STIM1 Regulates Endothelial Calcium Overload and Cytokine Upregulation During Sepsis.

BACKGROUND: Stromal interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) is now recognized as the main mechanism of the majority of nonexcitable cell calcium influx. Calcium overload is a primary mechanism of endothelial cell injury during systemic inflammatory response and sepsis. Whether STIM1-mediated SOCE plays a role in calcium overload in vascular endothelial cell injury remains unclear. MATERIALS AND METHODS: To explore the role of STIM1-gated SOCE in vascular endothelial cell calcium overload and inflammation, we established a human septic serum or lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) experimental system and derived ribonucleic acid interference (RNAi)-mediated STIM1, ORAI1 (orai gene [HGNC: 25896 Entrez Gene: 84876] coding protein, ORAI Calcium Release-Activated Calcium Modulator 1), and transient receptor potential channel 1 (TRPC1) (core components of store-operated Ca2+[SOC]) downregulated HUVECs, as well as STIM1 overinduced HUVECs. RESULTS: Our results show that sepsis serum or LPS stimulation increased STIM1 in HUVECs and increased all cytokines except for VEGF and the inflammatory mediators tumor necrosis factor, intercellular cell adhesion molecule-1, and endothelin-1 in a time-dependent manner. RNAi-mediated knockdown of STIM1 significantly inhibited serum or LPS-induced inflammatory cytokine expression, and STIM1 overexpression in HUVECs promoted LPS-mediated induction of these cytokines. Meanwhile, similar to the blocking effect of the specific SOC inhibitors Gd3+ and La3+ on LPS-induced calcium influx, RNAi-mediated depletion of STIM1 or the SOC proteins TRPC1 and ORAI1 could significantly inhibit serum or LPS-induced extracellular calcium influx, as well as the expression of the inflammatory cytokines tumor necrosis factor, intercellular cell adhesion molecule-1, and endothelin-1. Simultaneous downregulation of the SOCE core units TRPC1 and ORAI1 inhibited LPS-induced calcium influx and cytokine expression, which could not be restored by inducing STIM1. Forced expression of nuclear factor-κB (NF-κB) in HUVECs significantly induced STIM1 expression, whereas RNAi-mediated depletion of NF-κB significantly inhibited STIM1 mRNA levels and significantly reduced the thapsigargin-mediated SOCE calcium influx, which was similar to results with the NF-κB inhibitor wogonin. CONCLUSIONS: Septic serum stimulates the expression of STIM1, cytokines, and inflammatory mediators in HUVECs. STIM1-mediated SOCE is required for Ca2+ influx induced by LPS or septic serum and contributes cytokines and inflammatory mediators in septic serum-stimulated HUVECs. In addition, STIM1-mediated SOCE on Ca2+ influx by septic serum or LPS involves NF-κB signaling.

Downregulation of miR-218 by nicotine promotes cell proliferation through targeting CDK6 in non-small cell lung cancer.

BACKGROUND: Nicotine, an important component of tobacco, is a major risk factor of lung cancer, but the mechanism through which nicotine promotes lung cancer development remains unclear. METHODS: Eighty patients with lung cancer were enrolled in this study, 34 of whom did not smoke and the others did. The expression of miR-218 and CDK6 messenger RNA (mRNA) was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A luciferase reporter system was used to identify the direct target of miR-218. The protein expression of CDK6 was analyzed by using Western blotting. Cell proliferation was analyzed using an approach of calculation of cell number under a microscope. RESULTS: Nicotine decreased miR-218 expression in non-small cell lung cancer (NSCLC) cells and promoted proliferation of NSCLC cells. Smoking patients with NSCLC had lower expression of miR-218 in tumor compared with NSCLC patients who did not smoke. We found that miR-218 directly targeted the CDK6 mRNA 3'untranslated region and inhibited its expression in NSCLC cells and also observed a negative correlation between the expression of miR-218 and CDK6 mRNA in lung cancer tissues. Furthermore, miR-218- or nicotine-induced proliferative effects of NSCLC cells were rescued by the recovery of the expression level of CDK6. CONCLUSION: Nicotine promotes proliferation of NSCLC cells through regulating the miR-218/CDK6 axis, which may be a potential therapeutic target for lung cancer.

Hydrogen attenuates radiation-induced intestinal damage by reducing oxidative stress and inflammatory response.

