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Background Proton pump inhibitors (PPIs) are widely used to treat digestive system diseases. Previous studies have suggested conflicting results between PPIs treatment and digestive tract cancers (DTCs). We utilized the FDA Adverse Event Reporting System (FAERS) database to assess the effect of PPIs use on DTCs through data mining. Method This study examined the association between six PPI agents and DTCs by mining the FAERS database from January 2004 to September 2021 by using Open Vigil 2.1. The reporting odds ratio (ROR) with 95% confidence intervals (CIs) was used to detect statistically significant associations between PPIs and DTCs. High Level Terms (HLTs) and Preferred Terms (PTs) were defined by the Medical Dictionary for Regulatory Activities 24.0 (MedDRA24.0). Result A total of 2553 DTCs adverse event reports were screened, with positive signals obtained from gastric neoplasms malignant (GNM) (ROR: 1.09, 95% CI: 1.01-1.18) and bile duct neoplasms malignant (BDNM) (ROR: 1.80, 95% CI: 1.44-2.25). Esomeprazole showed the strongest signal (ROR: 1.85, 95% CI: 1.66-2.06) for GNM, while rabeprazole for BDNM (ROR: 2.94, 95% CI: 1.32-6.56), and female PPI users had a higher risk of BDNM (ROR: 2.44, 95% CI: 1.77-3.35). Among Subordinate PTs, adenocarcinoma gastric, and the combination of “bile duct cancer” and “cholangiocarcinoma” were highly associated with PPIs use. Conclusion By mining the FAERS database, we provided important clues for the association between PPIs use and DTCs risk.

This article reports a promising approach to enhance the oral delivery of nuciferine (NUC), improve its aqueous solubility and bioavailability, and allow its controlled release as well as inhibiting lipid accumulation. NUC-loaded poly lactic-co-glycolic acid nanoparticles (NUC-PLGA-NPs) were prepared according to a solid/oil/water (s/o/w) emulsion technique due to the water-insolubility of NUC. PLGA exhibited excellent loading capacity for NUC with adjustable dosing ratios. The drug loading and encapsulation efficiency of optimized formulation were 8.89 ± 0.71 and 88.54 ± 7.08%, respectively. NUC-PLGA-NPs exhibited a spherical morphology with average size of 150.83 ± 5.72 nm and negative charge of −22.73 ± 1.63 mV, which are suitable for oral administration. A sustained NUC released from NUC-PLGA-NPs with an initial exponential release owing to the surface associated drug followed by a slower release of NUC, which was entrapped in the core. In addition, ∼77 ± 6.67% was released in simulating intestinal juice, while only about 45.95 ± 5.2% in simulating gastric juice. NUC-PLGA-NPs are more efficient against oleic acid (OA)-induced hepatic steatosis in HepG2 cells when compared to naked NUC (n-NUC, *p < 0.05). The oral bioavailability of NUC-PLGA-NPs group was significantly higher (**p < 0.01) and a significantly decreased serum levels of total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), as well as a higher concentration of high-density lipoprotein cholesterol (HDL-C) was observed, compared with that of n-NUC treated group. These findings suggest that NUC-PLGA-NPs hold great promise for sustained and controlled drug delivery with improved bioavailability to alleviating lipogenesis.

Liver cancer is the fifth most commonly diagnosed malignancy, of which hepatocellular carcinoma (HCC) represents the dominating histological subtype. Antiangiogenic therapy aimed at vascular endothelial growth factor (VEGF) has shown promising but deficient clinical prospects on account of vasculogenic mimicry, a highly patterned vascular channel distinguished from the endothelium-dependent blood vessel, which may function as blood supply networks occurring in aggressive tumors including HCC. In this study, we used a new cationic peptide, disulfide cross-linked stearylated polyarginine peptide modified with histidine (H3R5), as a reducible vector, cell penetrating peptide-modified aptamer (ST21) with specific binding to HCC cells to conjugate to peptide H3R5 as the targeting probe, miRNA-195 (miR195) as a powerful gene drug to inhibit VEGF, and fasudil to suppress vasculogenic mimicry by blocking ROCK2, all of which were simultaneously encapsulated in the same nanoparticles. Fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient and miR195 was condensed through electrostatic interaction. ST21-H3R5-polyethylene glycol (PEG) exhibited excellent loading capacities for both fasudil and miR195 with adjustable dosing ratios. Western blot analysis showed that (Fasudil)ST21-H3R5-PEGmiR195 had strong silencing activity of ROCK2 and VEGF, as compared with (Fasudil)H3R5-PEGmiR195. In vitro and in vivo experiments confirmed that ST21-modified nanoparticles showed significantly higher cellular uptake and therapeutic efficacy in tumor cells or tumor tissues than the unmodified counterparts. These findings suggest that aptamer-conjugated peptide holds great promise for delivering chemical drugs and gene drugs simultaneously to overcome HCC.

