The impact of intermittent and repetitive cold stress exposure on endoplasmic reticulum stress and instability of atherosclerotic plaques.

BACKGROUND: The incidence of acute coronary syndrome caused by the rupture of atherosclerotic plaque and subsequent arterial thrombosis increases as the weather gets colder. However, the association between cold stress and atherosclerotic plaque rupture is currently unknown. METHODS: An atherosclerotic plaque model was established in rabbits by balloon injury and a high-fat diet with or without cold stress (4 °C, 1 hour per day, 20 weeks) at the onset of modeling. Additionally, oxidized low-density lipoprotein (ox-LDL) was applied to induce the formation of macrophage foam cells in vitro. RESULTS: Serum lipid profiles and inflammatory cytokines (ox-LDL, high-sensitivity C-reactive protein, and interleukin-8) were significantly higher in cold stress-exposed rabbits than in controls (P<0.05). Animals with atherosclerotic lesions that were exposed to cold stress had increased macrophages, foam cells, intima-media thickness, and neovascularization in the plaque, along with significantly thinned plaque fibrous caps. Moreover, we found that cold stress induced more apoptotic cells in the atherosclerotic plaques and up-regulated endoplasmic reticulum stress (ERS)-associated proteins CHOP, GRP78, and p-JNK (P<0.05). In addition, tunicamycin treatment promoted ox-LDL-induced apoptosis, expression of CHOP and GPR78, and the p-JNK level in macrophage foam cells, while JNK inhibitor sp600125 reduced cell apoptosis and the p-JNK level. The three main ERS sensors sensors phosphorylated extracellular signal-regulated kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme1 (IRE1) declined significantly after ox-LDL treatment. CONCLUSIONS: Cold stress may enhance the instability of atherosclerotic plaques through activating ERS and enhancing cell apoptosis. Up-regulated CHOP levels mediated by PERK and ATF6 and the activated IRE1-XBP1-JNK pathway contributed to the apoptosis of foam cells.

Krüppel-Like Factor 2 Is a Gastric Cancer Suppressor and Prognostic Biomarker.

Gastric cancer (GC) is a common digestive tract tumor. Due to its complex pathogenesis, current diagnostic and therapeutic effects remain unsatisfactory. Studies have shown that KLF2, as a tumor suppressor, is downregulated in many human cancers, but its relationship and role with GC remain unclear. In the present study, KLF2 mRNA levels were significantly lower in GC compared to adjacent normal tissues, as analyzed by bioinformatics and RT-qPCR, and correlated with gene mutations. Tissue microarrays combined with immunohistochemical techniques showed downregulation of KLF2 protein expression in GC tissue, which was negatively correlated with patient age, T stage, and overall survival. Further functional experiments showed that knockdown of KLF2 significantly promoted the growth, proliferation, migration, and invasion of HGC-27 and AGS GC cells. In conclusion, low KLF2 expression in GC is associated with poor patient prognosis and contributes to the malignant biological behavior of GC cells. Therefore, KLF2 may serve as a prognostic biomarker and therapeutic target in GC.

[Effect of 2-methoxyestradiol on human cervical cancer cells HeLaS3 and xenografts].

OBJECTIVE: To evaluate the effects of 2-methoxyestradiol (2-ME(2)) on human cervical cancer HeLaS3 cells and cervical cancer xenografts. METHODS: Cell proliferation assay and cell cycle analysis were used to measure HeLaS3 cell growth and cell cycle progression after 2-ME(2) treatment. Fluorescent microscopy to observe the cell morphology and DNA electrophoresis to measure apoptosis. In addition, the effect of 2-ME(2) on the expression of inducible nitric oxide synthase (iNOS) was measured by Western blot. Moreover, human cervical cancer model was set up using HeLaS3 cells and 2-ME(2) (75 mg/kg) was orally given for 14 d. Tumor volume was determined and apoptosis was detected by in situ cell death. RESULTS: Newly-formed cell amount in treated group was 81% of that in control group after 1 micromol/L 2-ME(2) treatment for 48 h (P < 0.05), and was 19% of that in control group after 2-ME(2) treatment for 96 h (P < 0.01). G(2)/M phase cells were increased to 55% from 16% of the control (P < 0.01), and apoptotic cells were increased to 16% from 4% of the control, after 5 micromol/L 2-ME(2) treatment for 20 h. Nuclear condensation and abnormal metaphase cells were found by fluorescent microscopy. Typical DNA ladder was found by DNA electrophoresis. And the expression of iNOS was increased by 2-ME(2) in a time- and concentration-dependent manner, in parallel with apoptosis. Moreover, apoptosis was prevented by the iNOS inhibitor 1400W. In vivo, tumor volume was reduced 34% while compared with the control group. In situ cell death detection found more apoptotic and necrotic cells in 2-ME(2)-treated group. CONCLUSIONS: 2-ME(2) inhibits human cervical cancer HeLaS3 cells and tumor growth in cervical cancer xenografts. Thus 2-ME(2) has the therapeutic potential for cervical carcinoma.