The small intestine is known to be particularly sensitive to radiation, and the major limiting factor of radiotherapy is the gastrointestinal syndrome that subsequently develops after its administration. The detrimental effects of radiation are mostly mediated via the overproduction of reactive oxygen species (ROS), especially the hydroxyl radical (·OH). Because hydrogen is a selective ·OH scavenger, we hypothesized that hydrogen might exert a protective effect against radiation-induced intestinal damage. Herein, radiation models were built both in mice and in an intestinal crypt epithelial cell (IEC-6) line. In the animal experiment, we demonstrated that hydrogen-rich saline significantly reduced radiation-induced intestinal mucosal damage, improved intestinal function, and increased the survival rate. In addition, radiation-induced oxidative stress damage and systemic inflammatory response were also mitigated by hydrogen treatment. Moreover, hydrogen treatment decreased cell apoptosis and maintained intestinal epithelial cell proliferation in mice. In vitro experiments using the IEC-6 cell line showed that hydrogen-rich medium significantly inhibited ROS formation, maintained cell viability, and inhibited cell apoptosis. Importantly, hydrogen treatment prevented mitochondrial depolarization, cytochrome c release, and activity of caspase-3, caspase-9, and PARP. Moreover, the decreased expression of Bcl-xl and Bcl-2 and the increased expression of Bax protein were also blocked by hydrogen treatment. In conclusion, our study concurrently demonstrated that hydrogen provides an obviously protective effect on radiation-induced intestinal and cell injuries. Our work demonstrated that this protective effect might be due to the blockage of the mitochondrial apoptotic pathway.

[Meta-analysis of the effects between endotracheal intubation and laryngeal mask airway for patients with out-of-hospital cardiac arrest].

OBJECTIVE: To comprehensively evaluate the resuscitation effect of endotracheal intubation (ETI) ventilation and laryngeal mask airway (LMA) for out-of-hospital cardiac arrest (OHCA). METHODS: Databases such as Cochrane Library, PubMed, Embase, Ebsco, Elsevier, OVID, Springer, Proquest, and China biomedical literature database (CBMdisc), CNKI, Wanfang database, Chinese Science and Technology Journal Full-text Database, VIP Chinese biomedical journal database were searched from the establishment of literature database to December 2017 to study the difference of effects between ETI and LMA for patients with OHCA. The effect determination indexes included the return of spontaneous circulation (ROSC) rate, 1-month survival and 1-month neurological recovery. After evaluation of the quality of included studies and extraction of the data, the software of RevMan 5.3 was used to analyze those outcomes. RESULTS: A total of 9 articles, including 7 English, 2 Chinese; 5 prospective studies and 4 retrospective studies were included. All of the literatures had high quality, and the Newcastle Ottawa scale (NOS) scored 7-9 points. The Meta-analysis showed that ETI was significantly more beneficial than LMA in improving the rate of ROSC [odds ratio (OR) = 1.51, 95% confidence interval (95%CI) = 1.42-1.62, Z = 12.35,P < 0.01], and 1-month survival (OR = 1.16, 95%CI = 1.06-1.26, Z = 3.41, P < 0.01), and there was no significant difference in 1-month neurological recovery (OR = 1.13, 95%CI = 0.96-1.32, Z = 1.49, P = 0.14). CONCLUSIONS: ETI has higher recovery success rate and survival rate than LMA for the rescue of OHCA adult patients, but the improvement of the nervous system is unclear.

[Response of interspecific competition between Ulva pertusa and Grateloupia filicina to UV-B irradiation enhancement].

The interspecific competition between Ulva pertusa and Grateloupia filicina and it's response to the UV-B irradiation enhancement were analyzed using mono-culture and co-culture methods. The study adopted reasonable experimental design and took biomass as the main examined index. Results showed that the relation of interspecific competition included both allelopathy effect and nutrient competition. Specific growth rates of U. pertusa under treatment with abundant nutrition and limited nutrition was 2.54 and 2.47 times of those of G. filicina. Thus, compared to U. pertusa, G. filicina was in inferior position. UV-B irradiation could inhibit the growth of U. pertusa and G. filicina under the condition of mono-culture. The higher the dosage and the longer exposure of UV-B irradiation were, the more significant the inhibitive effect was. When they were cultured together, low dosage [1.6 kJ x (m2 x d)(-1)] and medium dosage [4.8 kJ x(m2 x d)(-1)] of UV-B irradiation reduced the competitive ability of U. pertusa, and weights of U. pertusa and G. filicina declined 6.81% and 3.88% in low dosage, and 10.47% and 6.98% in medium dosage, respectively. So the relation of interspecific competition tended to be at a balanced level even though U. pertusa was still the dominant algae. However, on the 12th day, weight of U. pertusa decreased by 13.09%, but the value of G. filicina was 14.72%, which was higher than that of U. pertusa. Therefore, high dosage [9.6 kJ x (m2 x d)(-1)] of UV-B irradiation had more serious inhibitive effect on G. filicina, and competitive dominant position of U. pertusa tended to be more obvious. Thus, UV-B changed the relation of competitive balance of U. pertusa and G. filicina, which changed along with the dosage of UV-B. Moreover, UV-B irradiation might influence the metabolism of the allelochemicals produced by U. pertusa and G. filicina in a long time.