Nuciferine is an important drug candidate for the treatment of obesity-related diseases. However, few investigations have been conducted about the pharmacokinetics and tissue distribution of nuciferine to better understand its behavior and action mechanism in vivo. Thus, a sensitive and reliable liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method was established and validated for the quantification of nuciferine in rat plasma and tissue samples. The validated method was successfully applied to the pharmacokinetic and tissue distribution study of nuciferine in rats. One-compartmental pharmacokinetic parameters indicated that nuciferine had rapid distribution, extensive tissue uptake, and poor absorption into systemic circulation. The values of absolute bioavailability were (3.8±1.4)%, (4.2±1.3)% and (3.9±1.0)% after oral administration of 2.0, 5.0 and 10.0mg/kg nuciferine and intravenous administration of 0.2mg/kg nuciferine in rats. The results of the tissue distribution study suggested that nuciferine was distributed into the brain, liver and adipose tissue after intravenous administration. In conclusion, the present study may provide a material basis for study of the pharmacological action of nuciferine in the treatment of obesity, and meaningful insights into further study on dosage modification.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disease associated with lipotoxicity, lipid peroxidation, oxidative stress, and inflammation. Nuciferine, an active ingredient extracted from the natural lotus leaf, has been reported to be effective for the prevention and treatment of NAFLD. Per-Arnt-Sim kinase (PASK) is a nutrient responsive protein kinase that regulates lipid and glucose metabolism, mitochondrial respiration, and gene expression. The aim of the present study was to investigate the protective effect of nuciferine against NAFLD and its inhibitory effect on PASK, exploring the possible underlying mechanism of nuciferine-mediated inhibition on NAFLD. Relevant biochemical parameters (lipid accumulation, extent of oxidative stress and release of inflammation cytokines) in oleic acid (OA)-induced HepG2 cells that mimicked steatosis in vitro were measured and compared with the control. It was found that nuciferine and silenced-PASK (siRNA PASK) both inhibited triglyceride (TG) accumulation and was effective in decreasing fatty acid (FFAs). The content of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) were increased respectively by nuciferine and siRNA PASK without increase in glutathione (GSH). Malondialdehyde (MDA) was decreased respectively by nuciferine and siRNA PASK. In addition, nuciferine decreased TNF-a, IL-6 and IL-8 as well as the siRNA PASK group. IL-10 was increased by nuciferine and siRNA PASK respectively. Further investigation revealed that nuciferine and siRNA PASK could respectively regulate the expression of target genes involved in lipogenesis and inflammation, suggesting that nuciferine may be a potential therapeutic treatment for NAFLD. Furthermore, the modulated effect of nuciferine on (OA)-induced HepG2 cells lipogenesis and inflammation, which was accompanied with PASK inhibition, was also consistent with siRNA PASK, implying that PASK might play a role in nuciferine-mediated regulation on NAFLD.

Ras homolog family member A (RhoA) and Rho-associated coiled coil-containing protein kinases 1 and 2 (ROCK1 and 2) are key regulators of focal adhesion, actomyosin contraction and cell motility. RhoA/ROCK signaling has emerged as an attractive target for the development of new cancer therapeutics. Whether RhoA/ROCK is involved in regulating the formation of tumor cell vasculogenic mimicry (VM) is largely unknown. To confirm this hypothesis, we performed in vitro experiments using hepatocellular carcinoma (HCC) cell lines. Firstly, we demonstrated that HCC cells with higher active RhoA/ROCK expression were prone to form VM channels, as compared with RhoA/ROCK low-expressing cells. Furthermore, Y27632 (a specific inhibitor of ROCK) rather than exoenzyme C3 (a specific inhibitor of RhoA) effectively inhibited the formation of tubular network structures in a dose-dependent manner. To elucidate the possible mechanism of ROCK on VM formation, real-time qPCR, western blot and immunofluorescence were used to detect changes of the key VM-related factors, including VE-cadherin, erythropoietin-producing hepatocellular carcinoma-A2 (EphA2), phosphoinositide 3-kinase (PI3K), matrix metalloproteinase (MMP)14, MMP2, MMP9 and laminin 5γ2-chain (LAMC2), and epithelial-mesenchymal-transition (EMT) markers: E-cadherin and Vimentin. The results showed that all the expression profiles were attenuated by blockage of ROCK. In addition, in vitro cell migration and invasion assays showed that Y27632 inhibited the migration and invasion capacity of HCC cell lines in a dose-dependent manner markedly. These data indicate that ROCK is an important mediator in the formation of tumor cell VM, and suggest that ROCK inhibition may prove useful in the treatment of VM in HCC.

Background Studies have described vasculogenic mimicry (VM) as an alternative circulatory system to blood vessels in multiple malignant tumor types, including hepatocellular carcinoma (HCC). In the current study, we aimed to seek novel and more efficient treatment strategies by targeting VM and explore the underlying mechanisms in HCC cells. Methods Cell counting kit-8 (CCK-8) assay and colony survival assay were performed to explore the inhibitory effect of incarvine C (IVC) on human cancer cell proliferation. Flow cytometry was performed to analyze the cell cycle distribution after DNA staining and cell apoptosis by the Annexin V-PE and 7-AAD assay. The effect of IVC on Rho-associated, coiled-coil-containing protein kinase (ROCK) was determined by western blotting and stress fiber formation assay. The inhibitory role of IVC on MHCC97H cell VM formation was determined by formation of tubular network structures on Matrigel in vitro, real time-qPCR, confocal microscopy and western blotting techniques. Results We explored an anti-metastatic HCC agent, IVC, derived from traditional Chinese medicinal herbs, and found that IVC dose-dependently inhibited the growth of MHCC97H cells. IVC induced MHCC97H cell cycle arrest at G1 transition, which was associated with cyclin-dependent kinase 2 (CDK-2)/cyclin-E1 degradation and p21/p53 up-regulation. In addition, IVC induced apoptotic death of MHCC97H cells. Furthermore, IVC strongly suppressed the phosphorylation of the ROCK substrate myosin phosphatase target subunit-1 (MYPT-1) and ROCK-mediated actin fiber formation. Finally, IVC inhibited cell-dominant tube formation in vitro, which was accompanied with the down-regulation of VM-key factors as detected by real time-qPCR and immunofluorescence. Conclusions Taken together, the effective inhibitory effect of IVC on MHCC97H cell proliferation and neovascularization was associated with ROCK inhibition, suggesting that IVC may be a new potential drug candidate for the treatment of HCC.