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Apatinib has experienced a long‐term study in enhancing the sensitivity of various cancer cells to chemotherapy drugs. Currently, researches show that apatinib could attenuate the resistance of gastric cancer (GC) cells to paclitaxel (PTX), but the mechanism has not been fully elucidated, which therefore was explored in this study. PTX‐resistant GC cell, namely HGC‐27R, was established by exposure to stepwise‐increasing PTX. The cell viability of HGC‐27 and HGC‐27R under PTX or apatinib at different concentrations was assessed by CCK‐8 assay, while scratching test and invasion assay were used for investigating the harmful influence of GC cells resistance to PTX. The function of apatinib in HGC‐27R was studied by performing functional experiments (flow cytometry, scratching test, and invasion assay). Western blot was performed to measure the expressions of proteins concerning apoptosis, epithelial‐mesenchymal transition and janus‐activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. PTX‐resistant GC cell, namely HGC‐27R, was successively constructed. HGC‐27R cells showed resistance to PTX by promoting migratory and invasive capabilities. Apatinib not only inhibited cell viability of HGC‐27 and HGC‐27R, but also combined with PTX to suppress that of HGC‐27R. Apatinib enhanced apoptosis, diminished migration and invasion of HGC‐27R cells, elevated proapoptotic protein expression, and reduced Bcl‐2, vimentin, snail, MMP‐3, MMP‐2, and MMP‐9 expressions. The phosphorylation of JAK2 and STAT3 was repressed by apatinib. JAK2 partially reversed the effect of apatinib on enhancing sensitivity of GC cells to PTX. Apatinib strengthened sensitivity of GC cells to PTX by inhibiting JAK/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common human malignancies due to its invasiveness and metastasis. 5‐Fu is a widely applied chemotherapeutic agent against GC. Although 5‐Fu therapy has achieved improvements in GC treatment, a large fraction of patients developed drug resistance which significantly limited its clinical applications. Recent studies revealed the pivotal roles of long noncoding RNAs (lncRNAs) in tumorigenesis and progressions of various tumors, including GC. However, the biological roles and molecular mechanisms of lncRNA HAGLR in GC remain unclear. Here, we report HAGLR was upregulated in both GC tissues and cell lines. In addition, HAGLR was associated with a poorly survival rate of GC patients. Blocking HAGLR inhibited GC cells proliferation and sensitized GC cells to 5‐Fu. Bioinformatical analysis and luciferase assay demonstrated that HAGLR sponged microRNA (miR)‐338‐3p, which functions as a tumor suppressor in GC to downregulate its expressions. Moreover, from the established 5‐Fu resistant GC cell line (HGC27 5‐Fu R), we detected significantly elevated HAGLR, downregulated miR‐338‐3p, and glucose metabolism compared with parental HGC27 cells. We identified lactate dehydrogenase‐A (LDHA), a glucose metabolism key enzyme, was the direct target of miR‐338‐3p in GC cells. Rescue experiments demonstrated that restoration of miR‐338‐3p in HAGLR‐overexpressing HGC27 5‐Fu R cells successfully overrode the HAGLR‐promoted 5‐Fu resistance through targeting LDHA. Taken together, this study revealed essential roles and molecular mechanisms for the HAGLR‐mediated 5‐Fu resistance in GC, contributing to the development of new noncoding RNA‐based therapeutic strategies against chemoresistant GC. [ABSTRACT FROM AUTHOR]

Aims: Acute rupture or erosion of unstable atherosclerotic plaques is a major cause of adverse consequences of atherosclerotic cardiovascular disease, often leading to myocardial infarction or stroke. High uric acid (HUA) is associated with the increasing risk of cardiovascular events and death. However, the mechanism by which HUA promotes atherosclerosis and whether HUA affects plaque stability are still unclear., Methods: We constructed an atherosclerotic Apoe-/- mouse model with HUA. The progression of atherosclerosis and plaques was determined by Oil Red O staining, hematoxylin and eosin (H&E) staining, and Masson staining. TdT-mediated dUTP nick-end labeling assay and immunohistochemistry were used to observe the changes of apoptosis and autophagy in plaques, respectively. Then, we validated the in vivo results with RAW 264.7 cell line., Results: HUA promoted atherosclerosis and exacerbated plaque vulnerability, including significantly increased macrophage infiltration, lipid accumulation, enlarged necrotic cores, and decreased collagen fibers. HUA increased cell apoptosis and inhibited autophagy in plaques. In vitro results showed that HUA decreased cell viability and increased cell apoptosis in foam cells macrophages treated with oxidized low-density lipoprotein. An activator of autophagy, rapamycin, can partially reverse the increasing apoptosis., Conclusion: HUA promoted atherosclerosis and exacerbated plaque vulnerability, and HUA facilitates foam cell apoptosis by inhibiting autophagy.