinin through intravenous administration (i.v., 2 mg/kg) to ICR mice were performed. Results: The synthesized compounds showed better water solubilities than silibinin. Among them, compound 15 exhibited inhibitory activity against DU145 cells with IC50 value of 1.37 ± 0.140 µM. Moreover, it arrested cell cycle at G2/M phase and induced apoptosis in DU145 cells. Additionally, compound 15 also displayed longer half-life (T1/2 = 128.3 min) in liver microsomes than that of silibinin (T1/2 = 82.5 min) and appropriate pharmacokinetic parameters in mice. Conclusion: Overall, glycosylation of silibinin would be a valid strategy for the development of silibinin derivatives as anti-tumor agents.

Single-cell analysis identifies phospholysine phosphohistidine inorganic pyrophosphate phosphatase as a target in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic gastrointestinal disorder characterized by inflammation and ulceration, representing a significant predisposition to colorectal cancer. Recent advances in single-cell RNA sequencing (scRNA-seq) technology offer a promising avenue for dissecting the complex cellular inter-actions and molecular signatures driving UC pathology. AIM: To utilize scRNA-seq technology to dissect the complex cellular interactions and molecular signatures that underlie UC pathology. METHODS: In this research, we integrated and analyzed the scRNA-seq data from UC patients. Moreover, we conducted mRNA and protein level assays as well as pathology-related staining tests on clinical patient samples. RESULTS: In this study, we identified the sustained upregulation of inflammatory response pathways during UC progression, characterized the features of damaged endo-thelial cells in colitis. Furthermore, we uncovered the downregulation of phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has a negative correlation with signal transducer and activator of transcription 3. Significant downregulation of LHPP in UC patient tissues and plasma suggests that LHPP may serve as a potential therapeutic target for UC. This paper highlights the importance of LHPP as a potential key target in UC and unveils its potential role in inflammation regulation. CONCLUSION: The findings suggest that LHPP may serve as a potential therapeutic target for UC, emphasizing its importance as a potential key target in UC and unveiling its role in inflammation regulation.

Design, synthesis, and biological evaluation of novel 3-(thiophen-2-ylthio)pyridine derivatives as potential multitarget anticancer agents.

A series of novel 3-(thiophen-2-ylthio)pyridine derivatives as insulin-like growth factor 1 receptor (IGF-1R) inhibitors was designed and synthesized. IGF-1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU-DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR-1R. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC50 ] values, HepG2: 2.98 ± 1.11 µM and WSU-DLCL2: 4.34 ± 0.84 µM) exhibited good inhibitory activities against fibroblast growth factor receptor-2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC50 values ranging from 2.14 to 12.20 µM. Additionally, the cell-cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.

Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth.

Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy. Cancer Res; 76(23); 6924-36. ©2016 AACR.