KLF5 is frequently deleted and downregulated in prostate cancer, and recently it has been reported that KLF5 loss is enriched in the aggressive branches of prostate cancer evolution. However, why KLF5 loss is associated with prostate cancer aggressiveness is still not clear. Herein, we analyzed KLF5 expression in TCGA and GEO database, as well as prostate cancer tissue microarray, and found that KLF5 expression significantly decreased in prostate cancer accompanying with tumor progression; moreover, KLF5 downregulation was associated with shorter survival of patients. Interestingly, we also found that KLF5 expression was obviously lower in prostate cancer metastases than in localized tissues, indicating that KLF5 downregulation is associated with prostate cancer invasion and metastasis. To assess this effect of KLF5, we knocked down KLF5 in prostate cancer cells and found that KLF5 knockdown promoted invasive ability of prostate cancer cells in vitro and in vivo. Moreover, we found that KLF5 downregulation enhanced the expression of IGF1 and STAT3 phosphorylation, while block of IGF1 with antibody decreased the enhancement of STAT3 activity and prostate cancer cell invasive ability by KLF5 knockdown, indicating that KLF5 inhibits prostate cancer invasion through suppressing IGF1/STAT3 pathway. Mechanistically, we found that KLF5 interacted with deacetylase HDAC1 and KLF5 is necessary for the binding of HDAC1 on IGF1 promoter to suppress IGF1 transcription. Taken together, our results indicate that KLF5 could be an important suppressor of prostate cancer invasion and metastasis, because KLF5 could suppress the transcription of IGF1, a tumor cell autocrine cytokine, and its downstream cell signaling to inhibit cell invasive ability, and reveal a novel mechanism for STAT3 activation in prostate cancer. These findings may provide evidence for the precision medicine in prostate cancer.
Objectives Adequate humidity and temperature of the inhaled mixed air are important for patients weaning from ventilators. It can not only prevent the damage of dry gas on respiratory tract, but also facilitate the discharge of sputum. We aim to investigate the humidification and heating effects of artificial nose, Venturi device plus thermostatic humidification T-tube (referred as VT), Venturi device plus thermostatic humidification T-tube and PEEP valve (referred as VTP) in critical ill patients with tracheotomy in ICU.Design:Retrospective cohort study.Setting: Tertiary academic medical center.Patients: A total of 166 patients were engaged in this study. Clinical and laboratory examination data were used to determine the heating and humidification performance of 3 different methods.Methods A retrospective, single-center cohort study was conducted in all critically ill patients ready to be weaned from mechanical ventilators. Three groups of patients were compared in terms of vital signs, the effect of artificial airway heating and humidification, and blood gas indicators. Basic patient data (age, gender, mechanical ventilation duration, ICU stay, disease type) were recorded. Vital signs include heart rate, blood pressure, respiratory rate, oxygen saturation; The performance of heating and humidifying the artificial airway were defined as the number of sputum suction and coughing within 24 hours, sputum characteristics, whether there is bloody sputum formation, whether there is phlegm callus formation; Blood gas indicators include pH, oxygen partial pressure, carbon dioxide partial pressure, lactic acid, residual base, and bicarbonate.Results In terms of the heating and humidification performance of patients in ICU, the VT method and the VTP method were significantly superior to those of artificial nasal method.SpO2 was significantly higher in patients treated with the VTP method than that in patients treated with VT.ConclusionCompared with the artificial nose method, the VTP method and VT methods are better. In terms of improving oxygenation, the VTP method could improve the patient's oxygen sum more than the VT mothod.
Purpose
In recent years, metabolic alteration has been identified as a driver in the development of renal cell carcinoma (RCC), which plays a critical role in cancer cells to adapt to hypoxic environment and cell proliferation. Melatonin (MLT), a neurohormone secreted during the dark hours by the vertebrate pineal gland, induces metabolic reprogramming in cancer cells by suppression of aerobic glycolysis. Whether it can be used as a potential therapeutic tool in RCC is worth exploring.
Methods
In this study, we detected concentration of metabolites in RCC cells through metabo-lomic analyses using UPLC-MS/MS and the oxygen consumption rate was determined using the Seahorse Extracellular Flux analyzer.
Results
We found that MLT significantly inhibited proliferation and induced apoptosis in RCC cells, moreover, MLT increased ROS level and inhibited the activity of antioxidant enzymes. Furthermore, MLT up-regulated key TCA cycle metabolites while reduced aerobic glycolysis products, and induced higher oxygen consumption rate, more ATP production, and higher membrane potential in RCC cells, indicating that MLT enhances mitochondrial function and re-vert aerobic glycolysis to mitochondrial OXPHOS in RCC cells. Moreover, MLT treatment inhibited the phosphorylation levels of Akt, mTOR, and p70 S6 Kinase in RCC cells, while the application of NAC (inhibitors of ROS) not only restored the phosphorylation of these proteins but also decreased cell apoptosis. Consistently, MLT treatment significantly inhibited growth of RCC cell xenografts in nude mice.
Conclusion
Our results indicate that MLT treatment promotes intracellular ROS production via metabolic reprogramming and reducing antioxidants, which suppressed the activity of Akt/mTOR/S6K signaling pathway and induced apoptosis in RCC cells.
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