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Gemcitabine (GEM) is a first-line drug for pancreatic cancer therapy, but GEM resistance is easily developed in patients. Growing evidence suggests that cancer chemoprevention and suppression are highly associated with dietary phytochemical and microbiota composition. Ursolic acid (UA) has anti-inflammatory and anticancer effects; however, its role in improving cancer drug resistance in vivo remains unclear. In this study, the aim was to explore the role of UA in managing drug resistance-associated molecular mechanisms and the influence of gut microbiota. The in vitro results showed that receptor for advanced glycation end products (RAGE), nuclear factor kappa B p65 (NF-κB/p65), and multidrug resistance protein 1 (MDR1) protein levels were significantly increased in GEM-resistant pancreatic cancer cells (named MIA PaCa-2 GEMR) compared to MIA PaCa-2 cells. Downregulation of RAGE, pP65, and MDR1 protein expression not only was observed following UA treatment but also was seen in MIA PaCa-2 GEMR cells after transfection with a RAGE siRNA. Remarkably, the enhanced effects of UA coupled with GEM administration dramatically suppressed the RAGE/NF-κB/MDR1 cascade and consequently inhibited subcutaneous tumor growth. Moreover, UA could increase alpha diversity and regulate the composition of gut microbiota, especially in Ruminiclostridium 6. Taken together, these results provide the first direct evidence of MDR1 attenuation and chemosensitivity enhancement through inhibition of the RAGE/NF-κB signaling pathway in vitro and in vivo, implying that UA may be used as an adjuvant for the treatment of pancreatic cancer in the future. [ABSTRACT FROM AUTHOR]

Background: Cytoskeleton is a highly dynamic network that helps to maintain the rigidity of a cell, and the mechanical properties of a cell are closely related to many cellular functions. This paper presents a new method to probe and characterize cell mechanical properties through dielectrophoresis (DEP)-based cell stretching manipulation and actin cytoskeleton modeling.Methods: Leukemia NB4 cells were used as cell line, and changes in their biological properties were examined after chemotherapy treatment with doxorubicin (DOX). DEP-integrated microfluidic chip was utilized as a low-cost and efficient tool to study the deformability of cells. DEP forces used in cell stretching were first evaluated through computer simulation, and the results were compared with modeling equations and with the results of optical stretching (OT) experiments. Structural parameters were then extracted by fitting the experimental data into the actin cytoskeleton model, and the underlying mechanical properties of the cells were subsequently characterized.Results: The DEP forces generated under different voltage inputs were calculated and the results from different approaches demonstrate good approximations to the force estimation. Both DEP and OT stretching experiments confirmed that DOX-treated NB4 cells were stiffer than the untreated cells. The structural parameters extracted from the model and the confocal images indicated significant change in actin network after DOX treatment.Conclusion: The proposed DEP method combined with actin cytoskeleton modeling is a simple engineering tool to characterize the mechanical properties of cells. [ABSTRACT FROM AUTHOR]